428

Abstracts

1. ETHICS AND ECONOMY: COST-EFFECTIVITY AND QUALITY CARE FOR INFLAMMATORY RHEUMATIC DISEASES 1. QUALITY CARE AND MANAGEMENT OF RHEUMATOID ARTHRITIS G Stucki. Dept . of Rheumatology and Institute of Physical Medicine, University Hospital, Gloriastrasse 25, Zurich, Switzerland Quality management focusing on improving health-outcomes may be defined as clinical quality management. As opposed to quality assurance, quality management is process oriented. Effectiveness research examines 'what works in medicine' while clinical quality management asks "how can we apply this knowledge to improve medicine?". Its goal is to permanently improve outcomes by modifying processes, e.g. the planning and implementat ion of a therapy and/or of potentially modifiable structural variables in an ongoing learning process (1). From a clinical quality management perspective, control of disease activity in RA represents a measuremenUimprovement system with the goal to reduce pain in the short-term, and damage and consequent disability in the long-term. Within this dynamic framework disease activity and damage are intermediate clinical outcomes, while pain and disability are primary pat ientoriented outcomes. A comprehensive, simple measurement system including the disease activity score DAS (2), a radiological damage score (3), the muscle strength index MI (4), and from the patient perspective, the symptoms questionnaire RADAI (5), and the physical function questionnaire HAQ (6), allows for continuous adjustment of therapies for individual patients. Variation analysis of group data out of clinical practice may allow for identification of 'upstream conditions' and generation of hypotheses. These may be tested in controlled studies and their implementation in clinical practice can be monitored and encouraged. Clinical quality management opens clinical practice as a most important source of information. It offers a unique opportunity to bi-directionally link practice to research and to expand our understanding of outcomes as a result of alternative processes for a large spectrum of patients in a variety of settings. First experiences with the use of a clinical quality management system have been made in Switzerland since 1997. With the participation of all university and large hospital rheumatology units and increasingly private rheumatology practices, the clinical quality management concept has gained widespread acceptance. The concept may contribute to further establish the central of the rheumatologist in the management of all RA patients and thus has a political dimension as well (7,8). Measure Time phys ic ian Time patie nt Adm inist ratio n Variab le typ Rang e Median S

Sma llest detecta ble difference

DAS 3 Min

MSI 3 Min

Hx-Score 3 Min

Short cyc le &

Long cycle &

Co nt inuo us

Cont inuo us

Long cycle & Continuous 0%-100% # not del. not def.

0-1 0. 3.1 0.6

0%-100 % 39% 14 percentage units

RADAI

HAQ

ca. 3 Min Short cycl e & Ordi nal

ca . 5 Mi n Long cyc le & Ordin al

0-10 • 4.0 1.0

0-3 ' 1.31 0.17

#: 0 reflec ts a norm al value ; nd: not def ined; $ : in th e refer enc e pop ulation . University Hosp ital of Zurich ; &: Sho rt cy c le: 3-6 monthly; Long c ycl e: 6-1 2 mon thl y (shorter int ervals at start of di sea se)

2. COST-EFFECTIVENESS AND COST-UTILITY OF COMBINATION THERAPY IN EARLY RHEUMATOID ARTHRITIS: RANDOMISED COMPARISON OF COMBINED STEP-DOWN PREDNISOLONE , METHOTREXATE AND SULPHASALAZINE WITH SULPHASALAZINE ALONE A Verhoeven. Department of Internal Medicine / Rheumatology, University Hospital Maastricht, The Netherlands We assessed cost-effectivity and cost -utility of early intervention in rheumatoid arthr itis (RA) patients. Combined step-down

treatment with prednisolone, methotrexate and sulphasalazine was compared to treatment with sulphasalazine alone. The mult icenter 56-week follow-up randomised controlled double-blind COBRA trial comprised a full economic analysis of direct costs and utility analysis with rating scale and standard gamble measurement techniques. The combined-treatment group included 76 and the sulphasalazine group 78 patients. The mean total costs per patient in the first 56 weeks of follow-up were $5519 for combined treatment and $6511 for treatment with sulphasalazine alone (p=0.37). Outpatient care, in-patient care and non-health care each contributed about one third to the total costs. The combined-treatment group appeared to generate savings in length of hospital stay for RA, non-protocol drugs and costs of home help, but comparisons were not statistically significant. Protocol drugs and monitoring were slightly more expensive in the combined-treatment group. Clinical, radiographic and functional outcomes significantly favoured combined treatment at week 28. Radiographic out comes were also better for the combined treatment at week 28. Utility scores assessed by time-integrated rating scale and standard gamble measurement techn iques significantly favoured combined treatment. Conclusion: Combined treatment with predn isolone, methotrexate and sulphasalazine is cost-effective in early RA patients due to enhanced efficacy at lower or equal direct costs. Arco Verhoeven was coordinator of the COBRA trial, supported by grant (92-045) of the "Ziekenfondsraad, fonds Ontwikkelingsgeneeskunde, The Netherlands". The coordinating center was the Department of Internal Medicine / Rheumatology, University Hospital Maastricht, supervised by professor Sjef van der Linden, rheumatologist. The COBRA trial was initiated by professor Maarten Boers, rheumatologist and now professor Clinical Epidemiology at the Vrije Universiteit Univers ity Hospital, Amsterdam, The Netherlands. An article with corresponding data was published in the British Journal of Rheumatology.

3. COSTS OF ILLNESS IN ANKYLOSING SPONDYLITIS IN THE NETHERLANDS A Boonen , D van der Heijde, H van de Tempel , S van der Linden. Academic Hospital Maastricht, The Netherlands In the broader concept of patient outcome assessment in chronic diseases, psychosocial and economic endpoints need to be considered next to the classically recognized outcome measures. Economic endpoints are important from patient point of view as well as from societal point of view. The most important economic endpoints to be considered are labour force participation and health resource utilisation. However, little is known about the economic outcome of ankylosing spondylitis (AS). Therefore, economic outcome measures were included in a longitudinal study in AS. A consecutive sample (n=205) of patients under care of a rheumatologist and fulfilling the modified New York criteria of AS, entered a 2 year international (Dutch, French, Belgian) longitudinal, observational study. Demographic, clinical and socio-economic data were collected by clinical exam and questionnaires. In addition, patients received an economic diary every 2 months. Of 130 Dutch patients who completed 1 year of follow-up (76 attending an academic and 54 a general out-patient rheumatology department), the socio-economic baseline characteristics and the attributable health resource utilisation after one year are presented. At baseline 71% of patients were male; mean age was 45 years (SD=11.9); mean disease duration from diagnosis was 13.2 years (SD=13.9). Fourteen percent of patients had peripheral arthritis, 10% inflammatory bowel disease and 4.7% had a hip replacement. Mean Bath AS-Functional Index was 3.9 (SD=2.4); mean Bath AS Disease Activity Index 3.5 (SD=2.0). Of 124 patients of working age (20-65 years), 52% (55% men and 41% women) had a paid job (20% part-time and 32% full-time); 54% a full or partial disability pension. In this part of the Netherlands 59% of the

Abstracts

429

population have a paid job (17% part-time; 43% full-time); 8% a disability pension. Forty-eight percent of patients indicated their financial situation had got worse because of AS; 20% of patients had adaptations at home ; 35% aids or appliances. 4.7% had family help; 18.5% private household help. Forty-four percent of patients had tried alternative med icine in the course of AS. During the year of study, 69% of patients took ~ 3 days/week NSAIDs, 10% were treated with a DMARD. The number of visits to health professionals and number of technical exams are shown in the table below. GP rheum at ologi st s ot her speci alists alternat ive medi cin e ph ysioth erap ist rehabilit ation clinic

venapunc t ures X-rays

#Visit sly r/all 130 p at ient s

proportio n of pts

mean/pUyr

147 230 115 102 1805 206 #examsly r/a ll 130 pa t ient s

40% 68% 22 % 10% 39% 5%

1.13 1.17 0.83 0.78 13.89 1.5

proport ion of pts

mean/pVyr

386 145

69% 48 %

2.9 (6.7 studies/punctur e) 1.1

Further, because of AS, 6% of patients attended at least once the emergency department and 6% needed hospitalisation (total of 176 days; mean duration 22 days) with one hospitalisation for hip replacement. 5% needed major adaptations at home, 13% purchased aids or appliances and 3 ext ra patients needed professional house-hold help. 29% attended regularly an exercise group and 46% a swimming group. Two new patients received a disability pension. 39% of patients with a paid job had in total 1010 days of sick-leave. The mean duration of sick-leave was 40 days per patient. Conclusion: After a mean of 13 years of disease , AS had considerable consequences on the socio-economic status and lifestyle of the patients. The health resource utilisation during one year is important. This study prov ides the first steps towards defining the economic burden of illness due to AS more precisely, not only in the Netherlands but also in other European countries.

Seventy-five percent took NSAIDs ~ 3 days/week; 3.6% had total hip replacement. Sixty-four percent of the patients (71% men and 48% women) have a paid job compared to 60% (74% men and 47% women) in the general Dutch population. Thirty-four percent of pat ients have a disability pension (20% full and 14% partial) compared to 8% in the general population. Of the patients with a paid job, 27% work part-time compared to 29% in the general population. In a recent cross-sectional study among RA patients, 36% had a paid job and 39% a disability pension. In patients with AS, better physical function (measured by lower BAS-FI and fewer hip-prostheses) was associated with remaining at work. Withdrawal from labour force was more likely if patients had industrial or transportation professions. The chance of withdrawal was significantly decreased when the working situation had been adjusted to the disabilities of the patients. In the group AS patients with a paid job, 7.7% were in sick-leave due to AS at the moment of the questionnaire and 5.6% of all workdays were lost. Extrapolating these results to one year results in 12 extra days of sick-leave per patient per year due to AS. Patients in sick-leave had higher disease activity (BAS-DAI 5.1 (SD=2.3)). Conclusion: The number AS patients having a paid job is comparable to the general Dutch population and better than in RA. However, more patients have a (full or partial) disability pension and in the group working, the extra number of sick-days is substantial.

2. METABOLIC BONE DISEASES 5. THERAPEUTIC MODALITIES OF REGIONAL SYMPATHETIC DYSTROPHY SYNDROME B Cortet, B Delcambre. Service de Rhumatologie, Centre Hospitalier Universitaire de Lille, 59037, Lille cedex, France

4.

WORK DISABILITY IN ANKYLOSING SPONDYLITIS

o van

der Heijde, A Boonen, HS Miedema*, S van der Linden. University Hospital Maastricht, *TNO-PG Leiden , The Netherlands Labour force participation is recognized as an important outcome measure in chronic diseases. From societal point of view workdisability is a major contributor to the economic burden of illness . From patient point of view it has been shown that participation in labour force contributes to the overall well-being of the patient, not only because of the financial implications but also because of the positive influence on social contacts and self-esteem of the individ ual. Disease-related, work-related and psycho-social factors are shown to be associated with participation in labour force. Patients with ankylosing spondylitis (AS) clearly experience problems in performing their job. The pain and stiffness but also functional limitations can pose difficulties in performing protessional tasks. Few stud ies exist on the participation of pat ients with AS in the labour force. Moreover, because of differences in the organisation of health care and social security between countries, these data are difficult to extrapolate to other countries. No data exist on the situation in the Netherlands. Therefore, we assessed the labour participation and its determinants in a cross-sectional group of patients with AS in the Netherlands. In October 1997, all (n=943) patients (18-60 year) diagnosed with AS in the register of 28 (23% of total) rheumatologists nationwide, received a postal questionnaire. Patients were asked about demographic, clin ical socio-economic variables, including the Health and Labour Questionnaire, which assesses absence at work during the past 2 weeks. Response rate was 69% (n=658); 70% were male; mean age was 43 years (SD=9.6) and mean disease duration 12.3 years (SD=8.0). Mean Bath AS-Functional Index was 3.6 (SD=2.4) and mean Bath AS-Disease Activity Index was 3.9 (SD=2.4).

Reflex sympathetic dystrophy (RSD), which is now called complex regional pain syndrome of type I, is a complex and frequent disease clinically characterized by pain, tenderness, swelling and vasomotor changes which usually occur after a traumatic event. Although pathogenesis of RSD is unclear, there are some evidences suggesting that adrenergic sympathetic activity is one of the pathogenetic determinants of RSD. However data on this issue are conflicting and some authors suggest that vasomotor abnormalities could be due to antidromic release of neuromediators by the endings of polymodal C fibers. These findings support also the evidence of an exaggerated inflammatory response to injury in RSD. Therapeutic modalities of RSD include the use of drugs and physical therapy. Although pain medications such as analgesics and nonsteroidal anti-inflammaory drugs are widely used in Europe, calcitonin is usually the primary treatment used at early stages of the disease particularly in France. The efficacy of calcitonin therapy has been proven in open but also few controlled studies. The use of corticosteroids by oral or intraarticular route is also relevant but corticosteroids are poorly used in France in RSD. Moreover the numerous side effects of corticosteroids particularly for systemic corticosteroids must also be taken into account. When patients show no improvement with calcitonin or steroids, the use of regional sympathetic blockades is of interest. The 2 drugs mostly investigated are guanethidine and buflomedil. The efficacy of both guanethidine and buflomedil seems comparable, nevertheless buflomedil is characterized by a best benefiVrisk ratio. Furthermore the efficacy of guanathidine blocks is still controversial and a recent study concludes that guanethidine blocks do not provide long-term pain relief in RSD and are associated with adverse events in 1/3 of patients. In a retrospective study we have recently shown that buflomedil blocks are of benefit since 60% of our patients have considered the treatment as efficient. In this study we have shown that

430

Abstract s

psychic disorders, industrial accidents and a disease duration of more than 1 year provide less frequent good results. Other drugs regionally administrated such as bretylium, droperidol and ketorolac have also been assessed with conflicting results. Since RSD is usually characterized by pain associated with regional osteopenia possibly due to increased bone resorption, bisphosphonates could theorically be of interest in the management of RSD. 2 intravenously administrated bisphosphonates have been investigated in RSD, namely pamidronate and alendronate. Some open studies have shown that pamidronate is useful in the treatment of RSD particularly in non-traumatic RSD and in RSD evolving for less than 1 year. In our experience however pamidronate in RSD seems not well tolerated since up to 50% of patients developed at least one side effect. Alendronate has been shown to be effective in one randomized double-blind placebo-controlled study with a high safety profile. Indeed in this study only 15% of patients experienced fever the day after the first intravenous injection. Electric nerve stimulation and spinal cord stimulation have been proposed by some authors with interesting results. However the number of studies are very few and other works are required for confirming these preliminary results. The second way for RSD treatment is the use of physical therapy whose benefit is well demonstrated both in hot pseudoinflammatory and cold phase. Physical therapy must be performed in a pain-free environment. Hand therapy is the backbone of a treatment program for RSD and is often the only treatment necessary for simple cases. In other cases various physical modalities and rehabilitation programs can be used for decreasing pain and improving stiffness.

6.

GENETICS OF OSTEOPOROSIS

ML Brandi (Firenze) Osteoporosis is recognized to be an important disorder of aging and it is well known that peak bone mass is primarily under genetic control with up to 70% of variation in bone mineral density (BMD) believed to be determined by several genetic factors. Osteoporosis is, in fact , a polygenic disorder with a number of different genes playing a significant role. Most of the studies have focused the attention on one gene at a time. Examples are vitamin D receptor (VDR), estrogen receptor CJ. (Era), collagen type I, interleukin-6, and calcitonin receptor genes. However, the combined action of more than one gene should underlie the genetic basis of this disorder. Studies carried out in our laboratory showed the importance of Era genotype in modulating the VDR allelic effect on BMD. Discrepancies could also be generated by selection bias of patients and by the variable consideration given to the reciprocal interaction between environmental and genetic factors. These observations become even more relevant when one considers the differences in distribution of genotypes in populations of various ethnic origin (Le. Asiatic and Caucasian ancestry). The picture is quite more complex than thought at the beginning of this adventure. Future studies will focus on characterization of the genetic components of the osteoporosis risk either in association or in linkage analysis. An overview of published data and of future prospects will be presented.

7. ALTERED TRABECULAR ARCHITECTURE INDUCED BY CORTICOSTEROIDS: A BONE HISTOMORPHOMETRIC STUDY D Chappard", E Legrand 2, MF Basla!, M Audrarr', 'LHEA-

Laboratoire d'Histologie-Embryologie, 2Service de Rhumatologie. Faculte de Madecine, and CHU d'Angers, Angers Cadex - France

Corticosteroids (CS) are strongly effective pharmacological agents whose negative effects are to interfere with bone and calcium balance. Prolonged corticosteroid therapy induces

osteoporosis and fractures. The most significant adverse effects of CS on the skeleton are a direct inhibition of bone matrix synthesis by the osteoblast. However, other systemic deleterious effects have been recognized: reduction of calcium absorption in the gut, increased calcium excretion by the renal tubule and the production of hypogonadism in male. A marked reduction of bone mineral density (1Q-40%) is repeatedly reported by authors on DXA measurements. However, the pathophysiological mechanisms of the bone loss at the tissue level still remain elusive. Osteoporosis is characterised at the histomorphometric level by reduced bone volume (BVITV) and disruption of the 3D trabecular architecture. Several stereological methods have been proposed to characterise these alterations: measurements of trabecular thickness and trabecular number, star volumes, interconnectivity index (ICI) of the bone marrow spaces, and trabecular bone pattern factor (TBP,). These methods were computerized with a single program running on an image analyser to evaluate the bone changes in a series of iliac biopsies performed on 31 male patients. All of them were asthmatic and had received CS for a long term period. BVITV was reduced when compared to agematched controls. In the CS-treated population, exponential relationships were obtained between bone volume and the different connectivity parameters. The various methods used to measure connectivity were well correlated. When the population was divided into two groups (BVITV greater or less than a 11% threshold) the architectural disturbances were found to imply two mechanisms. A progressive decline in trabecular thickness was noted in both groups vs controls. Trabecular perforations were not established in the group with BVITV > 11% with the star volume or ICI, although some alterations were detected by trabecular bone pattern factor measurement. On the other hand, perforations were revealed in the group with BVITV < 11% by all the different methods. Perforations seemed to occur when trabecular thickness was below 70 urn, This strongly suggests that bone histomorphometry should consider bone volume ' in combination with detailed 3D descriptors of the trabecular architecture. Several histological methods need to be used in combination to appreciate the 3D architecture of trabecular bone. Perforations occurring on a scaffold of thin trabeculae can induce dramatic consequences, a condition which can be assimilated to a percolation mechanism.

8. TYPE I COLLAGEN GENE POLYMORPHISMS (COL-1A1) ARE ASSOCIATED WITH SUSCEPTIBILITY FOR FRACTURES IN ELDERLY WOMEN - THE OSTEOLIMB STUDY C Vandevyver!, P Stinissen, ,2, L Michiels', J-J Casslman", J Vanhoot", K Declerck" J Raus,,2, P Geusens' ,2. 'Dr. L WillemsInstituut, Universitaire Campus, Diepenbeek, 2Umburgs Universitair Centrum, Universitaire Campus , Diepenbeek, 3Centrum voor Menselijke Erfelijkheid, Onderwijs & Navorsing, K.U. Leuven Belgium The dimorphisms of type I collagen gene loci COL-1A1 and COL1A2 and their relationship with bone density and fracture history were investigated in 347 unrelated postmenopausal Caucasian women of 70 years and older. The overall distribution of the COL1A1 and COL-1A2 alleles in this study was similar to that previously reported in Caucasian study populations. No difference in bone mineral density at the spine, the proximal femur and the proximal radius was seen between the genotypes for any of the studied dimorphisms. However, in nonobese women, bone density in the spine was 10% higher in COL-1A1 B1B1 genotype compared to COL-1A1 B2B2 (p<0.05). In the total group of women, the COL-1A1 A1A1 genotype was associated with previous fracture of the hip [odds ratio (OR) and 95% confidence interval: 6.42, 1.73-23.79]. The COL-1A1 B2B2 genotype was associated with previous fracture of the hip (OR: 5.44, 1.42-20.82) and of the forearm (OR: 5.34, 1.92-14.84) and with the number of all previous fractures (OR for ?o 2 fractures: 5.78, 1.67-20.03, and

Abstracts for > 3 fractures: 26.58, 5.46-129.43). No such associations were found with COL-1A2 dimorphisms. We conclude that, in elderly women, bone density is associated with COL-1A1 B2B2 dimorphism in nonobese women, and this dimorphism is associated with the prevalence of previous hip and wrist fractures and with the number of all previous fractures. This polymorphism of COL-1A1 could be a useful marker for fracture risk.

9. PREVALENCE OF TRABECULAR MICROCALLUS FORMATION IN THE VERTEBRAL BODY AND THE FEMORAL NECK XG Cheng, PHF Nicholson*, G Lowet*, S Boonen, Y Sun, P Ruegsegger**, R Muller**, J Dequeker. Arthritis and Metabolic Bone Disease Research Unit and *Division of Biomechanics and Engineering Design, KU Leuven, Belgium, **Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH), Zurich, Switzerland Trabecular microcallus formation (TMF) has been described previously in the human vertebra and femur, but the difference in TMF prevalence at these two sites has not been studied and the role of TMF remains controversial. In this study, the 4th lumbar vertebra (L4) and right proximal femur were removed from 27 male and 23 female cadavers. A 2 cm cube cut from the centre of L4 and a 1cm-thick slice cut from the femoral neck were cleaned, defatted, and dried. The apparent density of the L4 cubes was determined as dry weighVbulk bone volume. Using a dissecting microscope at low magnification (4-BOx),TMF were identified and counted in both the vertebral and femoral samples. A 8 mm diameter core was then cut from the centre of the L4 cubes in the vertical direction, and selected histomorphometric parameters of the core were evaluated with an X-ray microcomputed tomography system (J.l-CT). There was a significantly greater prevalence of TMF in vertebral cubes (82%) than in the femoral slices (11%) (P<0.001). TMF prevalence did not differ significantly between males and females, but the mean number of TMF in the vertebra was significantly (P<0.05) greater in females (15.0/ vertebra) than in males (7.7/vertebra). In the vertebra, the majority of the observed TMF were in vertical trabeculae. Subjects over 60 years old had a higher TMF prevalence than those under 60 years old (P<0.01). TMF numbers increased with decreasing apparent density (P<0.05), whereas no significant correlations were found between TMF and bone volume (BVIlV), trabecular number (Tb.N), or trabecular thickness (Tb.Th) was assessed by J.l-CT. In two fractured vertebra, very few TMFs (2 and 4, respectively) were observed. These results demonstrated that the occurrence of TMF is strongly related to the anatomical site, probably due to differences in the applied loads and the trabecular structure between sites. The results were consistent with the hypothesis that TMF is a mechanism acting to maintain bone strength, but further studies are needed to clarify this important issue.

10. STRONTIUM RANELATE FOR THE PREVENTION OF BONE LOSS OF EARLY POSTMENOPAUSE JY Reginster1, C Roux 2, I Jupsin', OM Provvedini", P Blrman",

Tsouderos'', 'CHU Liege, Liege, France; 2H6pital Cochin, Paris, France; 31nstitut de Recherches Internationales Servier, Courbevoie, France

Strontium Ranelate (S12911 ; SR) is a potential new treatment for osteoporosis. The results of the " STRATOS" study (conducted in postmenopausal osteoporotic women with vertebral fractures) have indicated that the daily dose of 2g/day of SR significantly increases lumbar BMD (approximately, 3% per year) and significantly reduces (44%) the number of patients experiencing a new vertebral fracture during the second year of treatment (as judged by quantitative morphometry). The effects of SR on the

431 prevention of bone loss have been recently investigated during a bi-centre, double-blind, placebo-controlled study. Four groups of 40 early postmenopausal women without vertebral fractures were given either placebo or SR (125mg, 500mg or 1g/day) for two years . All subjects were also given a daily calcium supplement (500mg). The main characteristics of the study population were: age 54 ~ 3 years ; duration of menopause 3 ~ 1.5 years, lumbar BMD (as measured by DXA on Hologic densitometers) 0.932 ~ 0.135 g/cm 2 (mean ~ SO). The effects of the treatment on lumbar BMD were monitored throughout the study. Due to the absorption of strontium to bone , all measured BMD values were adjusted for bone strontium content, using a model previously established in vivo. At the conclusion of the study, the percent variation of lumbar BMD from baseline was significantly different in the group receiving 1g/day of SR as compared to placebo: + 1.41% ~ 5.33 versus 0.98% ~ 3.14, respectively [p<0 .05; 95% CI : 0.010, 4.776). Furthermore, 25% of the patients on placebo experienced adverse effects, as compared to 20% of the patients receiving SR. In conclusion, these results suggest that the daily administration of SR is well tolerated and that the dose of 1g/day for two years significantly increases lumbar BMD in early postmenopausal women without vertebral fractures. The effects on BMD of the administration of 2g of SR are being investigated.

11. BONE MASS, BODY COMPOSITION ANALYSIS AND TRUNK MUSCLE STRENGHT IN YOUNG ADULTS C Gregoir, M Claes, R Leclercq, K Zouaoui. Chu A. Vesale, Montigny Ie Tilleul, Belgium The relationship between Bone Mineral Density (BMD) and lean mass or fat mass remains controversial and depends on the studied population. The aim of this study is to evaluate BMD, lean mass, fat mass and trunk muscle strength in healthy and non athletic young adults. Methods: lumbar spine and whole body BMD , lean mass and fat mass are measured by dual X-ray absorptiometry, Hologic 1500W with body composition analysis. Trunk muscle strength is measured by a Cybex 6000TMC isokinetic dynamometer. 30 men aged 20 to 25 years and 24 women aged 18 to 25 years were recruited among nurse , physiotherapist and medical students. Results: BMD at whole body, but not at the lumbar spine, is significantly higher in men. In men, significant correlations are found between BMD and lean mass: L1-L4 BMD and lean trunk (r=0.45, p= 0.01); whole body BMD and total lean (r=0.63, p= 0.001; Spearmann Rank correlation). In women, only the whole body BMD is correlated to lean mass (r= 0.48, p= 0.01). In a multiple regression model lean mass remains a good predictor of bone mass. No correlation is found between BMD and fat mass, or BMD and nowadays calcium intake, or BMD and muscle strength. Conclusion: BMD is correlated to lean mass in young adults, men and women. Lumbar spine BMD is not correlated to trunk muscle strenght measured by isokinetic dynamometer.

BMI % fat calcium intake BMD L1-L4 BMDWB lean trunk lean total PT extensors, 30 PT flexors 30

men

women

23.7 ~ 2.6 18.5 ~ 6.03 671 ~ 284 1.093 ~ 0.13 1.208 ~ 0.09 28585 ~ 2889 58353 ~ 5704 308 ~ 74 219 ~ 49.5

22.9 ~ 3.5 * 33.6 ~ 5.6 ** 724 ~ 215 * 1.032 ~ 0.13 * 1.07 ~ 0.08 ** 21 366 ~ 2497 ** 41128 ~ 4908 ** 170 ~ 29 ** 112 ~ 23.5 **

* = ns, **= p-c 0.01; Mann-Whitney test

432

12. DETERMINANTS OF MUSCLE STRENGTH, MASS AND FUNCTION IN RELATION TO BONE DENSITY IN ELDERLY WOMEN P Geusens 1 •2, J Vanhoot" , K Deklerck", J Rausl ,2. IDr. L WillemsInstituut, I Limburgs Universitair Centrum, Belgium

Muscle strength (MS), muscle mass (MM) and muscle function (MF) decrease with aging and are related to fracture risk. However, the interrelations of MS, MM, MF are not well documented in elderly women. We investigated these intercorrelations in muscle parameters and their relation with bone density in 200 women of 70 years and older. Bone density and lean body mass were measured in the total body and regions of interest by DEXA (Hologic QDR 2000). Routine functional tests were performed. Grip and quadriceps strength were measured by standard techn iques. Serum IGF-1 (n=100) and free testosterone (n=200) were measured by RIA. All muscle parameters and bone dens ity in the hip and forearm decreased with age. Local bone dens ity was correlated with MS (r= .280*** in the arms and r=. 156* in the legs) and with MM (r= .142* in the arms and r= .306*** in the legs). MS was correlated with MM (r= .358*** in the arms and r=.214** in the legs). However, simple MF such as raising from a chair or walking on a line was related to MS (r=.160* to .233***) but not to MM. Physical activity during puberty was correlated with MM (r=.162 in the arms and .217** in the legs) while current physical activity was correlated with MS (r=.128* to .136*). MS and MF, but not MM, were correlated with IGF-1 (r=.153 to .337**). No correlations were found between MM or MS and serum free testosterone. We conclude that in elderly women MM, but not MS or MF, is related to physical activity during growth. MS and MF, but not MM, are related to current physical activity and IGF-1. None of the muscle parameters were related with serum free testosterone. *p<.05, **p<.01, ***p<.001

13. LACK OF ASSOCIATION BETWEEN ESTROGEN RECEPTOR GENOTYPES AND BONE MINERAL DENSITY, FRACTURE HISTORY OR MUSCLE STRENGTH IN ELDERLY WOMEN C Vandevrerl, J Vanhoof", K Deklerck1, P Stinissen 1, L Mischiels ,JJ Casslman", J Rausl .2, P Geusens l,2. IDr. L WillemsInstituut, Diepenbeek 2Limburgs Universitair Centrum , Diepenbeek, 3Centrum voor Menselijke Erfelijkheid, Onderwijs & Navorsing, Gasthuisberg, K.U. Leuven, Belgium The Pvu II polymorphism of the estrogen receptor (ESR)gene and its relation to bone mineral density (BMD), fracture history and muscle strength was studied in 313 postmenopausal (76 ± 5 years) women of Caucasian origin, of whom 142 had suffered from a fragility fracture after the age of 50 years (14 with fracture of the hip, 38 of the spine , 45 of the wrist and 85 of other fractures). We did not find a correlation between the ESR genotypes and BMD at the lumbar spine, the femoral neck and the proximal forearm nor with grip or quadriceps strength. The ESR genotype distribution was sim ilar in women with and without a history of fragility fracture. We further evaluated the relationship between the combination of vitamin D receptor (VDR) and ESR haplotypes and BMD in a random subgroup of 270 elderly women. A trend towards a lower BMD in the femoral neck was observed in women with the BBpp versus the bbPP haplotype, resulting in a difference in Z-score of BMD in the femoral neck of 0.5 (p=0.08). The significant association of quadriceps strength with VDR genotypes was not influenced by ESR haplotypes. We conclude that in elderly Caucas ian women the Pvu II ESR polymorphism is not associated with osteoporosis, fracture history nor muscle strength.

Abstracts 14. BONE DENSITY AND FRACTURE HISTORY, BUT NOT MUSCLE STRENGTH, ARE ASSOCIATED WITH SERUM TESTOSTERONE IN ELDERLY WOMEN - THE OSTEOLIMB STUDY P Geusens l ,2, J Vanhoof", C Vandervorst', S Boonerr', D

Vanderschuererr', R Bouillon", K Declerck", J Mertens1, J Rausl ,2. I Dr L Willems-Instituut, Diepenbeek, 2Department of Medicine, Limburgs Universitair Centrum, Diepenbeek, 3Centre for Metabolic Bone Diseases, KULeuven Belgium

Peak bone density and subsequent bone loss in women are related, among other factors, to sex hormones and muscle strength. Bone density is related to testosterone in pre-, peri- and postmenopausal women. Whether bone density, fracture history and muscle strength are related to testosterone in women over 70 years old is not known. We studied serum free testosterone (FT) in relation to bone density, fracture history and muscle strength in 741 healthy women over 70 years old. After adjustment for confounding factors, bone density was significantly correlated with serum FT in the spine (r=.137,p<.01), the hip (r=.133, p<.05), the proximal forearm (r=.188, p<.001) and in the total body (r=.136, p<.05). Bone density was significantly correlated with muscle strength (r=.123 to .213, p<.05 to p<.0001), but no correlation was found between FT and muscle strength. The odds ratio (with 95% confidence interval) between low and high FT for all past fractures after the age of 40 years was 1.54 (1.002.36), and for ~ 2 fractures 2.4 (1.33-4.34). Total testosterone was correlated with bone density in the forearm and total body, but not with fracture history or muscle strength. After adjustment for confounding factors, SHBG was not correlated with bone density, fracture history or muscle strength. We conclude that in elderly women, endogenous free testosterone is a significant determinant of both cortical and trabecular bone density. Serum free testosterone is associated with fracture history, but not with muscle strength. .

15. EFFECTS OF NAPROXEN OR ESTROGEN ON BONE MINERAL DENSITY, STRUCTURE, AND BIOMECHANICAL PROPERTIES OF SPINE AND FEMUR OF OVARIECTOMIZED RATS ON LOW CALCIUM DIET Y Jianq', J Zhao!, J Dequeker' , P Geusens 2. "Arthritls and

Metabolic Bone Disease Research Unit, Catholic University of Leuven, Pellenberg, Belgium 2Clinical Research Center for Bone and Joint Diseases, Dr. L Willems-Instituut, Limburgs Universitair Centrum , Diepenbeek, Belgium

Prostaglandins have been reported to stimulate bone resorption and formation. To study the effect of an anti-arthritic drug naproxen, inhibitor of prostaglandins, on osteopenia, and compare with estrogen replacement therapy, 150 female Wistar rats of 4.5-month were divided into baseline, sham-operation (sham), ovariectomy on low calcium diet (OVX+LCD), OVX+LCD treated with naproxen (+N) at 10 mg/kg/day or with estradiol (+E) at 0.2mg/kg/week. They were euthanized 1, 3, 6, and 9 months post-surgery. BMD and area of the lumbar spine L1-4, femoral neck, midshaft, and distal metaphysis were determined using DXA. The compressive test of the L1 vertebral body and torsional test of the left femur were performed. The right femoral midshaft and the proximal tibial metaphysis of rats of baseline and 1 month post-OVX were processed undecalcified for determining crosssectional moments of inertia (CSMls) and histomorphometry. BMD at most measured sites and time points was: sham > OVX+LCD+E > OVX+LCD+N > OVX+LCD. Naproxen and estrogen sign ificantly partially prevented OVX+LCD induced loss in L1 compressive strength and stiffness, respectively. No statistically significant difference in torsional strength and stiffness was found between sham and treated groups, in CSMls and static histomorphometric parameters between sham

Abstracts and naproxen treatment. Estrogen treatment suppressed gain in body weight, bone areas, and CSMls. Naproxen and estrogen partially reduced OVX+LCD induced deterioration of trabecular structure and connectivity in the proximal tibial metaphysis and osteoclastic bone resorption at 1 month post-OVX. Unlike estrogen that suppressed bone turnover, naproxen had no effect on OVX+LCD induced high bone turnover. Long-term naproxen or estrogen treatment partially prevented OVX+LCD-induced osteopenia. Naproxen was less potent than estrogen.

16. QUANTITATIVE ULTRASOUND OF BONE: CONGRUENCE WITH DIAGNOSIS OF OSTEOPOROSIS USING DUAL-ENERGY X-RAY ABSORPTIOMETRY P Geusens 1 ,2, J vannoot' , K Declerck", L Bruckers 2,3, G Molenberghs2.3, J Raus1 •2. lDr. L Willems-Instituut, 2Umburgs Universitair Centrum, 3Department of Biostatistics, Diepenbeek

Quantitative ultrasound (QUS) analysis of bone is an emerging method in the diagnosis of osteoporosis. However, congruence with bone mass measurements' using dual-energy x-ray absorptiometry (DEXA) is limited (1). In order to evaluate the predictive value of QUS for diagnosing osteoporosis as measured by DEXA, we evaluated 142 women between the ages of 25 and 90 years. Bone density in the total hip was measured by DEXA (Hologic 2000). QUS was measured by a Sahara device (Hologic Inc.) and by an Achilles device (Lunar Inc.). Speed of sound (SOS) results of QUS were used for this study. Analysis of congruence between SOS and DEXA was performed using kappa coefficients [value ± 95% confidence interval (CI)] and Fisher-discriminant analysis . Analysis was performed for the diagnosis of osteoporosis versus non-osteoporosis (T-score < and> -2,5 respectively) according to the definition of the World Health Organization. Kappa coefficients for osteoporosis versus non-osteoporosis between DEXA and QUS were 0.436 (95% CI: 0.302-0.570) for the Achilles device and 0.522 (95% CI: 0.397-0.646) for the Sahara device. Using discrimant analysis 79% of women with osteoporosis were correctly classified by the Achilles device and 77% by the Sahara device. We conclude that QUS is a valuable tool for selecting patients with osteoporosis as measured by DEXA. Further analysis is ongoing for the study of congruence based on the peak bone mass of Belgian women and between QUS and other skeletal sites measured by DEXA. (1) Grampp S et all. Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification. J Bone Miner Res 199712:697711

17. QUANTITATIVE ULTRASOUND MEASUREMENT IN ASSESSMENT OF BONE DISEASE IN PATIENTS WITH TERMINAL CHRONIC RENAL FAILURE AND COMPARISON WITH DENSITY BY DUAL X-RAY ABSORPTIOMETRY A Penazola, A Peretz, M Mesquita, M Dratwa , P Bergmann. Departments of Internal Medicine and Radioisotopes, CHU Brugmann, ULB, Brussels, Belgium Introduction: Qualitative ultrasound (QUS) have been shown to predict bone mineral density (BMD) with accuracy and it has been suggested that QUS provide additional informations on bone structure. In chronic renal failure (CRF), bone disease is characterized by highly variable rates of remodeling according to the degree of hyperparathyroidism, and by variable osteoid accumulation.

433 Aims: To compare the results of dual X-ray absorptiometry (DXA) and QUS in patients with terminal CRF and to explore if the relationship between QUS and DXA differs according to the degree of hyperparathyroidism. Patients and methods: We invest igate 54 patients in CRF, 34 on hemodialysis (HD) and 20 in peritoneal dialysis (DP), and 31 controls (C). BMD was measured at lumbar spine (LS) by DXA (Hologic QDR 1000) and QUS of the calcaneum was measured by Achilles (Lunar). Intact iPTH was measured by an immunoradiometric assay (N-tac PTH, Incstar)(N:10-55 pg/ml). Results: BUA and BMDL were significantly lower in HD (p<0.01) and DP (p<0.01) compared with C. SOS and S were decreased in HD only (p<0.01). The correlation between BUA and BMDL was significant in patients with CRF (r=0.45, p<0.05) and in controls (r=0.6, p<0.05) but the slopes are not statistically different. For patients with iPTH<208 pg/ml (median) the slope of regression was 35.6, r=0.52 while when iPTH was >208 pg/ml, the slope was 31.1, r=0.41. Conclusion: The present results show that QUS could be useful is assessing bone disease in terminal CRF. The relat ionship between BMDL and stiffness does not change according to the degree of secondary hyperparathyroidism; suggesting that in CRF, as in osteoporosis, QUS reflect essentially BMD. A limit of this study is that 2 different sites were measured for QUS (peripheral) and DXA (axial).

18. BONE MINERAL DENSITY IN PATIENTS WITH EATING DISORDERS Th-A Abatzi, H Borghs, J Joly, J Nijs, W Vandereycken 1 , J Peuskens", J Dequeker. Dept. of Rheumatology, University Hospitals Leuven, 1 Psychiatric Clinic Brothers Alexianen, Tienen; 2University Psychiatric Center, Kortenberg, K.U.Leuven, Belgium Background. Eating disorders usually start at puberty. These disorders may be associated with premature bone loss, and the patients may not have the opportunity to reach their peak bone mass. However, little is known of factors contributing to bone loss. Aim. To study bone mineral density (BMD) in different groups of patients with eating disorders in comparison to healthy agematched volunteers. Methods. BMD was measured by the dual energy x-ray absorptiometry technique on lumbar spine and femoral neck. In 68 female in-patients with anorexia nervosa (AN), mean age 19.5 years and mean weight 41.2 kg and 24 patients, mean age 19.2 and mean weight 53.9 kg with bulimia nervosa (BN), according to the criteria of Diagnostic and Statistical Manual of Mental disorders, 4th ed. All values were transformed to z-scores. Quantitative ultrasound technique (QUS) was also used as QUS is thought to be independent of weight. The results were compared to the reference values of 165 young healthy age matched females and expressed as z-scores, Results. BMD was significantly decreased in AN (-1.30 ± 0.16, p<0.001) but not in BN (-0.25 :!: 0.24). In 17 AN patients (25%) the BMD z-score was below -2.0 indicating osteoporosis, in 22 AN (32%) it was between -2.0 and -1.0 (osteopenic). BMD L2-L4 correlated with the duration of amenorrhea (r=-0.037; p<0.01). BMD L2-L4 correlated significantly with speed of sound (SOS), stiffness and broadband attenuation (BUA) (r=0.47; p<0.001) but only 3 patients had SOS and 6 BUA z-score values lower than <-2. Conclusions. Our data confirm that BMD at the spine is significantly decreased in patients with anorexia nervosa compared to bulimia nervosa. Contrary to current opinion the decrease is already apparent in young pat ients. The differences between DEXA and QUS results can be due to various factors including bone architecture, degree of mineralisation and other unknown variables.

434 19. EFFECT OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-II INSULIN-LIKE GROWTH FACTOR-I BINDING PROTEIN-3 ON BONE LOSS IN HIP FRACTURE PATIENTS: PRELIMINARY RESULTS FROM A DOUBLE BLIND PLACEBO-CONTROLLED PHASE II STUDY S Boonen, R Bouillon, P Broos, D Rosen, S Adams, J Raus, P Geusens. Katholieke Universiteit Leuven , Dr.L Willems-Instituut & Limburgs Universitair Centrum, Belg ium , and Celtr ix Pharmaceuticals, USA In spite of dramatic effects of recombinant human insulin -like growth factor-I (rhIGF-I) on bone turnover in older subjects, a corresponding increase in bone mass has not been documented. The administration of IGF-I complexed with its binding protein IGFBP-3 (rhIGF-I/IGFBP-3) allows the safe administration of higher doses of IGF-I than can be accomplished with rhlGF-1. The aim of this study was to evaluate the ability of rhIGF-I/IGFBP3 (Sornatokinev') to prevent bone loss after hip fracture in 22 elderly women. Within 72 hours after hip fracture, patients received continuous subcutaneous adm inistration of rhlGF-11 IGFBP-3 (0.5 mg/kg/day, n=8 or 1 mg/kg/day, n=8) or placebo (n=6) for a period of 8 weeks . Efficacy evaluations included a contralateral hip scan by dual emission x-ray absorptiometry and markers of bone turnover (including serum type I procollagen carboxyl-terminal propeptide and urine deoxypyridinoline). During the adm inistration of rhIGF-I/IGFBP-3, serum IGF-I increased significantly from 83±6 ng/ml (mean±SEM) up to 289±18 (0.5 mg/kg/day) and 393±28 ng/ml (1.0 mg/kg/day). Both doses were well tolerated and no therapy-induced hypoglycemia was observed. One month after the 2-month infusion, a femoral bone loss of -7% was observed in placebotreated pat ients, compared to a loss from baseline of less than 2% in the 1 mg/kg/day group. Bone formation and resorption increased in all three groups. From these preliminary data, we conclude that a 2-month infusion of rhIGF-I/IGFBP-3 in elderly women with recent hip fracture is feasible and well-tolerated. In addition, this study is the first to suggest a therapeutic effect of growth factor therapy on bone mass in an elderly target population.

20. MAJOR IMPACT OF FALLS ON OVERALL FRACTURE OCCURRENCE IN POSTMENOPAUSAL WOMEN P Geusens'·2, P Autier', J Venhoof", K Declerck', S Boonen", P Hemmer and J Raus' ,2. 'Clinical Research Centre for Bone and Joint Diseases , Dr. L Willems-Instituut, 2Limburgs Universitair Centrum, Diepenbeek, Belgium, 3European Institute of Oncology, Milan, Italy, "Division of Geriatric Medicine, Katholieke Universiteit Leuven, Belgium, 5Luxembourg Bone Club To study the relative importance of osteoporosis and falls in the occurrence of all symptomatic fractures in postmenopausal women, a systematic measurement of bone density by singlephoton absorptiometry of the forearm was performed together with a detailed questionnaire on falls and fractures by 74 general practitioners in a survey of 2649 community-based postmenopausal women (mean age 61, range 45-91 years). Osteoporosis was found in 15% of the patients, 19% reported one or more falls during the last year and 6% had a fracture during the last 2 years . The age-adjusted risk (with 95% confidence interval) for a recent fracture for 1 standard deviation decrease in bone density was 1.6 (1.3-1.8, p<0.001) in the total population, 1.4 (0.9-1.7, p>0.10) in women without a history of recent falls and 1.9 (1.3-2.1, p<0.001) in those with a history of recent falls. The age-, bone dens ity- and body mass index-adjusted risk for a recent fracture according to a history of recent falls was 7.5 (5.2-10.9, p<0.001) and 6.0 (3.111.5, p<0.001) for fractures during the last 2 years and during the last year, respectively. In women with osteoporosis without a recent fall, less than 1 in 20 had a fracture, but with a history of a recent fall, nearly 1 in 3 had a fracture. A careful examination of

Abstracts the data allowed to exclude that these results were mainly the consequence of a recall bias. We conclude that a history of recent falls is a major independent contributing factor to the occurrence of all recent symptomatic fractures in postmenopausal women. Falls are a much higher risk for all fractures than reported in prospective studies in which not all fractures were considered or in which falls were not recorded but were based on baseline risk evaluation for falling.

21. CONTRIBUTION OF BONE COMPOSITION AND ARCHITECTURE TO BONE STRENGTH AND THOUGH NESS OF HUMAN TRABECULAR BONE H Van Carnpenhout", H Druyts', J Aerssens", G Van der Perre", J Dequeker", S Boonen'', , Division of Biomechanics and Engineering Design, 2Division of Rheumatology, K.U.Leuven, B-3000 Leuven, Belgium Introduction: The effect of bone density on biomechanical characteristics is well known and is highly significant, 64 to 88% (1). Bone density, however, does not explain all biomechanical characteristics, architecture and material properties are considered to play an additional role. Methods: In order to study the effect of architecture and material properties, 64 lumbar spine bone samples, collected in the European Concerted Action BIOMED 1, Assessment of Bone Quality, have been analysed using cyl indrical samples for histomorphometric data (BVITV, trabecular number, th ickness and spacing) and biochemical analysis (calcium, phosphorus, hydroxyproline, total protein, osteocalcin and IGF1) in relation to mechanical testing under compression. Results: In multiple regression analyses, including all histomorphometric and biochemical parameters, the following measures contributed significantly to the breaking force (R2 =0.458): trabecular spacing (p<0.05), IGF1 (p=0.05). For energy absorption (toughness), trabecular number (p<0.001), IGF1 (p<0.005) and total protein (p<0.05) contributed significantly (R2 =0.344). Conclusions: These results indicate that architectural characteristics (trabecular number and spacing), and material characteristics (in particular IGF1 content) contribute to mechanical parameters as strength and toughness. The negative correlation of skeletal concentration of IGF1 and biomechanical strength and toughness may offer new insights in the pathophysiology of osteoporosis. (1) Cheng XG et al. Bone 1997;20:213-218

22. BONE MASS DENSITY CORRELATES WITH TENSILE SKIN PROPERTIES IN POSTMENOPAUSAL WOMEN I Van Cromphaut, N Franch imont, C Pierard-Franchirnont, GE Pierard , M Malaise. Dept. of Dermatopathology and Rheumatology, University of Liege, CHU Sart Tilman, Liege Purpose of the study: After menopause, skin atrophy and major bone loss are observed in women and it is possible that type I collagen, a major constituent of skin and bone, is regulated by similar local and systemic factors in both systems. However, little is known about the correlation between bone mass density (BMD) and the mechanical skin properties. In order to determine if functional parameters related to cutaneous atrophy may reflect bone loss, we have compared BMD w ith skin tensile properties in postmenopausal women. Methods: BMD was measured by dual X-ray absorptiometry (DXA) at the hip , the femoral neck and the lumbar spine, in 50 postmenopausal women (age 40 to 88). Among them, 25 were not

Abstracts

435

receiving any treatment beside Ca'" and eventually vitamin D3 supplementations but 5 of them were treated with steroids for rheumatic diseases. The 25 remaining women were either treated with hormone replacement therapy or biphosphonates and among this group, 8 were also treated with steroids. Being heterogenous, this population of postmenopausal women provided us with a large diversity of BMD values. Biological elasticity of the skin was evaluated by a non invasive method on the mid portion of the forearm using a computerized suction device (Cutometer SM 474). Results: Hip

r =0.4;

Biological elasticity (stat. correlation)

P < 0.01

Femoral neck r = 0.35; P < 0.05

Lumbar spine r = 0.34; P < 0.05

Conclusions: There is a good correlation between cortical and trabecular BMD and skin elasticity in postmenopausal women. This was observed for all the patients subgroups studied. However, additional data are needed to evaluate the influence of age, treatment and eventual underlying rheumatic diseases.

23. BONE IN RHEUMATOID ARTHRITIS: TRABECULAR LOSS IS RELATED TO STEROIDS AND CORTICAL LOSS IS RELATED TO THE DISEASE NM Franchimont, E Heuse, B Andre, C Ribbens, 0 Kaye, MG Malaise. Rheumatology Dept, University of Liege Introduction. Bone loss in rheumafoid arthritis (RA) is multifactorial and can be influence by the menopausal status, immobilisation, the use of steroid and disease activity itself. The importance of the negative influence of the disease is generally underestimated albeit correlations between time-integrated CRP (reflecting the disease activity) and generalized bone loss has been demonstrated in early (less than 12 months) RA. Methods. As RA is a chronic disease lasting decades, we investigated the importance of the disease activity by measuring bone density (DEXA, Hologic 1000) in two groups of RA patients exhibiting longstanding disease (mean of 8.5 years): a first of 13 patients (11 F/2M) that never received steroids and a second of 28 (18F/10M) receiving daily low doses of steroids. Bone density (Z scores of femoral neck, hip and lumbar spine L1-L4) were compared to the time-integrated CRP and to the cumulative dose of steroid administrated since the disease started. Results. Z scores are expressed as mean values (:I: SEM). Z femoral neck

Z hip

Z lumbar

Steroids

No

Yes

No

Yes

No

Yes

-Q.82

-Q.63 :t 0.17 P =0.002

- 0.69

- 0.55 :t 0.14 P =0.0036

- 0.03 :t 0.19

- 0.62 :t 0.41

:t

NS

NS

NS

Log time-integrated CRP Cumulative dose of prednisone (g)

0.23 NS :t

NS

NS

0.21

P =0.0092

A significant linear correlation was also observed between log time-intergrated CRP and the cumulative dose of steroids (P = 0.0001). Conclusions. (a) Non-steroid- and steroid-treated RA patients sharing matched age and disease-duration exhibited similar bone loss; (b) cortical bone loss only was highly related to the timeintegrated CRP levels independently of the presence or not of steroids; (c) trabecular bone loss only was highly related to the cumulative dose of steroids; (d) as patients with the most chronically active diseases (elevated time-integrated CRP) are also those exhibiting the highest cumulative doses of steroids, the early control of disease activity by steroid-sparing agents remains a challenge the rheumatologist has to deal with.

24. THE LOSS IN BONE TURNOVER AND BONE MASS OBSERVED IN MRLMPG/LPR LPR MICE IS INTERLEUKIN-GDEPENDENT N Franchimont, M Amling, M Prieme, M Malaise, R Baron, J Craft. Yale School of Medicine, New Haven, USA and CHU Sart Tilman, Liege MRL-Mpg/lpr Ipr (Ipr) mice develop an autoimmune disease resembling human systemic lupus erythematosous (SLE), characterized by auto-antibodies production and end organ disease. In addition Ipr mice are deficient in Fas, a gene that regulates apoptosis, and develop therefore Iymphoproliferation and early manifestations of SLE, while MRLMpg++ mice are Fas intact and develop SLE disease only at a later age. Interleukin-G (IL-G), a pleiotropic cytokine, has been involved in the pathogenesis of SLE but also of diseases associated with an increase in bone resorption. To address the possibility that IL-G plays a role in the SLE disease, we have intercrossed Ipr mice with C57BI/G mice deficient in the IL-G gene. We studied immunoglobulins and autoantibodies production, kidney and lymphoid organ disease but we also examined bone histology and histomorphometry since patients with SLE have been reported to have a decrease in bone mass. First generation heterozygotes were bred to generate F2 IL-G intact (IL-G+/+) or IL-G deficient (IL-G-/-) Ipr and MRL++ animals. At G month of age, the levels of total IgG and IgA, antiDNA and other auto-antibodies were markedly decreased in the sera of IL-G-/-Ipr mice compared to IL-G+/+lpr mice, on the contrary no auto-antibodies were detected in the sera of both MRL++ groups. Interestingly, IL-G+/+lpr mice had a marked decrease in trabecular bone volume, osteoid volume and osteoid surface compared to IL-G+/+MRL++ mice. This could be due to the lupus disease itself that was virtually absent in the MRL++ mice groups or to the direct effect of fas in bone metabolism. The decrease in osteoid surface and osteoid volume was partially corrected but bone trabecular volume was totally corrected in the IL-G-/-Ipr group compared to the IL-G+/+lpr group. An increase in osteoblast surface and numbers was observed in IL-G-/-Ipr mice while no significant difference could be observed in osteoclast surface. In conclusion, Ipr mice have a marked decrease in bone turnover and bone volume compared to MRL++ mice, an effect that is at least partially IL-6-dependent.

25. SAFETY AND EFFICACY OF FLUTICASONE AND BECLOMETHASONE IN MODERATE TO SEVERE ASTHMA RA Pauwels, JC Yernault, MG Demedts, P Geusens. University Hospital, University of Ghent; University Hospital, ULB Free University of Brussels; University Hospital, Catholic University of Leuven; and Dr. Willems-Institute LUC-Diepenbeek, Belgium There are still some concerns about the safety of high doses of inhaled glucocorticosteroids (ICS). We compared the safety and efficacy of fluticasone propionate (FP) and beclomethasone dipropionate (BDP) in 306 patients with moderate to severe asthma in a double-blind, multicenter, cross-over study of 12 mo duration. During the t-rno run-in period, bronchodilators were replaced by salmeterol 50 I-Ig twice daily, increasing morning peak expiratory flow rate (PEFR) by 28 Llmin (p < 0.001) and FEV1 by 6.2% predicted (p < 0.001). At randomization the current ICS was replaced by 500 I-Ig BDP or 250 I-Ig FP in accordance with previously taken 500 I-Ig BDP or 400 I-Ig budesonide (BUD). No significant differences between the two treatments regarding morning plasma cortisol, urinary excretion of calcium and hydroxyproline, FEV1,and PEFR were observed at any time point during the study. Osteocalcin and bone mineral density (BMD) were improved over baseline in the FP group, result ing in higher serum osteocalcin levels (mean difference 0.28 ng/ml; p < 0.001) and higher BMD in the spine (1.0%; p

Ab stracts

436 = 0.05), femoral neck (1.6; p < 0.01), and Ward's triangle (3.6%; p = 0.01) as compared with BDP. We conclude that chronic treatment with FP, at half the dose of BDP, results in a similar antiasthma effect but a more favorable safety profile with respect to bone metabolism and mineral density. Published in: Am. J. Respir. Crit. Care Med., 1998,157:827-832.

26. VELOCITY OF ULTRASOUND AT THE MID-TIBIA IN ELDERLY MALES S Goemaere, B Vanneuville, K Toye, M Daems, R De Muynck, H Myny, J Van den Saffele, JM Kaufman. Unit for Osteoporosis and Metabolic Bone Disease, Dept. of Rheumatology and Endocrinology, Univ. Hospital Ghent, Belgium Relative hypoandrogenism is not uncommon in elderly men. Androgens may playa specific role in the metabolism of cortical bone . In the present cross-sectional study we assessed velocity of ultrasound at the mid-tibia by soundscan 2000 (Myriad Ultrasound Systems ltd) in 286 community dwelling elderly men (7Q-85y) and in 137 controls (22-58y). Fasting blood and second void urine were obtained; BMD was assessed by DXA (Hologic QDR1000+). Subjects with diseases interfering with bone metabolism were excluded. Mean :!:SD

n

age (y)

tUV m/s

Hip g/cm2

Rad1/3 g/cm2

FreeT ng%

crsst,"

Elderly

28 6 13 7

75.9 :!: 4.2 34.6 :!: 9.0

3943 :!: 109 4020 :!: 87 -0.70

0.907 :!: .145 1.047 :!: .125 -0.96

0.701 :!: .080 0.759 :!: .055 -0.72

8.2 :!: 2.2 14.1 :!: 3.5 -2.68

2.45 :!:0.24 2.52 :!: 0.16 -0.29

Controls Ditta in SO a b

difference between elderly men and controls log transformation for urinary Orosslaps" (J.Ig/mmol creatinine)

In the control group tUV is correlated only with hip BMD (r=0.21*). In elderly males tUV is correlated with age (r=-0.23***), height (r=0.20***), weight (r=0.19**), hip BMD (r=0.33***), radius BMD (r=0.47***), free testosteron (r=0.15**), estradiol (r=0.16**), creatinine-normalized excretion of Orosslaps" (r=-0.24***) and desoxypiridinoline (r=-0.15*), and serum osteocalcin (r=-0.28**), but not with serum bone specific alkaline phosphatase, PTH or 25-0Hvit D. Significant determinators in a stepwise multiple regression were radius BMD, age and log Crosslaps (adj R2 : 0.24). Simple regression shows a decrease of 5.9 mis/year and 105 m/sec/ 10g(CrosslapsR) and an increase of 0.61 m/s/gr/cm2 (BMD Rad). In this study tUV is decreased in elderly men and negatively related to markers of bone turnover; sex-steroid levels are not independent determinators. The findings for tUV in elderly men are similar to those for BMD at cortical sites . Remark: * p=.05 ; ** p=.001 ; *** p=.0001

27. INDICES OF BONE TURNOVER IN ELDERLY MEN S Goemaere, B Vanneuville, K Toye, M Daems, R Demuynck, H Myny, J Van den Saffele, JM Kaufman. Osteoporosis and Metabolic Bone Disease Unit, Dept. of Rheumatology & Endocrinology, Univ Hospital Ghent, Belgium Data on biochemical markers of bone turnover in elderly men are scarce. In the present cross-sectional study we assessed markers of bone turnover in community dwelling elderly men (70-85y;n=286) and younger controls (22-58y;n=137). Subjects with diseases or medications known to interfere with the bone

metabolism were excluded. A fasting blood sample and fasting second void urine was obtained before 10 a.m. Bone formation was assessed by serum osteocalcin (OC) and bone-specific alkaline phosphatase (BsAP) ; bone resorption was evaluated by urinary calcium (Cau ) , desoxypyridinoline (DPC) and ELISA Crosslaps" normalized for urinary creatinine. Log transformation of the data was performed. Bone mineral density (BMD) was assessed by DXA (Hologic QDR1000+). In younger controls, age was the only parameter that correlated with BsAP, OC and CrssL (r=-0.32,-0 .54,-0.28***, respectively). In the elderly, correlation amongst and between serum markers and urinary markers was highly significant (r= 0.32 to 0.61***), except for only weak correlations with Cau • Oa, was related with serum creatinine (r= -0.41 ***) and PTH (r=-0.18**). BsAP was correlated with serum creatinine (r = -0.12*) and PTH (r=0.12*). OC was correlated with age (r= -025***) and free testosteron (r = -0.13*). CrssL was correlated with age (r=-O.17***), E2 (r=-0.15**) and serum creatinine (r=-0.28***). DPD was correlated with 250-0H vit D (r=-0.17***), creatinine (r=-0.31***) and IGF-BP3 (r=0.19***). In multiple regression models only weak predictions of the bone turnover markers could be ach ieved (adj R2 values ranging from 0.07 to 0.16). In contrast to younger males, in whom BMD was not correlated with indices of turnover, a significant negative correlation between markers of bone turnover and BMD was observed for elderly men (r ranging from -0.15** to 0.30***). In conclusion, in men markers of bone turnover are correlated with serum creatinine and it might be useful to adjust data for this parameter. Markers of bone turnover are negatively correlated to BMD in the elderly but not in younger men. Remark: * p=0.05 ; ** p=0.001 ; *** p=0.0001

28. HYPOPHOSPHATEMIC RICKETS AND VIT D DEFICIENCY IN AN ADULT MAN E Krulthof", A Stuer", S Goemaere\ H Mielants\ EM Veys l . of Rheumatology, Univ. Hosp . Ghent

1 Department

A 50 year old man presented with inc reasing pain since several weeks at the left thigh. As a child , he had been diagnosed as having rickets and was treated with a vit D preparation. At that time tibial and femoral osteotomies to straighten his legs were performed. At present physical examination we noted a man of short stature (1 m55) with femora vara and severe pain on the left midfemur at palpation. Laboratory findings included an elevated alk. phosphatase to 143 U/L, a normal serum Ca, hypophosphatemia (1.99 mg%), a decreased level of 1,25(OH) vit D3 (30 pg/mL) and a slightly elevated PTH (82.6 pg/mL). Renal tubular reabsorption of phosphate was decreased to 77%; calciuria was decreased to 24 mg/24h. Renal function tests and amino acid excretion were normal. A global elevated MDP-uptake was found on 99Tc bone scintigraphy with a hot spot at the left midfemur. Xrays showed, apart from bowing and Looser's zones, a pseudarthrosis at the osteotomy site of the left femur. Familial history revealed short stature in his sister and 2 brothers, as well as in his 3 daughters; the latter were treated for hypophosphatemic rickets. The diagnosis of untreated X-linked hypophosphatemic rickets (XLHR) responsible for present osteomalacia and the pathological fracture was withheld. Our pat ient revealed also a decreased 25(OH) vit D3 with an elevated PTH probably due to concomitant mild vit D deficiency. Therapy was initiated with calcitriol 0.5J.1g daily and a 1 g daily phosphate solution. Furthermore orthopedic surgery consisting of emplacement of a Marchetti-nailing was performed with subsidence of the pain. After 2 months of treatment, the biochemical parameters were normalised. Conclusion: we report a patient with XLHR, untreated in adult life, with concomitant vit D deficiency and a pathological fracture.

A bstracts

437

29. VITAMIN D AND DIETARY CALCIUM STATUS IN PATIENTS LIVING IN NURSING HOMES COMPARED TO AMBULATORY PATIENTS JP Devogelaer, TC Le Thi, D Dienst, G Depresseux. Department of Rheumatology, St-Luc University Hospital, Brussels, Belgium Hypovitaminosis D is nowadays considered as a main determinant for hip fracture in elderly people living in nursing homes. The vitamin D status of ambulatory patients is comparatively less well known. We have therefore compared the values of serum 250H vitamin D and of hip BMD's in 122 females living in nursing homes with those of 102 fully ambulatory females from the outpatient clinic. The results (mean ± SEM) are given in the table.

n= Age (years) 250HD (nmol/I) % of values < 18 nmol/I S. creat (mmol/I) Tot. alk. p'se (UlI) Fern. neck BMD (g/cm~ Dietary calcium (mg)

Nursing home patients

Outpatients clinic patients

p

122 83.1 ± 0.6 23.7±1.4

102 74.8 ± 0.6 40.3 ± 2.5

< 0.0001 < 0.0001

45 100.4 ± 3.2 216.1 ± 6.2 0.513 ± 0.007

16 88.2 ± 1.4 182.8 ± 5.8 0.543 ± 0.009

0.0010 0.0001 0.011

392.9 ± 16.6

643.4 ± 31.9

< 0.0001

There was a positive correlation between 250HD and femoral neck BMDs in ambulatory patients only, with a r amounting to 0.254 (p < 0.033). In conclusion, a low calcium diet and hypovitaminosis Dare extremely common in patients living in nursing homes, with a proportion of patients with very low values of 250HD amounting to 45% . In ambulatory patients, up to 16% of patients also have very low values, although the calcium diet is more elevated, but still deficient. There was a positive correlation between 250HD and femoral neck BMD only, in the ambulatory patients. Physiologic vitamin D supplementation should be considered in elderly patients in Belgium.

30. PHOSPHATE DIABETES (AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS/OSTEOMALACIA; ADHR/O). A CASE REPORT B Coopman, L Goethals. Department of Physical Medecine and Rheumatology, A.Z. Stuivenberg Renal phosphate wasting disorders are a form of heriditary rickets and osteomalacia. Autosomal dominant transmission of phosphate wasting has been described. The best known form however is the XLHRlO. The literature states that phosphate diabetes is present when phosphate reabsorption is deficient resulting in an increased phosphaturia. A 34 year old man presented with bilateral knee pain, proximal muscle weakness, bone pain and a spontaneous fracture of the left ulna (after minor trauma). Biology showed an increased serum alkaline phosphatase and PTH. The values of serum phosphate, 25(OH)Vit D and 1,25(OH)2 Vit D were decreased. After correction, by substitution, of the serum values of 25 (OH) Vit D, serum PTH became normal but serum levels of 1,25(OH)2 Vit D and phosphate remained abnormally low. Calculation of Tmp/GFR showed decreased values, conformable to a phosphate leak. BMD (DEXA) was performed and showed mild osteoporosis of the spine and marked osteoporosis of the hip. Bone biopsy confirmed the diagnosis of osteomalacia. Family history showed that the patient's father was diagnosed with phosphate diabetes. After exclusion of a mesenchymal tumour the diagnosis of ADHR/ o was made.

Treatment with oral phosphate-, calcium supplements and calcitriol was started. Therapy resulted in clinical recovery, normalisation of serum PTH, phosphatemia and calcitriol. Control BMD showed an improvement in patient's osteoporotic status.

31. MYOPATHY AND ELEVATION OF MUSCULAR ENZYMES, SECONDARY TO HYPOPARATHYROIDISM CM De Gendt, JF Van Offel, LS De Clerck, WJ Stevens. Department of Immunology, Allergology and Rheumatology, University Hospital Antwerpen A 36 year old woman with a history of osteoarthritis, consulted with extreme fatigue, myalgias and muscle weakness since one year. Clinical examination revealed a normotensive, obese (170 ern, 103 kg) female, diminished muscle strength without atrophy and symmetrical reflexes. Chvostek's sign was negative and Trousseau's sign positive. Laboratory results showed an ESR of 60 mm/h, normal renal function, calcium 5.1 mg/dL (8.8-10.2), ionised calcium 0.65 mmol/L (1.17-1.30), phosphate 4.6 mg/dL (2.6-4.6), s-magnesium 1.5 mg/dL (1.6-2.6), albumin 5.0 mg/dL (3.5-5.1) , creatine kinase 189 UlL (10-50) , lactate dehydrogenase 264 UlL (120-220). Calciuria was low (25 mgld) , intact PTH 20 pg/mL (20-75), 25OH-vit D3 34 nmol/L (25-75), 1,25-di(OH)-vit D 56 pg/mL (3Q-80). Electromyography showed no signs of myositis. A d iagnosis of hypoparathyroidism was made. The increase of creatine kinase and lactate dehydrogenase was attributed to a secondary myopathy. Treatment with 1000 mg calcium and cholecalciferol 25000 lEI 14 days was started without any effect, but alfacalcidol 2 x 1 !!g/ d induced normalisation of calcium levels with disappearance of myalgias and normalisation of CPK. Symptoms recurred after lowering the dose of alfacalcidol. Conclusion: In patients with myalgias, signs of myositis and hypocalcemia, hypoparathyroidism should be excluded. Therapy with alfacalcidol and calcium can induce remission .

32.

BRUCELLAR OSTEOMYELITIS

L Schatteman*, D Verresen **, L De Clercq*, H Mielants*. *Dept of Rheumatology, **Dept of Pneumology, St. Augustinus-St. Camillus Hospital, Antwerpen, Belgium A 35 year old lady was hospitalized for spiking fever (40°C), fatigue, myalgia, arthralgia, muscle weakness and night sweats. A few days later she complained of inflammatory pain at the knees without synovitis but tenderness and warmth at the distal femur epiphysis of both knees, and proximal tibia epiphysis at the right sight. She presented with high inflammatory parameters and a normochromic normocytotic anaemia. All cultures remained negative. Technetium bone scan as well as HIG-bone scan revealed hot spots in both distal femur metaphyses and the proximal tibia metaphysis. On MRI of the right knee a sign ificant increase of the signal was found at the same places suggesting int ramed ullar inflammation. All viral and bacterial ant ibodies were negative, except for the WRIGHT-test who raised from 1/160 to 1/ 640. Patient told to have consumed non-sterilized goat's cheese from a local farmer in Spain 6 weeks earlier. Patient was treated with Doxycycline 2 x 200 mg per day and Rifampycine 15 mg per day during 3 months; all symptoms disappeared and biology, bone scans and MRI normalized. Multiple osteomyelitis is a rare but known complication of brucellosis.

438 33. SEA-BLUE HISTIOCYTOSIS IN AN ADULT PATIENT, PRESENING WITH MULTIPLE VERTEBRAL FRACTURES P Voiders, V Taelman, R Westhovens, FP Luyten. Department of Rheumatology, University Hospitals KU Leuven A 55-year-old lady with a history of Morbus Parkinson since 3 years, was referred to our department with recent onset of severe backpain, hyperkyphosis and dyspnoea. She was only since 2 years in menopause. An X-ray of the dorsolumbar spine showed multiple vertebral fractures (Ds-Dg-D,rL2-L3-4-Ls). A chest X-ray was suggestive for interstitial lung disease. We also noted an enlarged spleen with moderate thrombopenia. Bone densitometry did not reveal osteopenia / osteoporosis. Calcium , phosphor and alkaline phosphatase in serum and 25-hydroxyproline in urine were normal. Interestingly, there was a very low level of high density lipoprotein cholesterol. A bone marrow aspirate showed abundance of histiocytes loaded with undigested lipid material referred to as sea blue histiocytosis. Electron microscopic evaluation of a bone biopsy was suggestive for a lipid storage disorder, type Niemann-Pick. Patient developed severe respiratory insufficiency, requiring temporary artificial ventilation. Differential diagnosis, therapy and further follow-up of this rare case will be discussed.

34. DISTRACTION OSTEOGENESIS IN TREATMENT OF PAGET DISEASE DEFORMITIES: A CASE REPORT P Voiders, V Taelman , R Westhovens, J Dequeker. Department of Rheumatology, University Hospitals Leuven A 76-year-old woman is followed at our department since 1975 for a polyostotic Paget's disease with localisation in the skull, dens, right pelvis, both femo ra and left tibia. Despite treatment with calcitonin and different bisphosphonates, markers of disease activity remain elevated. In 1991, she experienced a pathological, mid-diaphyseal fracture of the left femur on a pre-existing varus deformity. The fracture was stabilised with an IIizarov frame and varus was corrected. During rehabilitation she complained of debilitating pain in the left tibia which showed a severe varus and antecurvatum deformity. Correction was achieved by a closing wedge osteotomy at the apex of the deformity and fibulotomy. Again an llizarov frame was applied which could be removed after 111 days. Pain control and knee function remain well until now. IIizarov distraction osteogenesis seems to be an additional treatment option for severe deformities in Paget's disease.

35. MEDICAL IMAGING IN A CASE OF DIFFUSE SKELETAL CYSTIC ANGIOMATOSIS LA Verbruggen, M Shahabpour. Rheumatology Unit and Radiology Department, Academical Hospital VUB, Brussels, Belgium A case of diffuse cystic angiomatosis is described in a 30 year old female patient, presenting with pain in the cervical, upper dorsal and lumbar spine , as well as in the shoulders and knees. Routine hematology and biochemistry were normal. No evidence of visceral involvement was found. Radiographs and magnetic resonance imaging showed multiple cyst ic lesions in the spine and pelvis, right humerus and distal radius , both proximal and distal femora and the proximal tibiae. Typical lesions included round or ovoid osteolytic or cystic lesions of different sizes, often with sharply defined, sclerotic margins, or else confluent with decreased central trabeculations. Bone densitometry using dual energy X-ray absorptiometry showed normal values in the lumbar spine and hip, apparently unaffected by the presence of cyst ic lesions .

Abstracts Skeletal scintigraphy showed several hyperactive areas, including the humeral heads and right proximal humerus, the left great trochanter and the bone tissue around the knees. These images may help distinguish between quiescent and metabolically active cysts.

3. SPONDYLOARTHRITIS 36.

MEDICAL IMAGING OF THE SACRO-ILlAC JOINTS

B Vande Berg, J Malghem, B Maldague. UCL, St Luc, Brussels Radiological assessment of the sacro-i1iac joints (SIJ) has always been a challenge because of the complex anatomy of the joint, the high frequency of subchondral bone changes in the normal population and the poor specificity of the changes observed in inflammatory disorders. Radiographs remain the cornerstone in medical imaging of the SIJ, but it is obv ious that CT and magnetic resonance imaging (MRI) also contribute occasionnally. The radiographic image of the SIJ is complex. Because of the obliquity of the SIJ in the transverse plane, the articular portion of the SIJ projects laterally and inferiorly whereas its large fibrous portion projects medially and superiorly on anteroposterior radiographs. Variations in orientation of the articular plane in transverse and sagittal planes can cause great variability in the radiographic appearance of the SIJ. Elementary lesions observed in inflammatory disorders include subchondral bone erosion or sclerosis, bone marrow edema and joint effusion. Their detection varies according to the imaging techniques. Subchondral bone erosions, depicted on conventional radiographs and best visualized on CT images are generally fuzzy and lead to enlargement of the articular space due to resorption of the subchondral bone plate. Bone sclerosis, also better detected on CT than on radiograph ic images is generally ill-delimited and extends far from the articular limit, reaching frequently the fibrous part of the SIJ. Marrow infiltration (probably by fibrovascular t issue and interstitial edema) is exclusively detected on MR images and frequently indicates active disorder. It is replaced by fatty marrow when the disorder becomes more quiescent. Joint effusion is not visible on radiographs and is best depicted on MR images. It is generally very limited. None of these changes is specific because they can also be encountered in degenerative disease of the SIJ. One additional point, the distribution of the lesions, warrants to be remembered to help in making, if possible, the distinction between both conditions. Inflammatory lesions involve any area of the joint whereas degenerative or mechanical lesions involve almost exclusively the anterior and lateral third of the SIJ. In other words, involvement of the inferior and medial aspect of the SIJ is almost pathognomonic for an inflammatory disorder. Qualitative changes can also help differentiate inflammatory from degenerative lesions . Inflammatory changes Elementary Erosions : fuzzy and lesions deep Bone sclerosis: extensive and ill-delimited No osteophytosis Prominent marrow infiltration Distribution Any area Generally asymmetric* at early stage Frequently bilateral* Slow Evolution * in early stages

Degenerative changes Erosion: well delimited and superficial Bone sclerosis: compact and welldelimited Variable osteophytosis Discrete marrow infiltration Lateral and anterior third Symmetric Frequently bilateral Extremely slow

Abstracts Practical issues Cases in which radiographs show 51J changes of uncertain origin can be tentatively solved by following the next costeffective guide-lines: 1. Is there any previous film available? A previous film totally normal would suggest progressive changes and thus an inflammatory disorder. If the abnormality is unchanged, the lesion can be either degenerative or inflammatory but quiescent. 2. How is the pubic joint on the available pelvis film? In case of degenerative disease of SIJ, the pubic joint can show mechanical abnormality. In case of inflammatory diseases of the SIJ, the pubic joint can also be abnormal and show changes more suggestive of inflammatory lesion. Severe mechanical changes of the SIJ are generally associated with mechanical pubic changes. Severe SIJ changes without pubic lesions are more frequently of inflammatory origin. 3. How is the thoracolumbar spine junction? Look for syndesmophytes and erosions which are frequent at the begining of the inflammatory disorders. 4. What about obtaining follow-up conventional radiographs? In active disorders, changes do occur in several months (612 months).

37. TRIALS AND TRIBULATIONS OF THE HUMAN SACROILIAC JOINTS DL Gardner, G McLauchlan. Department of Pathology, University of Edinburgh, UK Throughout the vertebrate kingdom, the anatomy of the synovial sacroiliac (51) articulations is surprisingly constant. The joints transmit the weight of the upper body to the lower limbs and protect the central nervous system from impact loads. However, detailed understanding of the relationships between the complex structure of the 51 joints and their functions is incomplete. Methods. To extend understanding of human 51 joints, we dissected the pelves of 36 patients dying in hospital. From 24 cases, the surfaces of the opened left joints were inspected before surveys made by scanning electron microscopy. The right joints were divided into horizontal blocks from which semiserial sections were stained to demonstrate morphology, proteoglycan, fibrous collagens, fibrin and amyloid. Other tissue was prepared for transmission electron microscopy. The Zeiss Highly Optimised Microscope Environment (HOME) system was used to make measurements across the entire width of all sections, recording sacral and iliac cartilage thickness and subchondral bone end plate thickness. Chondrocyte numbers were assessed by point counting. Results. The thin sacral bone end plate underlay thick hyaline articular cartilage of low cellularity but rich in proteoglycan and with a well defined superficial surface lamina of fibrous collagen. The iliac bones displayed a denser, trabecular texture: a relatively thick end plate supported thin articular cartilage in which islands of chondrocytes were circumscribed by concentric condensations of fibrous collagen. The anterior spinal ligaments frequently displayed deposits of amyloid and the inter -chondral joint space often contained free fibrin (17/24). Sacral cartilage was thicker than iliac (p<0.001; 16 cases, 783 observations) but the sacral bone end plate was thinner than iliac (p=0.008; 12 cases, 608 observations). There was no demonstrable relationship between age or sex and sacral or iliac cartilage thickness, sacral/iliac cartilage thickness ratios, sacral or iliac subchondral bone end plate thickness or sacral/iliac bone thickness ratios. The number of cells per unit volume of sacral cartilage was approximately half that of the iliac cartilage. When a 'correction' was made for cartilage thickness, each sacral cell appeared to oppose a single iliac cell . Conclusions. The two parts of the iIio-sacral articulations have widely different forms. The thin bone trabeculae, thick hyaline

439 cartilage and sparse chondrocytes of the sacral component contrast with the dense bone, thin cartilage and high cellularity of the iliac moiety. In the erect posture, the wedge-shaped sacrum rests upon but also hangs from the adjacent iliac bones. Thus, the chondrocytes of the thick hyaline sacral cartilage may respond optimally to compressive stress whereas the cells of the quite different iliac cartilages recognise tensile and shear stresses, disintegrating as age advances and initiating joint fusion.

38. DYNAMIC MAGNETIC RESONANCE IMAGING OF THE SACROILIAC JOINT J Braun, *M Bollow, J Sieper. Dept. of Nephrology & Rheumatology, Free University, *Dept. of Radiology, Humboldt University and DRFZ, Berlin, Germany Inflammation of one or both sacroiliac joints is characteristic for spondylarthropathies (SpA) often leading to typical low back pain at night and at rest with improvement after exercise, described by the term inflammatory back pain (IBP). 5acroiliitis (51) comes in varying intensity with some patients remaining asymptomatic. IBP and asymmetric peripheral arthritis of the lower limbs are the main clinical symptoms and criteria for the classification and diagnosis of SpA. 51 is pathognomonic for ankylosing spondylitis (AS), especially in early disease. In other SpA acute and chronic 51 occur in 10-40%. In a 20-year-followup of 150 ReA patients 29 HLA B27-positive patients developed sacroiliitis and 23 AS. In undifferentiated SpA (uSpA) 51 occurs in 60-70%, 1/3 can proceed to AS after a mean of 9 years. In juvenile SpA, 51 and IBP are not the initial features, but rather entheropathy and tarditis, wh ile spinal symptoms occur only in 12%. AS may develop after a mean of 7 years . In a recent study we found a higher init ial frequency of 51: 130 HLA B27-typed children with juvenile chronic arthritis were examined by dynamic magnetic resonance imaging (dMRI) to screen for 51. In the subgroup with a clinical diagnosis of juvenile SpA 50% of the children (mean age 11 years) had evidence of 51 as detected by MRI; half of these reported symptomatic back pain. Objective evidence of an advanced radiological degree of 51 is cr itical for the diagnosis of AS and important for the differentiation between AS and uSpA. In early and acute stages of 51 the diagnosis can be difficult because conventional imaging has limited capacity when no bony changes are yet present. In advanced disease ankylosis becomes the very characteristic feature of AS. This development can take years, but might also occur rapidly in about 20% of the patients with severe disease. Imaging of the sacroiliac joints has to consider their complicated anatomy. These S-shaped joint structures course obliquely from a lateral to a medial position, hereby causing substantial overlap of the ilium with the sacrum on standard anteroposterior projections of the pelvis in the supine position, which obscures the joint space. Posteroanterior projection techniques in the prone position with the tube angled 25-30 degrees partly counteract this problem. CT and MRI take advantage of their ability to 'cut' these joints into slices, in principle this prevents overlap of the structures. However, the anatomy of the sacroiliac joints with the superior part being ligamentous is important for the evaluation of axial imag ing, since the insertions of the ligaments cause irregularity and widening of the joint space and might also make interpretation of the subchondrium difficult. In this regard it is crucial to know that i1ial subchondral sclerosis of the iliac part of the sacroiliac joint is a natural ageing phenomenon similar as joint space narrowing and erosions. Thus, sclerosis and ankylosis can easily be overdiagnosed by CT. For the detection of early bone changes such as eros ions and ankylosis CT can be superior to MRI. MRI is better in the imaging of cartilage and by providing dynamic measurements.

Ab stracts

440 Our MRI approach of taking paraxial slices has recently been impress ively evaluated and confirmed by studying MR images of an autopsied sacroiliac joint. Standard sequences used nowadays are a T1 weighted turbo spin-echo and a T2*-weighted gradient-echo sequence. Some recent advantages in MRI technology are the use of optimal coils such as the body-array coil and the use of matrices with higher resolution. Furthermore, 'short tau inversion recovery' (STIR) sequences are increasingly used, since they provide better fat/water contrast effects by totally suppressing fat signals . STIR sequences are able to visualize inflammation similar, but, in our experience, not always, as good as dMRI using T1-weighted sequences after i.v. gadolinium-DTPA administration. Relying on our experience with > 300 sacroiliac joints now imaged by MRI and dMRI, we are confident to express the opinion that dMRI is the method of choice to detect early SI, especially in children and women. However, this skilful techn ique is too expensive to be used for mass screening . Thus, a thoughtful clinical indication is mandatory.

39. SOME PRACTICAL ASPECTS IN DIAGNOSING AND TREATING ANKYLOSING SPONDYLITIS RJ Francois. H6pital Militaire Reine Astr id, Brussels, Department of Rheumatology Clinique St-Pierre, Ott ignies , Belgium History taking in ankylosing spondylitis (AS). Calin proposed a set of five questions to differentiate inflammatory from mechanical back pain. In AS patients (many with long lasting disease) and orthopaedic patients with sciatica, he found 95% sensitivity and 76% specificity. This might not be true for early AS and common low-back pain (LBP) in young patients, as shown in the Brussels military hospital by D Franco is. Calin's questionnaire was answered by 63 AS patients and 214 LBP patients. Francois found less sensitivity (57%) and almost equal specificity (78%) as Calin. In another study in men <30 years old, 57 patients with normal CT scans of sacro-iliac joints were compared to 54 with definite sacroiliitis. A set of three questions (night pain, morning stiffness, gluteal pain) yielded a better diagnostic value with sensitivity 92%, specificity 75%. Spinal mobility. The value of measuring more than forward flexion and chest expansion (CE) was assessed in 100 AS patients. Ten cervical and dorsolumbar movements in different planes and CE were measured . Results are tabulated in table 1. All tests were normal in 20% of all patients, in a third of the more recent cases and still in 2 out of 30 late cases. Modified Schober's test and/or CE were normal in most recent cases and still in a quarter (8/30) of the later ones. Thirty-nine of the whole group have normal CE and lumbar flexion with some other abnormal measurement; this is especially true in the early stages (22/29). Disease duration

All tests normal

CE &lo r LF ani

CEILF nl, any other an! Any test ani

Total

1- 5 year 6- 10 yea r >10 yea r Total

15 3 2 20

7 12 22 41

22 11

6 39

44 26 30 100

29 23

26

60

Table 1. Results of spinal movement measurements in 100 AS patients according to disease duration. NI: normal. Ani: abnormal. CE: chest expansion. LF : lumbar flexion Treatment of progressive AS deceives both patient and physician. A subset of patients go on to total spinal ankylosis despite continuous use of NSAID. The value of sulfasalazine on axial involvement remains controversial. Systemic corticosteroids, disease modifying drugs as used in rheumatoid arthritis, and radiotherapy have not been properly assessed. X-rays seem to be useful in selected cases. Obviously, other drugs are needed. A rationale for trying bisphophonates might rest on the number of osteoclasts that are observed in some pathological specimens. But what might be the dangers of inhibiting only the 'reparative' ossification?

40.

ESR VS CRP IN ANKYLOSING SPONDYLITIS (AS)

A Spoorenberg1, D Van der Heijde1, E De Klerk1, M Douqados", K de Vlam2, H Mielants2, S Van der Linden'. 'University Hospital Maastricht, The Netherlands, 2University Hospital Gent, Belgium, 3Groupe Hospitalier Cochin, Paris, France Objective: To determine whether CRP or ESR is a more specific variable measuring disease activity (DA) in AS. Methods: We studied 191 out-patients with AS. To assess DA we used: physician and patient assessment of DA on a VAS and the BASDAI. In addition, both CRP and ESR were measured. The AS patients were divided into two groups: those with spinal involvement only (n=149) and those with peripheral arthritis and/ or inflammatory bowel disease (n=42). Results: The mean CRP and ESR were 16.1 mg/l and 12.7 mm/ h in the spinal group and 24.8 mg/l and 20.8 mm/h in the peripheral group. In both groups the Spearman correlations between CRP and ESR were similar (0.48, 0.50). There was poor correlation between CRP, ESR and the DA variables «0.34). Sensitivity for both ESR and CRP was >90% for DA physician and between 43.8 and 77.5 for DA patient and BASDAI, while specificity was between 44.4 and 84.4 for all DA measures. The positive predictive values of CRP and ESR were low (0.15 - 0.69) and the average misclassification between both CRP, ESR and DAwas 29%. Conclusion: In both spinal and peripheral AS, CRP and ESR are not very specific variables assessing DA and neither of these acute phase reactants seems to act superior.

41. THE BATH ANKYLOSING SPONDYLITIS FUNCTIONAL INDEX (BASFI) VERSUS THE DOUGADOS FUNCTIONAL INDEX (D-FI) A Spoorenberg', D Van der Heijde', E De Klerk', M Douqados'', K de Vlam2, H Mielants2, S Van der Linden'. 'University Hospital Maastricht, The Netherlands, 2University Hospital Gent, Belgium, 3Groupe Hospitalier Cochin, Paris, France Objective: Is BASFI or D-FI superior in AS? Methods: We studied 191 out-patients with AS. To measure disease act ivity (DA) we used: physician and patient assessment of DA on a VAS and the BASDAI. In addition, the BASFI (score: 0 10) and the D-FI (score: 0 - 40) were completed. Damage was assessed by 2 radiological scores of the spine; BASRI-s (Bath Ankylosing Spondylitis Radiology Index-spine) and a modified SASSS (Stoke Ankylosing Spondylitis Spine Score). Results: Mean scores for BASFI and D-FI were 3.2 (r.: 0-10) and 9.0 (r.: 0-35) resp . Spearman correlation between the two indexes was 0.88. The average correlation with disease activity variables was 0.52 for BASFI and 0.50 for D-FI. For both BASFI and D-FI the correlation with BASRI-s was 0.42 and with SASSS 0.36. Sensitivity for both indexes was between 75% and 95% while specificity was between 75% and 85% for all three DA measures. Misclassification between BASFI, D-FI and DA was 23% and 27°/~ resp. Conclusion: Both BASFI and D-FI perform equally in relation to disease activity and damage.

42. RADIOLOGICAL SCORING METHODS IN ANKYLOSING SPONDYLITIS K de Vlam', A Spoorenberq'', D Van der Heijde 2, E De Klerk 2, M

Douqados", H Mielants', S Van der Linderr', 'University Hospital Gent Belgium, 2University Hospital Maastricht, The Netherlands, 3Groupe Hospitalier Cochin, Paris, France Objective: To compare reliability and sensitivity to change of different AS radiological scoring methods. Methods: SI joints were scored in 5 grades using two different scoring methods. Cervical and lumbar were graded (0-4 BASRI)

Abstracts

441

and scored in detail (0-72 SASSS). Hips were graded Q-4 (Larsen). Thirty AS radiographs were scored twice with an interval of \4weeks by two observers. Further, 184 AS radiographs, baseline and after one year follow up, were scored in pairs to measure sensitivity to change. Results: Both methods scoring the SI joints showed moderate intra- and interobserver reliability (K 0.37 0.66). The Larsen score for the hips showed poor inter- and moderate intraobserver reliability (K 0.17 -0.58). The SASSS score showed good inter- and intraobserver reliability for the lumbar and cervical anterior site (ICC >0.91) and moderate for the posterior site (ICC 0.85). The BASRI spine showed moderate till good agreement (k 0.46 0.84). None of the scoring methods proved to be sensitive to change over one year based on the smallest detectable difference. Conclusion: Scoring methods for the spine and SI joints are reliable but insensitive to change over one year.

43. THE USE OF HIGSCAN IN DETECTION OF SPINAL INFLAMMATION IN ANKYLOSING SPONDYLITIS K de Vlam, C Van de Wiele, H Mielants, RA Dierickx, EM Veys. Department of Rheumatology and of Nuclear Medicine, University Hospital Gent, Belgium Objective: To determine the effectiveness of technetium-99m labelled polyclonal human immunoglobulin G (99mTc-lgG/HIGscan) scintigraphy to detect spinal inflammation in patients with ankylosing spondylitis. Methods: 6 Ankylosing spondylitis(AS) patients with inflammatory axial pain and 4 spinal osteoarthrosis (OA) patients with mechanical axial pain underwent a 99mTc-MDP bone scintigraphy with SPECT and a 99mTc-lgG scintigraphy with SPECT. Results: AS well in patients with spinal OA as in patients with AS, complaining of axial back pain, the bone scintigraphy revealed foci of markedly increased tracer accumulation in the vertebral bodies (VB) and in the zygapophyseal joints (ZA). A 99mTc-lgG scintigraphy of the region of increased uptake on bone scintigraphy could neither in patients with AS nor in patients with spinal osteoarthrosis reveal increased tracer accumulation (Table). SPECT AS VB ZA

bone 1 13

SPINAL OA HIG

o o

bone

o 4

HIG

o o

Conclusion: The data suggest that 99mTc-lgG scintigraphy is not useful in detecting inflammatory spinal lesions in AS.

44. REPRODUCIBILITY OF A NEWLY DEVELOPED SCORING METHOD FOR ZYGAPOPHYSEAL JOINT INVOLVEMENT IN ANKYLOSING SPONDYLITIS K de Vlam, H Mielants, EM Veys. Department of Rheumatology, University Hospital Gent, Belgium Objective: To assess the reproducibility of a newly developed scoring method for zygapophyseal joint (ZA) involvement in AS. Methods Oblique roentgenograms of the lumbar spine and lateral roentgenograms of the cervical spine of 20 AS patients assessed for interreader agreement for zygapophyseal joint involvement using a newly developed scoring method. The intrareader and interreader reliability was assessed for the "level score" of the ZA joints as well as for the dichotomous variables (presence and absence of ZA ankylosis) at each level.

Results: levelscore agreem Intra 1 C-ZA L-ZA Intra 2 C-ZA L-ZA Inter C-ZA L-ZA

% 80 47 % 75 74 % 80 66

dichotomous var Kappa

agreem

Kappa

0.55 0.19

88 91

0 0.42

0.61 0.5

92 93

0.84 0.75

0.66 0.52

97 95

0.93 0.88

Conclusion: The intrareader and interreader reliability is poor to excellent for the dichotomous variables but is fair to poor for the levelscores in both the ZA joints. Considerable disagreement occurs in the levelscores when minor abnormalities are present.

45. INVOLVEMENT OF THE ZVGAPOPHYSEAL JOINT IN ANKYLOSING SPONDYLITIS: RELATION TO THE BRIDGING SYNDESMOPHYTE K de Vlam, H Mielants, EM Veys. Department of Rheumatology, University Hospital Gent, Belgium Objective: To determine the prevalence of zygapophyseal joint (ZA) ankylosis in ankylosing spondylitis (AS) and the relation of this ankylosis to the presence of bridging syndesmophytes). Methods: X-rays of the cervical and lumbar spine of 50 ankylosing spondylitis patients were scored by a vertebral body score according to Taylor and a newly developed score for ZA joint involvement. Results: At the cervical level 22% of the ZA joints were ankylosed and 12% of the levels presented bridging syndesmophytes. At the lumbar level 22% of the ZA joints were ankylosed and 16% of the vertebral levels showed ankylosis in both ZA joints. Bridging syndesmophytes were present in 11% of the vertebral levels. Simultaneous presence of ankylosis of the ZA joints and bridging syndesmophytes is shown in 14% of the cervical levels and in 9% of all lumbar levels. Moreover ankylosis of the ZA joint is present in 8% of the cervical levels without bridging syndesmophytes and in 21% lumbar levels without presence of bridging syndesmophytes. The presence of bridging syndesmophytes at a given level without ankylosis of the respective ZA joint was rare: 4 of 201 lumbar levels and 4 of 238 cervical levels. Ankylosis of the ZA joint and presence of bridging syndesmophytes at the same levels is markedly associated in AS but seems to be asymmetric. Conclusion: The ZA joint is affected in a major way in ankylosing spondylitis. The involvement of the ZA joint and the presence of syndesmophytes is related. An asymmetric relation suggests that the ZA joint is primarily involved in ankylosing spondylitis.

46. PREVALENCE OF CLINICAL AND SUBCLINICAL SPONDYLOARTHROPATHY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE K de Vlam, M De Vos, K Vandekerckhove, H Mielants, E Cesmeli, F De Keyser, C Cuvelier, E Veys. Depts of Rheumatology, Gastroenterology and Pathology, University Hospital Ghent, Belgium Data about the prevalence of spondyloarthropathy (SpA) and subclinical sacroiliitis in IBD are scarce and disparate. Study design: We performed a prospective study including 75 consecutive patients (CD/UC=58/17) consulting at GI unit. Forty seven patients (62%) had a history of IBD longer than 5 years. Clinical evaluation was performed by a rheumatologist. Radiology

Abstracts

442 assessment included an anteroposterior view of the sacroiliac joints. Results: Clinical diagnosis of SpA, including inflammatory low back pain and/or peripheral synovitis was found in 21 patients (28%) (ESSG-criteria). Uni- or bilateral sacroiliitis ;;:, stage 2 was present in 26 patients (34%). In 10 patients (13%) uni- or bilateral sacroiliitis ;;:, stage 2 was the only articular manifestation. Schoberindex was abnormal in 27% patients ( 36%). Diagnosis of ankylosing spondylitis (AS) was found in 6 patients (8%). Enthesitis was found as a unique manifestation in 6 patients. Globally, clinical articular involvement was found in 27 patients (36%). Articular involvement, both clinical and asymptomatic, was found in 37 patients (49%). No differences in prevalence were found between patients according the duration of bowel disease. In11.

Ent hesiti s

back pain

Synoviti s clinical

SpA

Sacroiliitis 3 stage 2

AS

17

8

7

21

(11%)

(9%)

(28%)

26 (34%)

CD

19%

12 %

22%

34%

7%

UC

35%

6%

7% 18 %

47%

35%

12%

N

(23%)

6 (8%)

cun art invol v

27 (36%)

propria lymphocytes (LPL), while ex E ~7 is preferentially restricted to intra-epithelial lymphocytes (IEL). Aim: To invest igate the co-expression of ex4 ~7 and ex E ~7 on lymphocytes isolated from colon biopsies. Methods: Colon biopsies from 12 patients with a normal colonoscopy were obtained for the mechanical isolation of LPL and IEL, and subsequently characterized by f1owcytometry for ex4~7 and ex E ~7 integrins. Results are expressed as median with range on CD3 positive cells. Results: LPL ~7 positive lymphocytes are mainly double positive for exE and ex4. In IEL, ~7 positive lymphocytes are almost exclusively exE ~7 single positive. A small fraction is exE and ex4 double positive.

LPL IEL

47 (38-63) 0.3 (0-1)

3 (1-7) 70 (32-84)

19 (12-34) 8 (1-39)

31 (16-41) 19 (16-34)

31% 53%

Conclusions: Articular involvement is a much more common extra-intestinal manifestation of IBD than generally believed. In 28% of the patients the diagnosis of SpA is made. In 13% of the patients sacroiliitis is the unique articular manifestation. Longterm follow-up is necessary to evaluate the clinical significance of these findings.

47. DOWNREGULATION OF CD30 ON GUT LYMPHOCYTES IN CROHN'S DISEASE SUGGESTS A TH1 PATIERN D Baeten , N Van Damme, D Elewaut, E Cesmeli, P De Metter, C Cuvelier, H Mielants, G Verbruggen, F De Keyser, M De Vos, EM Veys. Dept. of Rheumatology, Gastroenterology and Pathology, University Hospital Ghent, De Pintelaan 185, 9000 Gent, Belgium Aim: Various reports indicate that CD30 on T lymphocytes is associated with a Th2 phenotype. As Crohn's disease (CD) is believed to be a Th1 mediated pathology and some patients with spondyloarthropathy (SpA) develop microscopic and macroscopic gut lesions, we invest igated if lymphocytes in both pathologies showed identical cytokine patterns. Normals (NO) and ulcerative colitis (UC) were used as control groups. Methods: Using IL2 cell lines were generated by 3 week culture from colon (NO=23; SpA=21; UC=24; CD=23) and ileum (NO=15; SpA=10; UC=5; CD=4) biopsies obtained during i1eocolonoscopy . Flowcytometric analysis of CD30 expression was performed on CD3, CD4 and CD8 subsets. Results: In colon CD30 is clearly reduced on CD3 lymphocytes in CD compared to normals (p=0.0071), SpA p=0.005) and UC p=0.041). Similar differences are observed in CD4 and, even more impressive, in CD8 subsets. Despite the low number of cell lines, in ileum CD30 is also significantly reduced on the CD8 subset in CD compared to normals (p<0.02) and UC (p<0.02), but this should be confirmed by additional data. Conclusion: CD30 expression is significantly reduced on T cell lines from colon and ileum in Crohn's disease compared to normals, spondyloarthropathies and ulcerative colitis. This suggests a Th1 like pattern of gut inflammation in CD.

48. CO-EXPRESSION OF ex4 ~7 AND ex E ~7 ON LAMINA PROPRIA AND INTRA-EPITHELIAL LYMPHOCYTES N Van Damme, M De Vos', E Cesmeli', D Baeten, P Dernetter, C Cuvelier , H Mielants, G Verbruggen, EM Veys, F De Keyser. Depts. of Rheumatology, Gastroenterology' and Pathology, University Hospital Ghent, Belgium Introduction: The ~7 integrins playa critical role in the homing of T-cells in the gut. ex4 ~7 is almost exclusively expressed on lamina

49. ISOLATION OF HUMAN COLONIC LAMINA PROPRIA AND INTRA-EPITHELIAL LYMPHOCYTES: MECHANICAL VERSUS ENZYMATIC ISOLATION N Van Damme, M De Vos 1, E Cesrneli', F De Keyser, D Elewaut, D

Baeten, P Demettef, C Cuvelief, H Mielants, G Verbruggen, EM Veys. Depts. of Rheumatology, Gastroenterology' and Pathology2, University Hospital Ghent, Belgium The isolation of IEL and LPL without alterations of phenotypical characteristics of the cell is difficult. Therefore, we wanted to develop a mechanical isolation technique and to investigate differences between enzymatical and mechanical isolation. Methods: 20 Patients with a normal colonoscopy wete considered for the enzymatical isolation; IEL were isolated with DnIEDTA and LPL with collagenase AlDNAse. 12 Patients with a normal colonoscopy were considered for the mechanical isolation. The colonic biopsies were collected in PBS + CaCI2 and squeezed out between two cover glasses to enrich for the LPL. The rest of the biopsies were stirred in Ca-free PBS to enrich for the IEL. We determined CD4/CD8, ex E ~7 , ex4 ~7 and CD20 by flowcytometry. Results: When comparing the mechanical versus the enzymatical extraction, we found a lower CD4/CD8 ratio, a significant increase for exE ~7 and very few B cells in IEL. A significant increase for CD20 and a preservation of ex4 ~7 was found in LPL. Conclusion: This technique enables the isolation of IEL and LPL, from the same biopsies, without using any enzymes. Moreover, this method prevents the artificial alterations of membrane marker expression as encountered in enzymatical extraction.

50. E-CADHERIN, ex-CATENIN AND y-CATENIN ARE UPREGULATED IN INTESTINAL CRYPTS FROM SPONDYLOARTHROPATHY PATIENTS WITH NON-INFLAMED BOWEL MUCOSA P Dernetter", D Baeterr', E Cesmeli", M De Vos 3 , N Van Darnrne", K de Vlam2 , H Mielants", G Verbruggen 2 , F De Keysef, EM Veys2 , C Cuvelier". Depts. of Pathology", Rheumatology2 and Gastroenterology 3, University Hospital Ghent, Belgium Introduction: Previously we demonstrated an upregulation of the E-cadherin/catenin complex in inflamed bowel mucosa. As 66% of spondyloarthropathy (SpA) patients develop subclinical inflammatory bowel disease, we wondered if they would express higher E-cadherin/catenin levels in still non -inflamed mucosa. Methods: Ileal and colonic biopsies from 10 SpA patients without bowel inflammation and from 7 controls were stained with monoclonal antibodies against E-cadherin, ~-catenin and

Abstracts y-catenin and a polyclonal antibody against cx-catenin. Crypt and superficial epithelium were scored separately on a 4 point scale, in ileum as well as in colon. Results: Statistically significant upregulation was found for E-cadherin, cx-catenin and y-catenin in colonic crypts, for E-cadherin in colonic superficial epithelium and for E-cadherin and cx-catenin in ileal crypts. For ~-catenin no significant changes could be detected. Conclusion: Upregulation of 3 components of the E-cadherin/ catenin complex was found in non-inflamed bowel mucosa of SpA patients. This upregulation possibly precedes the development of inflammatory bowel disease.

51. FURTHER CHARACTERISATION OF SACROILIAC INFLAMMATION IN ANKYLOSING SPONDYLITIS L Neure", RJ Franco is'', R Bywaters", J Sieper", J Braun' . 1 Dept. of Rheumatology, Free University Berlin, Germany, 2Hopital Militaire Reine Astrid, Brussels, Department of Rheumatology Clinique St-Pierre, Ottignies, Belgium, 3Prof. Em., London, UK. Objective: Sacroiliitis is a pathognomonic feature of ankylosing spondylitis (AS).The nature and function of the inflammatory cells involved is incompletely defined. Patients and Methods: Paraffine sections of sacroiliac biopsies performed several years ago obtained at autopsy (n=2) or by open surgery (n=5) of 7 AS patients of different disease stages, 1 control with cerebral malignancy and bone marrow (BM) biopsies of 4 patients with non-rheumatic inflammatory diseases were investigated by immuno-histology using antibodies against T cells (CD3 and CD8), macro phages (CD68) and the cytokines IL1 ~ and TNF-cx. Results: AS patients of all stages showed myxoid deformation of the BM partly invading bone and cartilage. Some inflammatory infiltrates consisted of fibroblasts. Synovitis was clearly evident in 3 cases, while moderate inflammation of the ligamentous part of the joint was only present in one. The BM of AS patients was hypercellular on the sacral compared to the iliac side and to controls. In the iliac BM CD68+ and CD3+ cells were abundant and more ~L-1 ~ and TNF-cx were found as in the controls. Discussion: The most characteristic finding of AS in all stages was myxoid deformation of the BM partly invading bone and cartilage. The origin of this subchondral granulation tissue is not clear, it might evolve from the bone marrow. Involvement of the entheses is not impressive in the sacroiliac joint. Macrophages, monokines ·and T cells are clearly present in increased frequency in inflamed sacroiliac joints of AS patients.

52. DISTRIBUTION OF BONE SCINTIGRAPHIC JOINT INVOLVEMENT IN PERIPHERAL PSORIATIC ARTHRITIS (pPsA) H Zmierczak*, C Van de Wiele+, K de Vlam*, RA Dierickx+, H Mielants*, EM Veys*. Dept. of Rheumatology* and Div. of Nuclear Medicine+, University Hospital Ghent, Belgium Objective: To evaluate retrospectively the bone scintigraphic distribution of limb joint involvement in pPsA. Methods: Total body and detail bone scintigraphies, performed 4 hours after the injection of 925 MBq 99 Tc-MDP, of 32 male and 23 female patients, meanly 43.6 years old, with psoriasis, peripheral inflammatory arthropathy of 2 years median duration and negative for rheumatoid factor were examined for pathologic hypercaptations at peripheral joints. Results: 699 of 3498 evaluated joints, meanly 12.7 joints/patient showed hypercaptations, 381 at the right, 318 at the left body side, 390 joints were bilaterally involved, 309 unilaterally involved. 89% of the patients had poly-, 9% oligo-, 1 patient monoarticular manifestation.

443 Hypercaptation was seen most frequently at the wrists (61 of 104 evaluated joints), followed by the MTP-1 (48/102), the midfeet (49/106), IP-hand (44/102), MCP-1 (38/102), MCP-2 and 3 (32/102), PIP-3-hand (29/102) and the ankles (27/106). Least frequently involved were PIP-5 (1/88), DIP-5 (4/88), PIP-4, DIP-2 and 4 (5/88) of the feet and DIP-5 (51102) of the hand. In the finger joints involvement frequencies decreased from MCP (129/510) to PIP (75/408) then to DIP (61/408), in toe joints from MTP (123/478) to PIP (23/352) to DIP (20/352). Digit joints were involved in 95% of the patients, the non digit joints in 96%; ray distribution was noted in 35%, DIP involvement in 44%. No isolated DIP manifestations were seen. Rates of bilateral versus unilateral pathologic captations were highest for the shoulders (8/2), wrists (48/13) and DIP-4-hands (10/3); least for the ankles (4/23), PIP-3 (0/8) and PIP-4 (0/5) of the feet. Conclusions: The scintigraphic presentation of pPsA is mainly polyarticular. Digit and non digit joints are simultaneously involved in the majority of the patients. Wrists-, midfeet-, ankles-, MTP-1 and IP-hand were the most frequently pathologic joints. In digits the involvement frequency was clearly higher for MCP/MTP and decreased from proximal to distal. Bilateral versus unilateral manifestation rates differed notably in different joint regions. Isolated DIP manifestation did not occur.

53. PERIPHERAL ENTHESOPATHY IS FREQUENT IN PERIPHERAL PSORIATIC ARTHRITIS (pPsA) H Zmierczak*, C Van de Wiele t , K de Vlam*, RA Dlerickx ", H Mielants*, EM Veys*. Dept. of Rheumatology* and Div. of Nuclear Medicinet, University Hospital Ghent, Belgium Objective: To investigate the frequencies of peripheral enthesopathy in pPsA patients by anamnesis, clinical assessment and bone scintigraphy. Methods: 24 male and 21 female patients, meanly 43.6 years old , with psoriasis, peripheral inflammatory arthropathy and negative for rheumatoid factor were questioned about their history of enthesopathic complaints and clinically assessed for tenderness at the entheses of the extensor carpi ulnarls, patellar tendons, Achilles tendons, the plantar fascia and the trochanter major femoris. Total body and detail 99m-Tc-MDP bone scintigraphies of 45 PsA patients with a median disease duration of 2 years were scored for pathologic captations at the clinically assessed enthesis locations. Results: 25 of 45 patients (56%) mentioned a history of typical heel pain; the other regions were considered as anamnestically poorly reliable. Six patients (13%) had one or more tender entheses at clinical assessment , 5 times at the Achilles tendons, once at plantar fascia, 3 times at the extensor carpi ulnaris insertions. 20 bone scintigraphies (44%) showed in total 35 hypercaptations at the scored entheses, 15 at the fascia plantaris, 7 at the Achilles tendons, 5 at the patellar tendons, 2 at the extensor carpi ulnaris insertions, 6 at the trochanter major femoris. Bilateral involvement of the same region was observed in 8 patients. Conclusions: Peripheral Iigamental or tendon insertion enthesopathy is frequent in pPsA. Bone scintigraphy is likely to visualise subclinic involvement.

54. FUNCTIONAL EVALUATION OF THE LUMBAR SPINE WITH RACHIMETRY A Peretz, M Moris, C Fauconnier. Rheumatology Unit, CHU Brugmann, Brussels , Belgium Introduction. Rachimetry is a PC-assisted new technique used to quantify the functional poss ibilit ies of the lumbar spine during in a three-dimensional motion: antero-posterior flexion-extension, right and left latero-flexion, and rotat ion. The technique is

444 designed to measure the relative participation of the hips and the lumbar spine during the movement of flexion and extension. Theoretically, the relative participation is set at 50%. The results are expressed as rachimetric indices (RI) in flexion or extension. Purpose. 171 patients attending the "back school" of our hospital were evaluated before and after the training by classical clinical indices and rachimetry. The most frequent abnormal movement observed in patients with low back pain is a participation of the lumbar spine in flexion or in extension > 50% as the consequence of a decreased availability of the pelvic and hip motion. The working hypothesis is that low back pain might be partly due to an overuse of the lumbar spine. Results. A significant increase in antero-posterior flexion (total flexion : 54 :t: 12cm vs 58 :t: 10 cm, p<0.001) and extension (total extension: 24 :t: 7 cm vs 28:t: 7cm, p<0.001) was observed which was obtained by an increase in the motion of the hip and pelvic complex. Rl were also significantly improved after back school training: Rl flexion 1.04 :t:0.8 vs 0.78 :t: 0.42, p<0.001; RI extension 1.0 :t: 0.53 vs 0.84 :t: 0.34, p<0.001. Discussion and conclusion. Rachimetry appears as a useful tool to evaluate the functional abilities of the lumbar spine. The reeducation of patients with low back pain will then be guided by the results of the rachimetry. The short term effects of such a reeducation in back school training can be measured by rachimetry.

55. OSSIFICATION OF THE POSTERIOR LONGITUDINAL LIGAMENT IN A PATIENT WITH ANKYLOSING SPONDYLITIS AND DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS H Mielants*, L Schatteman*, L De Clercq*, A Stuer**, K de Vlam*. Dept of Rheumatology *St. Camillus-St. Augustinus Hospital, Antwerpen and **University Hospital Gent, Belgium Ossification of the posterior longitudinal ligament (OPLL) first described in Japanese patients, is a radiological feature found in association with ankylosing spondylitis (AS) and with diffuse idiopathic skeletal hyperostosis (DISH) and can cause cord compression. A 62 year old man presented features of AS: reduced axial mobility, partial involvement of the articular part of the sacroiliacal joint, bilateral dorsal syndesmophytosis and presence of enthesitis and features of DISH: absence of inflammatory axial pain, plump aspect of syndesmophytes, ventral sacroiliacal ossification, absence of zygoapophyseal joint involvement and absence of HLA B27. OPLL was found between C2 and C6 and between L2 and L5 without neurological signs. Although this ossification causes an important narrowing of the cervical spinal canal on CT-scan , the patient presented no neurological abnormalities. The question remains if OPLL is associated with AS or with DISH, or is an acc idental phenomenon.

56. DYSPHAGIA IN A PATIENT WITH GIANT OSTEOPHYTES

o Ebo, *L Goethals, P Bracke, A De Schepper, LS De Clerck. University Hospital Antwerpen and *General Hospital Stuyvenbergh, Belgium A 79-year old man presented with increasing dysphagia and moderate cervical pain, with significant loss of cervical mobility. Clinical examination revealed no muscular pareses and no sensory loss. The gait was undisturbed. There were no bladder nor bowel dysfunction. There was slight loss of the right knee jerk reflex and the right Achilles tendon reflex was absent. The serum C-reactive protein, a complete blood count as well as other laboratory evaluations were normal. Plain radiographs of the cervical spine showed a massive ankylosing bone bridge at the anterior of all cervical vertebral bodies and visible interapophyseal joints with degenerative changes, suggestive for diffuse skeletal hyperostosis (DISH). On CT scanning the massive anterior bone bridge was confirmed. Moreover, presence of

Abstr acts trabecular bone within the excrescences, severe stenosis of all neuroforamina and posterior osteophytes with shortened A-P diameter of the spinal canal were found. Clinical alterations of DISH include spinal rigidity, syndromes caused by dynamic overload of the "mobile segment» and syndromes due to space occupation. Protrusion of hyperostotic formations into the spinal canal can occur, producing medullar compression, or outwards, pressing on the oesophagus, trachea or larynx. Dysphagia due to external bone compression is produced close to the superior fixation point at C6, either above it, due to posterior pressure on the hypopharynx or even pharynx, or below it. The intensity can be very variable, from very mild to severe as in our patient, allowing only the swallowing of liquids, and associated with hoarseness, respiratory difficulty or loss of weight mimicking an oesophageal tumour.

4. SYSTEMIC DISEASES AND VASCULITIS 57. SIGNIFICANCE AND THERAPEUTIC RELEVANCE OF NATURAL SELF-REACTIVE ANTIBODIES IN HEALTHY INDIVIDUALS M Kazatchkine. Universite Pierre et Marie Curie et Hopital Broussais , Paris, France This presentation focuses on the properties of natural selfreactive antibodies present in the IgG and IgM fractions of normal human serum. Natural IgG and IgM autoant ibodies exhibit a high degree of V-region-dependent connectivity. Connectivity is observed between IgG molecules as well as between IgG and autologus anti-idiotypic IgM molecules. It provides a basis for the ability of therapeutic pools of normal IgG (intravenous immunoglobulin, IVlg) to neutralize circulating autoantibodies and to modulate the expansion of self-reactive B cell clones in patients with antibody-mediated autoimmune diseases. V-region-dependent interactions shape the serum IgG auto reactive antibody repertoire that differs from one individual to another in serum whereas it appears highly conserved between individals when it is analyzed in the purified IgG fraction of the serum. Thus, repertoires of natural IgG and IgM antibodies are not random but restricted to a set of dominant self antigens that do not vary throughout life. The infusion of normal IgG (IVlg) was shown to be beneficial in patients with a variety of autoimmune disorders and in several experimental models of autoimmune disease. Within the normal immunoglobulin pool, we have characterized autoantibodies to several membrane molecules of lymphocytes that may be relevant for the immunomodulatory effects of IVlg, including antibodies to CD4, to conserved regions of HLA class I, to the RGD motif, Fc gamma receptor and Fas. Aff inity-purified autoantibodies to these molecules were isolated from normal IgG and shown to exert potent immunomodulatory functions)n vitro . Taken together these observations support the concept that natural self-reactive antibodies play an important role in maintaining immune homeostasis and controlling physiological autoreactiv ity. These properties are directly relevant for the use of normal immunoglobulin in the treatment of autoimmune conditions.

58. STEM CELL TRANSPLANTATION FOR AUTOIMMUNE DISEASES P Durez. Department of Rheumatology, H6pital Erasme, Brussels Autoimmune diseases (AID) are rarely life-threatening in the short term but they are a source of major disability and may considerably shorten life. The numerous available treatments are mostly able to decrease disease activity without curing the disease and consequently preventing irreversible organ damage. Recently, stem cells transplantation (SCl) after myeloablative chemotherapy has been proposed to beat severe and refractory AID. In animal models of AID, such as experimental allergic

Abstracts

445

encephalitis or adjuvant induced arthritis in rats, SCT has been reported to be effective. Furthermore, a moderate number of case reports of improvement or even cure of patients after BMT for hematologic complications (mainly aplastic anemia) secondary to the treatment (gold salts, D-penicillamine) has also been reported. Both allogeneic and autologous bone marrow transplantation have been used although autologous transplantation have been privileged for obvious safety reasons. More recently, following a consensus meeting, several groups have initiated clinical trials aimed at primarily treating AID by SCT. In February 1998, 57 patients with autologous stem cell transplants for autoimmune disease have been registered by Alan Tyndall (Basel) with the EBMT/EULAR Project. Transplants were for multiple sclerosis (n=26), systemic sclerosis (n=11), systemic lupus erythematosus (n=4), cryoglobulinemia (n=3), juvenile chronic arthritis (n=2), rheumatoid arthritis (RA) (n=2) and miscellaneous conditions (n=8). Among these patients, five died of progressive underlying disease or infectious complications.This survival rate appears to be comparable to autologous transplantation for malignant disease. In our medical department, 2 patients with severe and refractory RA performed SCT. In order to avoid retransplantation of autoreactive T cells, patients did receive T cell depleted stem cell graft. Mobilization of peripheral blood stem cells was achieved using cyclophosphamide (1.5g/m 2) and etoposide (300 mg/m~ followed by G-CSF administration (5Ilg/kg). The leukapheresis product was enriched in CD34+ stem cells and further depleted of CD4+ and CD8+ cells using the Isolex 300i device (Baxter Immunotherapy Division, Santa Ana, CAl. The HSC transplant was found to be devoid of T cells both by flow cytometry and polymerase chain reaction (PCR) for T cell receptor mRNA. Transplantation of T cell-depleted HSC was performed following administration of busulfan 4 mg/day from day-7 to day-4 and cyclophosphamide 60 mg/day from day-3 to day-2, according to consensus guidelines. In both patients, first evidence for improvement of joint inflammation was noted at the end of the 'first month post-SCT. At the last follow-up (9 months and 3 months post-TCD), clinical remission was maintained as assessed by the lack of joint symptoms in absence of antiinflammatory medication in both patients and by a normal CRP level in one of them (at 9 months). Side effects consisted of severe mucositis in both patients and an episode of Pneumocys tis carinii successfully treated in one of them. Nine months postSCT, immunological analyses in patient 1 revealed a CD4+ cell count of 386/mm 3 with a normal Vb repertoire, a normal proliferative response to candidin in vitro and a positive delayed-type skin hypersensitivity react ion to candid in in vivo. These observations suggest that autologous T cell-depleted SCT is a promising therapy for severe and refractory RA allowing maintained clinical remission even after recovery of cell-mediated immunity. However, mucosal toxicity is a major side effect of this procedure. REFERENCES

Krance , R. & Brenner, M.K. BMT beats autoimmune disease. Nature

4,153-155 (1998).

Moo.

Tyndall, A. & Gratwohl, A. Blood and marrow stem cell transplants in autoimmune disease: a consensus report written on behalf of the European league against rheumatism (eular) and the European group for blood and marrow transplantation (ebmt). Bone Marrow Transplant. 19,

643-645 (1997).

59. IMMUNOHISTOLOGIC ANALYSIS OF THE CELL INFILTRATE AND THE EXPRESSION OF ADHESION MOLECULES IN MUSCLE BIOPSIES FROM PATIENTS WITH RHEUMATOID VASCULITIS PC Verschueren' v', AE Voskuyt", C van Uffelenl, AH Zwindermanl, FC Breedvetd", PP Tak1 • "Leiden University Medical Center, Leiden, The Netherlands, 2Catholic University, Leuven, Belgium and 3Free University Hospital, Amsterdam, The Netherlands Objective. Histologic analysis of muscle biopsies can be used to detect vasculitis in patients with rheumatoid arthritis (RA). The aim of this study was to determine the additional value of an

immunohistologic analysis of the cell infiltrate and the expression of adhesion molecules. Methods. Three groups of RA patients were studied: 1) without clinical signs of vasculitis (n=6); 2) with recent onset of extraarticular features and a clinical suspicion of vasculitis but normal rout ine histology (n=11); and 3) with recent onset of extraarticular features and histologically proven vasculitis (n=14). The third group consisted of patients with fibrinoid necrosis in either a muscle biopsy or in other biopsy specimens. A control group of osteoarthritis (OA) patients was also included (n=5). Frozen sections were analyzed with the following monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD68, anti-l CAM1, anti-VCAM-1 , anti-E-selectin, and anti-HLA-DR. The slides were evaluated using a semiquantitative scoring system (0-4). Results.There was a gradual increase in the mean immunohistologic scores for the various markers from group 1 to group 3. Statistically significant differences in the mean scores for most markers were detected between groups 1 and 2, but not between groups 2 and 3. Higher immunohistologic scores corresponded with perivascular infiltrates as determined by routine histology in all groups. Conclusion. The differences in the immunohistologic scores between the patient groups probably reflect the pathophysiological events that lead to vasculitis. Whether the increased number of inflammatory cells and the increased expression of adhesion molecules in biopies from patients with clinical suspicion of vasculitis but negative routine histology point to a higher sensitivity of immunohistologic methods to make the diagnosis vasculitis, remains to be determined in larger clinical studies.

60. DECREASED PRODUCTION OF TYPE-1 CYTOKINES (IL-12, TNF-o:, IFN-y) IN WHOLE BLOOD CELL CULTURES OF PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS B Andre, C Ribbens, 0 Kaye, Y Vrindts, 0 De Groote, MG Malaise. Rheumatology Department, University of Liege, Belgium Introduction. Because SLE has an immunological Th-2 profile and because IL-12 inhibits type 2-immune responses , we investigated the production of this cytokine and other type-1 (TNF-o:, IFN-y) or type 2 (IL-4, IL-10) cytokines by whole blood cells in 15 patients with active SLE, in 18 patients with inactive SLE and in 13 age- and sex-matched normal controls. Methods. WBCs were incubated for 24 h in the presence of LPS 1 ng/ml (TNF-o:) or 100 ng/ml (IL-10, 1L-12), of PHA 1 Ilg/ml (TNF0:) or 10 Ilg/ml (IL-4, IL-12, IFN-y). Cytokine production was assessed by ELISA. Results. mean values (:l: SEM) [pg or UI (IFNy)/ml/1000 WBCs]. Cytokine

Active SLE

Inactive SLE

Normal controls

IL-12 (LPS) IL-12 (PHA) IFN-g (PHA) TNF-a (LPS) TNF-a (PHA) IL-10 (LPS) IL-10 (PHA) IL-4 (PHA)

65.3 :l: 15$ 36.4:l: 15$ 0.9:l: 0.2$ 30.0 :l: 5.2$ 28.0 :l: 5.7$ 22.5 :l: 5 16.0 :l: 3.9 2.3 :l: 0.5

189.8 :l: 22 124.6:l: 22 3.1 :l: 0.5 61.2 :l: 12.1 61.6:l: 8.2 24.0 :l: 3.2 22.6 :l: 3 2.1 :l: 0.3

176.6 :l: 16.6 97.3:l: 13.5 1.9:l: 0.3 71.6 :l: 9.5 85.8:l: 6.7 29.1 :l: 3.4 34.5:l: 6.5 4.2 :l: 0.8

($): P< 0.051 as compared to inactive SLE or normal controls (Mann-Whitney) Linear negative correlations (P< 0.05) were observed between IL-12, IFN-y and TNF-o: production in SLE patients (active + inactive). The defect observed in the production of type -1 cytokines was not dependent on the presence of low dose steroid (7.5 mg/d of prednisone). Both steroid- and non-steroidtreated patients with active SLE produced significantly less type1 cytokines than steroid- and non-steroid-treated patients with inactive SLE. Steroid-treated patients (active or inactive) (24/37) had lower IL-12 and IL-10 productions than the non-steroid treated patients of their group.

Abstracts

446

Conclusions: (a) WBCs of patients with active SlE produce significantly less Il-12, IFN-y and TNF-ex than WBCs from inactive SlE or from normal controls whereas no significant changes were observed in Il-10 and Il-4 productions; (b) the relative imbalance between Il-12 and Il-10 production may explain the decreased production of Th1-type cytokines in this disease; (c) low dose steroids influence the production of cytokines when using the ex vivo whole blood cell technique.

61. PARADOXICAL IMMUNOLOGICAL EFFECTS OF 2CHlORODEOXYADENOSINE THERAPY FA Houssiau, A Delannoy', J-P Devogelaer. Rheumatology and °Hrematology Units, Cliniques Universitaires Saint-luc, louvain Medical School, Bruxelles, Belgium 2-chlorodeoxyadenosine (cladribine, 2-CdA) is an immunosuppressive analog of deoxyadenosine used for the therapy of hairycell and chronic leukesmla and for low-grade lymphoma. In preliminary trials, the drug was found effective in several autoimmune disorders, including multiple sclerosis, RA, psoriatic arthritis and SlE. We wish to report some paradoxical immunological effects of 2-CdA therapy observed in one patient suffering from SlE GN who experienced a severe lupus flare during therapy despite profound drug-induced lymphopenia, and in three patients given 2-CdA treatment for chronic lymphoid leukeernia (Cll) who developed Coombs-positive hesmotytlc anaemia (2 pat ients) or inflammatory polyarthritis with antinuclear antibodies (1 patient). These observations, together with four other cases of autoimmune hremolysis reported in Cll patients given 2-CdA, indicate that 2-CdA therapy might be associated with various paradoxical humoral-type immunological side-effects. The intriguing recently reported observation that 2-CdA therapy does not down-regulate serum IgG titers and does not suppress type-2 cytokine expression but rather increases Il-4 mRNA levels in PBMC from some SlE patients, suggests a possible physiopathological explanation for these side-effects, given the role of type-2 cytokines in humoral immunity.

62. EFFECTS OF GLUCOCORTICOID (GC) THERAPY ON PROXIMAL FEMUR MARROW: A lONGITUDINAL MAGNETIC RESONANCE (MR) STUDY FA Houssiau, G Depresseux, J MalghemO, J-P Devogelaer, B Vande Berg". Rheumatology and °Radiology Departments, Cliniques Universitaires Saint-Luc, louvain Medical School, Bruxelles, Belgium Objective: To study the changes in heematopoletlc marrow in patients given GC therapy. Patients and Methods: Two sets of high-resolution coronal T1weighted MR images of one hip were performed 19 :t 5 months apart (mean :t SEM) in 18 patients (11 with SlE and 7 with RA). Fourteen of them were treated with GC (5 to 30 mg prednisolone/ day) immediately after the first MR, while the 4 others remained GC-free. A marrow conversion index (MCI; [signal int ensity of the proximal femur metaphysis/signal intensity of the greater trochanter] x 100) was calculated and the values compared over time. An increase in MCI value indicates an increase in fat content of the prox imal femur marrow. Results: The MCI changes over time (i. e. the MCI value at follow-up minus the initial MCI value) correlated positively with the mean GC daily dose (r = + 0.71; P = 0.001)0 More specifically, patients given a mean prednisolone daily dose> 7.5 mg (n = 6) had a greater mean MCI change over time compared to those who did not receive GC (n = 4; P = 0.01) and to those given a mean prednisolone daily dose ,;;; 7.5 mg (n = 8; P = 0.02; Student's ttest).

Conclusion: GC therapy is associated with an increase in fat content in the proximal femur marrow of patients given prednisolone doses higher than 7.5 mg/day. This result might be related to the occurence of hip avascular necrosis in patients given high-dose GC therapy and, conversely, might explain why lower doses are relatively safe in this respect.

63. MATERNAL AND FOETAL OUTCOME IN LUPUS PREGNANCY: A PROSPECTIVE STUDY ON 17 CASES FOLLOWED IN A LUPUS-IN-PREGNANCY CLINIC FA Houssiau, E Pete, D Jard inet, E Lavenne", J-P Devogelaer, C Hubinont". Rheumatology, "Obstetrics and #Hremostasis Depart ments, Cliniques Universitaires Saint-Luc, Louvain Medical School, Bruxelles, Belgium Objective: The negative impact of systemic lupus erythematosus (SlE) on pregnancy is well-known, in particular when the disease is undiagnosed or active at the time of pregnancy and in patients with antiphospholipid antibodies. Recent data suggest that maternal and foetal outcome is more favourable in SLE patients when their pregnancy is followed very regularly by a multidisciplinary team. Methods: Pregnant SlE patients followed in the lupus Clinic were referred to the lupus-in-Pregnancy Clinic and examined jointly by a rheumatologist and an obstetrician on a very regular basis. Biological work-up was performed monthly, as well as ultrasound and Doppler studies of uterine and foetal (including umbilical and cerebral) artery blood flow. Cardiotocography was performed every week from week 24 onward. Results: 17 pregnancies occured in 14 SlE patients, 10 of which had a past history of renal disease and 7 antiphospholipid antibodies. Eight patients were treated with glucocorticoids and 7 with azathioprine at the start of (and during) pregnancy. Early fretal loss was observed in 4 cases. The remaining 13 pregnancies ended-up in life-birth (mean :t SD weight: 2,277 :t 810 g), after 34.5 :t 3 weeks of pregnancy (mean :t SD). Seven of these 13 children required neonatal care. Pre-eclampsia was observed in 4 mothers and hypertension without pre-eclampsia in four others. Two patients experienced a lupus flare during pregnancy and 2 others within 6 months after an early fretal loss. No permanent damage was observed in mothers, except in one with borderline kidney function at the start of pregnancy who developed chronic renal failure 3 years later. Conclusion: No late foetal loss nor permanent maternal damage directly related to pregnancy were observed. However, morbidity was high, in particular related to prematurity and pre-eclampsia.

64. SERUM ANTI-PROTEINASE 3 ANTIBODIES ARE ASSOCIATED WITH VASCULITIS BUT NOT SPECIFICALLY WITH "ACR CRITERIA-POSITIVE" WEGENER'S GRANULOMATOSIS V van Pesch, C Lefebvre#, M Jadoul', J-P Tomasi", J-P Devogelaer, FA Houssiau. Rheumatology, General Internal Medicine", Nephrology" and Autoimmune Seroloqy" Departments, Cliniques Universitaires Saint-luc, Louvain Medical School, Brussels, Belgium Anti-neutrophil cytoplasmic antibodies (ANCAs) are detected in the serum of patients suffering from a wide spectrum of diseases, including various systemic vasculitides and other chronic inflammatory conditions. By contrast, anti-proteinase 3 (PR3) antibodies (Ab), a subset of ANCAs, are purported to be more specific for Wegener's granulomatosis (WG). We reviewed the clinical diagnosis of all anti-PR3 Ab-positive cases seen in our University Hospital in the last ten years. Amongst the 48 anti-PR3 Ab-positive patients identified ("" 10 IU/ml by ELISA), 35 have been evaluated clinically and serologically at the time of diagnosis and were therefore analysed

447

Abstracts further. Only two-thirds of these patients (n = 22) suffered from vasculitis. Diseases such as ulcerative colitis, chronic hepatitis, sarcoidosis, etc. were diagnosed in the remaining 13 anti-PR3 Ab-positive patients. However, the mean (:!: SD) anti-PR3 Ab titer was significantly higher in the "vasculitis" group compared to the "non-vasculitis" group (228:!: 310 versus 41 :!:351U/ml; p =0.004 by unpaired t-test). We also investigated whether, within the subgroup of anti-PR3 Ab-positive vasculitis patients, anti-PR3 positivity was associated more specifically with WG. Interestingly, anti-PR3 Ab were detected in 9 vasculitis patients who did not fulfil the ACR classification criteria for WG. Moreover, the mean (:!: SD) anti-PR3 Ab titer was not higher in vasculitis patients fulfilling the ACR criteria for WG versus those who did not (228 :!: 357 versus 267 :!: 2971U/ml). In conclusion, high anti-PR3 Ab serum titers are associated with vasculitis but not specifically with " ACR criteria-positive" WG.

65. INTERLEUKIN-12 AND INTERLEUKIN-18 SYNERGISTICALLY INDUCE THE PROLIFERATION OF SPLENOCYTE-DERIVED NK CELLS FROM LUPUS-PRONE MICE BR Lauwerys, J-C Renauld", FA Houssiau. Rheumatology and ' Experimental Medicine Units, Louvain Medical School, Bruxelles, Belgium Introduction: We have recently shown that interleukin (IL)-12 and IL-18 synergistically inhibit immunoglobulin production by B-cells in a murine lupus model (chronic graft-versus-host-disease). Therefore, we investigated whether this cytokine combination had similar or 'distinct immunoregulatory 'effects in another lupusprone strain, namely (NZB x NZW) F1 (NZBIW) mice. Results: Unstimulated splenocytes from NZBIW mice were cultured with and without IL-12 and/or IL-18. While addition of either cytokine alone did not influence cell proliferation, a str iking synergy was observed when both cytokines were combined. Of note, addition of IFN-y was ineffective in this respect, thereby suggesting that IFN-y did not mediate the synergy between IL-12 and IL-18 for the proliferation of NZBIW splenocytes. FACS analysis revealed that cells proliferating in response to IL-12 and IL-18 were NK cells, i. e. CD3-negative, DX-5-positive and Ly-49positive large granular cells. Consistently, these cells exerted a cytolytic activity on Yac-1 cells, a murine NK target. Conclusion: IL-12 and IL-18 synergistically, induce the proIileration of NK cells from NZBIW splenocytes. This observation might be relevant to immunomodulation.

66, INHIBITION OF IN VITRO IMMUNOGI:OBULIN PRODUCTION BY IL-12 IN MURINE LUPUS-LIKE CHRONIC GRAFT-VERSUS-HOST DISEASE: SYNERGISM WITH IL-18 BR Lauwerys, J-C Benauld, FA Houssiau. Rheumatology and ' Experimental Medicine Units, Louvain Medical School, Bruxelles, Belgium We investigated the effects of interleukin (IL)-12 on immunoglobulin (Ig) production in vitro in murine chronic graft-versus-hostdisease (cGVHD), a lupus-like model of overt B-cell activation induced by allogeneic stimulation. Addition of IL-12 to cGVHD splenocytes strongly inhibited total Ig (lgK), IgM and IgG1 production. Although IL-12 down-regulated IL-4, IL-5, IL-9 and IL-10 production, its inhibitory activity on Ig production could not be ascribed to down-regulation of these cytokines, as addition of saturating doses of IL-4, IL-5 and/or IL-9 did not reverse the inhibitory activity of IL-12. Interestingly, IL-12 was also found to suppress the stimulating effect of IL-4 and IL-5

on Ig synthesis by cGVHD splenocytes. Several lines of evidence indicated that the inhibitory activity exerted by IL-12 on Ig production was mediated by IFN-y. First, IFN-y was produced in large amounts upon IL-12 stimulation. Second, it displayed a potent inhibitory activity on Ig production. Third, Ig production was also inhibited by IL-18, a recently cloned IFN-y-inducing cytokine. Finally, the inhibitory activity of IL-12 was blocked by anti-IFN- y mAb. We also investigated whether IL-12 downregulated Ig production by purified cGVHD B-cells. We found that IL-12 had only a marginal inhibitory activity on highly purified B-cell populations isolated from cGVHD splenocytes and stimulated with IL-4 and IL-5, and that IL-18 was inactive in this respect. However, when the two cytokines were combined, a striking synergy was unmasked not only for IgG1 inhibition but also for IFN-y production by these B-cell populations. In conclusion, our results demonstrate that IL-12 inhibits in vitro Ig production by activated splenocytes through IFN-y production and that it synergises with IL-18 on activated B-cells to inhibit Ig production, through up-regulation of IFN-y production by B-cells.

67, IDENTIFICATION OF D1METHYLARGININES IN THE CTERMINAL PORTION OF SMD1, INVOLVED IN IMMUNE REACTIVITY WITH SLE SERA L Meheus', A Union', J Raymackers", F De Keyser, B Vanderborght, C de Abreu Costa, JA Papi, H Brahms, R LOhrmann. 'Innogenetics, Ghent, and University Hospital Ghent, Belgium Anti-SmD antibodies are a major pathognomonic marker for SLE. However , the recombinant SmD1 protein produced in E. coli and S. cerevisiae is not a suitable antigen source for diagnostic purposes since it is less immunoreactive than its natural counterpart. In the course of sequencing internal peptides derived from natural SmD1, dimethylation of arginine in all 9 Cterminal GR-repeats was observed. Subsequent epitope mapping of recombinant SmD1 produced in the baculovirus expression system resulted in the identification of a single linear epitope containing those 9 dimethylarginines (aa9Q-aa119). In contrast, the non-dimethylated C-terminal peptide was not immunoreactive with patient sera. Further screening of 95 SLE sera with both the modified and non-modified peptide in a line immunoassay (L1A) confirmed the immunoreactivity of the modified peptide with patient sera containing anti-SmD antibodies. We demonstrated that dimethylarginines are missing in E. coli expressed SmD1. Consequently, we postulate that the lower immunoreactivity of E. coli SmD1 observed in immunoblotting and L1A but also in ELISA after refolding (Ou et aI., 1997) is related to the lack of this modification. Taken together, our results suggest that the dimethylarginines in SmD1 play an important role in the autoimmune response in SLE,

68. SYSTEMIC LUPUS ERYTHEMATOSUS AND NON HODGKIN LYMPHOMA A Stuer', F Offner, E Kruithot", H Mielants\ F De Keyser', EM Veys' . 'Dept. of Rheumatology and 2Hematology, University Hospital Ghent, Belgium A 73-year old female patient presented with symmetrical polysynovitis of hand- and foot joints, wrists, knees and ankles. There was a diffuse skinrash on the right upper arm and breasts. Patient complained of morning stiffness, alopecia, photosensitivity , Raynaud's phenomenon, dry eyes and a marked weight loss. Laboratory variables were within normal limits except for a normocytic anemia and an elevated C-reactive protein of 2.24 mg% . There was a positive ANA fluorescence with homogeneous pattern . A skinbiopsy was normal. The diagnosis of SLE was

Abstracts

448

established according to the ARA criteria. Patient was treated with Hydroxychloroquine and a daily regimen of 20 mg Prednisolone. There was a persistent polysynovitis and skin rash despite augmenting the daily dose of corticosteroids to 40mg. Twelve months after admission , patient developed two solid subcutaneous nodules at the right orbita and left upperarm. Histopathological examination of one nodule showed a centroblastic B-Iymphoma, high-grade with CD 20 expression and IgG K-monoclonality. Further staging revealed pathological enlarged Iymphonodi pre- and paratracheal, precarinal and bilateral paraaortic and it was concluded to a Non Hodgkin Lymphoma stage IV. Patient was treated with chlorambucil, etoposide and corticosteroids monthly. A possible association between systemic lupus erythematosus (SLE) and Iymphoproliferative diseases has already been suggested in several case reports and small series. Our case report is of interest because it remains unclear whether this is a primary diagnosis of SLE with a secondary evolution to NHL or an atypical presentation of a lymphoma, masked by high-dose corticosteroids.

70. DETECTION OF ANTI-SSA/R060 REACTIVITY BY HEP2000(TM) TRANSFECTED CELLS I Peene", W Van Ael", T Vervaet", M Vandenbossche", EM Veys', F De Keyser'. 'Department of Rheumatology, University Hospital Gent, Belgium, "BMD, Brugge, Belgium In a period of 16 months, we identified by double immunodiffusion (ID thymus/spleen) and Line Immuno Assay with recombinant R052 and R060(INNO-L1A ANA,lnnogenetics,Gent,Belgium) 134 patients with anti-SSA/Ro reactivity. 127 Of these patients and an additional 54 non-SSA sera were further tested by indirect immunofluorescence on HEp-2000(TM)cells (transfected with R060 cDNA; Immunoconcepts, Sacramento, USA) and compared with non- transfected HEp-2 cells at a dilution 1/40. 10-15% Of the transfected cells show a distinct bright speckled nuclear staining pattern with prominent nucleolar staining upon incubation with anti-SSA/Ro sera (SSA/Ro specific pattern). 126 SSApatients were also analysed by double immunodiffusion with native R060 (ID nR060; Immunovision, Arkansas, USA). Table: Detection of SSA/Ro specific pattern on HEp-2000(TM)

Number HEp-2000 10 nRoGD

69. DISTAL GANGRENE DUE TO VASCULITIS, TREATED WITH INTRAVENOUS PROSTAGLANDINS (PROSTIN VRE:), IN A PATIENT WITH SYSTEMIC SCLEROSIS F Van den Bosch, F De Keyser, H Mielants, EM Veys. Department of Rheumatology, University Hospital Gent, Belgium A 72-year old caucasian female was diagnosed with systemic sclerosis and secondary Sjogren syndrome in 1986. She was treated with Penicillamine and experienced an initial favourable response. However, from October 1987 to December 1993 she didn't show up for further follow-up. In December 1993 she presented again with a deterioration of the systemic sclerosis, osteoporotic fractures of the vertebrae, and muscle atrophy. Initially there was some concern about the possibility of a multiple myeloma, but subsequent investigations showed no arguments for this diagnosis. In June 1994, she developed progressive cyanosis of the toes, with local infection. Despite aseptic wound care, and nifedipine as a vasodilating agent, the cyanosis of the right foot persisted, and necrosis developed in toes 1 to 4. The patient was hospitalised and treated with bed rest, further aseptic wound care, and IV antibiotics. Nevertheless necrosis worsened. Further investigations (arteriography) showed a distal occlusion of the superficial femoral artery and a proximal occlusion of the popliteal artery. Surgical sympathectomy and bypass of the occluded arterial region was performed. Although the bypass proved open, necrosis worsened even more with progressive impairment of the right midfoot. At that time nifedipine was pushed to a maximal dose of 40 mg daily (higher dose was not possible for toxicity reasons) en cyclical (monthly) therapy with Prostaglandin E1 (PG E1) was installed (central venous infusion for 72 hours, started at 6 ng/kg/min. up to lOng/kg/min.). A progressive amelioration was noted over the next months, with complete regression of the necrosis of the midfoot en toes 3 and 4. After 4 cycles of therapy with PG E1, toes 1 and 2 (which .d idn't show any further amelioration) were amputated (under therapy with PG E1). There were no problems with wound healing. Our patient showed only a dose dependent lowering of the systolic blood pressure and treatment was guided according to this value; we could reach the maximal dose of 10 ng/kg/min. Headache and flushing, which are commonly reported, were not seen in our patient. Today, 3 years after the last PG E1 infusion, there are still no signs of recurrence of vasculitis, cyanosis and/or necrosis. Conclusion: intravenous prostaglandins are a promising possibility in treating severe vasculitis of systemic diseases.

10. L1A52+ L1A60+

10L1A52+ L1A60+

10. L1A52+ L1A60-

10L1A52. L1A60-

44 40 42'

12 9 10

20 16 16

34

10+ L1A52L1A60+

10L1A52L1A60.

TOTAL

10+ L1A52L1A6o-

11 2 3

5 5

127 76 80

, 1 serum not analysed Conclusions The sensitivity for the SSA specific pattern on HEp-2000(TM)in ID+ SSA samples is 86% (60/70) versus 28% (16/57 ) in 10- SSA samples. A subgroup of anti-SSA/Ro positive patients (monospecific anti-52 without precipitation capacity) is not identified by the specific SSA pattern on HEp-2000(TM), indicating that only Ro-60 antibodies cause the pattern. The apparently monospecific anti-52 antisera with precipitation capacity reveal anti-R060 reactivity by Ouchterlony with native R060 in 16/20. The sensitivity of HEp-2000(TM) in this subgroup is 80%.

71. DETECTION OF ANTI-SSA REACTIVITY BY IMMUNODIFFUSION DEPENDS ON ANTI-RO 60 REACTIVITY I Peene", F De Keyser', I Vanneste", S De Keyser", EM Veys', L Meheus". 'University Hospital Gent, Belgium, " Innogenetics, Gent, Belgium 82 Sera with anti-SSA/Ro reactivity, defined by double immunodiffusion (ID thymus/spleen) and Line Immuno Assay with recombinant R052 and R060 (INNO-L1A-ANA, Innogenetics, Gent, Belgium) were further analysed by Western Blot with recombinant coli R060 (WB coli), WB ~with native R060 (WBn60; Immunovision, Arkansas, USA), L1A with native R060 (L1An60), L1A with a mixture of recombinant and native Ro 60 (L1Arec/n60) and double immunodiffusion with native R060 (ID nR060). A clear positive test result for anti-R060 in at least one of the assays was found in 66 sera. For each method we determined the sensitivity. Table. Sensitivity for the detection of anti-SSA/R060 reactivity.

Sensitivity number of sera

10 nRoGD

10 thymus! spleen

WBcoli

67% 44/66

60 % 38/63

82% 53/65

we

n60

74% 49/66

L1A'

UA reel

roo

L1A n60

n60

76% 48/ 63

82% 53/65

83% 55/66

, Cases with borderline intensity are also included. Conclusions: all but one sera with antl-nnoso reactivity on double immunodiffusion (natural and conformational) are recognized by WB coli (recombinant and denaturated). The apparently monospecific anti-R052 (INNO-L1A ANA) antisera with precipitation capacity reveal anti-R060 activity in 88%. The non-precipitating monosz group shows no reactivity against R060 in 57%. 93% Of

Abstracts the 10+ samples reveal anti-R060 reactivity. These data strongly indicate that immunodiffusion depends upon anti-R060 reactivity.

72. MONOCLONALITY IN PRIMARY SJOGREN'S SYNDROME - LONGTERM FOLLOW-UP IN A SINGLE PATIENT P Voiders, V Taelman, R Westhovens. Department of Rheumatology, University Hospitals KU Leuven Patients with primary Sjogren's syndrome have a 44 times higher risk to develop a lymphoma. A monoclonal B-cell population (biopsy) and extraglandular manifestations often announce the development of a lymphoma. In this case a 42-year-old nurse was known with primary SIgren's syndrome since 1980. In 1991, she experienced extraglandular symptoms with purpura at the lower limbs and ankle synovitis, requiring low dose steroids. There were multiple swollen lymph nodes in the cervical and supraclavicular regio, and bilateral parotic swelling. A biopsy of the lymph nodes showed only benign changes and there was a monoclonal IgM kappa mixed cryoglobulinemia. In 1995 she developed a large supraclavicular swelling, without other systemic manifestations. A biopsy of the supraclavicular gland was suggestive for a Non-Hodgkin lymphoma. Chemotherapy (CHOP) resulted in a complete remission. However, one year later, a relapse was documented. Patient was treated with stemcell transplantation and till now she is do ing well.

73. OCCURENCE OF SCLERODERMA IN 2 PAIRS OF MONOZYGOTIC TWINS F De Keyser, R Joos, I Peene, JM Naeyaert*, EM Veys. Rheumatology and *Dermatology Department, University Hospital Ghent, Belgium VG and VR are female monozygotic twins. VG developped scleroderma at age 47, with progressive sclerodactylia, Raynaud's phenomenon, digital ulcers, inflammatory arthralgias, and interstitial lung disease. ANA was strongly positive with anti-scl70 antibodies. VR developed an infarct-like digital lesion at age 61, together with arthralgia and progressive sclerodactylia. ANA was strongly positive, but anti-scl70 antibodies were not found. RS and RN are another pair of female monozygotic twins. RS presented with polysynovitis, flexion contracture of 2 fingers and a dystrophic nail. There were depigmented, indurated and atrophic skin lesions over the left forearm and dorsum of the hand, compatible with scleroderma. ANA was weakly positive. One year later, she developed a new linear lesion over the left upper arm. RN had a very similar and simultaneous disease onset with polyarticular joint pain and swelling, a depigmented skin lesion over the dorsum of the left hand and restr icted mobility of the wrists. ANA was weakly positive. The diagnosis of scleroderma was made in both patients.

74. SCLERODERMA AND HEART DISEASE: A TRICKY SITUATION R Joos 1,F Raeman', E Keyzer, J Vanwelderr', K de Vlam'. ' Dept of Rheumatology and 2Dept of Cardiology, Service of Internal Medicine, AZ Jan Palfijn, Merksem - Antwerpen, Belgium Four patients with a coincidence of scleroderma and heart disease are presented. 1. A.S., a 30 year old man of Turkish origin, is known with a severe form of CREST for three years. A year ago he presented with atypical chest complaints for which no clear diagnosis was obtained in spite of extensive cardiologic, pneumologic and gastro-enterologic investigations. Re-

449 cently an acute episode of left ventricular failure, together with intraventricular conduction disturbances was noted. 2. J.B., a 39 year old woman, known with diffuse scleroderma and Raynaud's phenomenon, and calcinosis, presented with acute retrosternal pain and sweating end of march 1998, coming home from a holiday in North Africa. Investigations included gastroscopy (showing esophagitis), ECG , echocardiography and cycloergometry and heart enzymes (CK was normal, gammaGT, LDH, and transaminases were elevated). No cardiac abnormalities could be found. After two days a discrete elevation of CK and GOT was noted. One week later she was admitted with an acute myocardial infarction due to a single vessel disease with occlusion of the right coronary artery. 3. C.R., a 50 year old man, heavy cigar smoker, is known with systemic scleroderma, urticarial vasculitis and myositis since 8 years. Two years ago he presented with atypical chest pain. A diagnosis of hyperventilation was supposed. Recently (April 1998) he was admitted with a prolonged period of chest pain, apparently due to coronary heart disease, proven by cycloergometry. 4. S.J., a 60 year old woman, was seen by the cardiologist for cardiac decompensation. A diastolic dysfunction was diagnosed by means of echocardiography, which showed mild left ventricular hypertrophy (septum 14 mm and posterior wall 15 mm) and impaired diastolic relaxation. A complete CREST-syndrome was diagnosed during hospitalisation. Literature overview of the association between heart disease and different forms of scleroderma is discussed. Coronary heart disease due to large vessel involvement seems to be equally frequent in scleroderma as in non scleroderma patients. Cardiac decompensation and ventricular arrhythmia's are the most frequent scleroderma linked cardiac disorders. Heart disease is the second most frequent cause of death in scleroderma patients. Conclusion: 1. If patients with scleroderma present with atypical symptoms that might be related to heart disease, a more thorough search should be made than usual to rule out cardiac involvement. 2. Non cardiac organ involvement due to the scleroderma such as oesophageal symptoms, pulmonary function disturbances and thoracic cage symptoms, can disturb a correct diagnosis of cardiac involvement.

75.

DERMATOMYOSITIS - LUPUS OVERLAP MIMICKING JCA R Joos", N Van den Bossche", LA Verbruggen 2, EM Veys1, J

Vande Walle'. 'Centre for Pediatric Rheumatology, University of Gent, and 2Rheumatology Unit, Free University of Brussels, Belgium

L.N., a twelve year old girl of caucasian origin, presented with polyarthralgias, diffuse muscle pain and weakness, fatigue , headache, gastralgia, anorexia, subfebrility and Raynaud phenomenon. Since the age of five she suffered from polyarthritis involving ankles, knees, wrists, elbows, finger and toe joints. Treatment with sulfasalazine was ineffective. Treatment with salicylates and methotrexate as well. Clinical examination revealed impaired joint mobility of the cervical spine, elbows, wrists, knees, ankles and fingers. Muscle wasting and weakness of proximal muscles of arms and legs were present. Muscle felt firm on palpation. Atrophic skin lesions were found at the extensor side of the MCP and PIP joints of the fingers . A hard nodule was present at PIPIlI. Laboratory investigations showed a moderate inflammation (sedimentation rate 18 mm/hr, CRP 0.86 mg/dl and normal muscle enzymes except for aldolase at 8.6 U/I (nl 0.5-7.6) . ANA and anti DNA were present. ENA (immunoprecipitation) was negative but L1A showed the presence of anti R052 and histone antibodies. On skin biopsy

450 continuous granular deposits of IgM (= lupus band test) were found . Muscle biopsy showed perimysial and perifascicular inflammatory infiltrates and fibrosis. The nodule was calcified with perivascular inflammatory infiltrates. Joint X-Ray was normal. This patient initially presenting as a polyarticular form of juvenile chronic arthritis evolved towards an overlap syndrome with elements of different forms of auto-immune disease . The differential diagnosis is extensively discussed. Actually the patient is treated with a combination of methotrexate 5 mgl week, ciclosporin (3 mg/kg/day) 100 mg, prednisolone 12 mglday and folic acid. Evolution seems to be favorable with improving functional capacities.

76. CASE: ANTIRIBOSOMAL RNP ANTIBODIES IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND PSYCHOSIS B Vanneuville " F De Keyser*, I Peene*, JM Naeyaert", EM Veys. 'Dept. Rheumatology; "Dept. Dermatology, University Hospital Ghent

Ab stracts cytology, normal renal function and electrolytes, normal protein electrophoresis, normal complement factors, positive ANA 1/320 with negative a-ds DNA and positive ENA (SSA), normal CRP, normal thyroid function; there was a pathological Saxon test. CT of the orbita showed an ovaloid mass in the musculus rectus lateral is, without abcedation, oedema or liquefaction but with dislocation of the optical nerve. MRI confirmed the mass in the m. rectus lateral is. A biopsy of this mass revealed a small lymphocytic non Hodgkin lymphoma. Local radiotherapy was given (36 Gray in 18 sessions), with complete remission until now. Conclusion: the presumed ocular myositis in this women with SLE and secondary Sjogren was in fact a muscular localisation of a non-Hodgkin lymphoma. Resistance to immunosuppressive therapy should point the clinician to a diagnosis of malignancy.

78. FEVER AND MENINGEAL IRRITATION IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AV Mertens, WJ Stevens, LS De Clerck. Department of Immunology, Allergology and Rheumatology, University Hospital Antwerpen

A 41-years old woman presented with complaints of fatigue, poor concentration, diminished reaction time and memory, sleep disturbances. There was fotosensibility and diffuse arthralgy. She had a medical history of lymphocytic infiltration of the skin of the face 10 years before and in 1997 she developed a GravesBasedow disease. Clinical examination revealed only a facial erythema and a localised alopecia. Laboratory investigations showed a slightly elevated sedimentation rate and leucopenia; homogenous ANA 4+; positive ENA: SSB, SmD, ribosomal RNP; positive antimitochondrial and antiparietal cel antibodies. Control of the ENA two years before was negative. Biopsy of the skin demonstrated immunoglobulin and C3 deposition at the basal membrane on immunoflurorescence technique. MRI of the brains was negative . Congitive dysfunction is a fairly common problem in SLE and can occur even in the absence of active systemic disease or major neurologic and psychiatric events. Fatigue, pain and depression are the three highest scoring problems. Psychiatric disturbance has been linked to social stress , even in the absence of physical disability. Especially serum antiribosomal RNP antibodies are highly specific for lupus psychosis, including organic brain syndrome and nonorganic psychosis, while there is no abnormal elevation of anti-ribosomal RNP levels in the CSF. It is suggested that serum anti-ribosomal RNP playa nonspecific pathogenetic role in the development of diffuse cerebral damage, since cerebral dysfunction may be secondary to inhib ition of prote in synthesis. This assay is easely reproducible and may help distinguish SLE-induced psychiatric disease from that caused by other processes.

A 28 year old woman with SLE presented with fever, headache, neck stiffness, vomiting and a red rash over the entire body, especially the face. The patient, a nurse with little use of tobacco and no use of alcohol, used chronically prednisolone 25 mg EC and azathioprine 100 mg a day for treatment of the SLE, diagnosed in 1989. Since February she used nizatidine for epigastric discomfort. One week before adm ission she had an infection of the upper respiratory tract. Clinical neurologic examination confirmed the presence of neck stiffness. Heart, lung and abdominal examination were normal. Blood pressure was 110/60. Heart rate 120 bpm. Body temperature at the moment of presentation was 38,8° C. ESR was normal , CRP 1.4 mgldl, there was no leucocytosis, a positive ANA 115000 (SSA) as was known before. A lumbar puncture was performed and revealed clear flu id, with 3 WBCI mm3. All cultures of blood, urine and spinal fluid remained negat ive. Serolog ic evaluation of the most common viruses showed no arguments for active infection. Rx thorax, CT and NMR of the skull showed no evidence for infection or vasculitis. After repeated anamnesis, a causal link could been found between the intake of nizatidine and the clinical picture of fever, meningeal irritation and skin rash. Up to three times the patient stopped and restarted nizat idine intake on her own , with respectively amelioration and relapse of the clinical picture. Conclusion: nizatidine, a new H2 receptor antagonist, can cause a drug fever with meningeal irritation. Differential diagnosis with flare up of SLE or infection has to be made.

77. OCULAR MYOSITIS IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

79. SLEEPING SICKNESS AND SECONDARY CEREBRAL LUPUS

AV Mertens, LS De Clerck, 'MJ Tassignon, WJ Stevens. Department of Immunology-Allergy-Rheumatology and "Ophtalmology, University Hospital Antwerp

MP Guillaume, M Pegnyemb, S Cherifi, F Supiot, N Hermanus, G Servais, R Karmali

A 45-year old women with a history of oligoarthritis, photosensitivity and hair loss with positive ANA and anti-ENA (SSA) was diagnosed as SLE in 1996. She also had ophthalmologic problems and a presumptive ocular myositis for which she was treated with steroids and azathioprine. Under this therapy the eye problems relapsed and she was transferred to our hospital. There was proptosis of the right eye, with blurred vision and pain . She also complained of subfebrilitas, excessive sweating, mouth dryness and arthralgias. Clinical invest igation revealed exophtalmia of the right eye with conjunctivitis, normal fundoscopy, vision 6/10 on the right and 101 10 on the left sight, xerostomia, no lymphadenopathy, no hepatosplenomegaly. Blood analysis showed normal ESR,

Chronic neurological manifestations in sleeping sickness are due to a leptomeningitis and meningoencephalitis with perivascular infiltration of both white and grey matters. In addition, as a consequence of a poly-clonal B cells activation, a wide variety of autoantibodies, which could modify the clinical presentation of the disease, can be observed. We report a case of an african patient presenting with all the biological manifestations of cerebral lupus but who was finally diagnosed as sleeping sickness. A 31 year old angolian man, living in Belgium for a year, presented with headache, cognitive impairment, weight loss and meningismus. CSF analysis revealed increased protein levels and leucocytes count, which were mainly lymphocytes. In both blood and CSF, antinuclear antibodies were detected, with a speckled

451

Abstracts pattern, including ds DNA, SSB and especially anti-Ku and antiribosomes P, the two latter being thought to be specific for cerebral lupus. In addition IgM were markely raised. Serology for Trypanosoma was negative in the CSF. On MRI, there was an hyperintense signal, on T2-weighted images, in the periventricular white matter, the basal ganglia and the brain stem. There was also a mild contrast uptake in the leptomeninges. These findings were not characteristic of cerebral lupus. He was treated unsuccessfully with multiple immunosuppressive drugs including steroids, cyclophosphamide, cyclosporine and plasmapheresis. Finally, Trypanosomia appeared on blood thick smear and in the CSF. He was treated by a 14-day course of Eflornithine and all the clinical manifestations disappeared. Moreover all nuclear antibodies previously described became undetectable. In conclusion, specific antibodies for cerebral lupus and known as such, can also be encountered in the course of a trypanosomiasis.

80. OCULAR INFLAMMATORY DISEASES: SYSTEMIC INVOLVEMENT AND COMPLICATIONS OF TREATMENT A Peretz', MP Guilaume', L Caspers 2. Brugmann University Hospital: , Internal Medicine Department, 20 phtalmic Immunology Unit, Brussels, Belgium Introduction. Uveitis is an intraocular inflammatory disease and keratitis is corneal inflammation often associated with systemic diseases treated with immunosuppressive drugs. Purpose. We investigated 34 patients with non infectious uveitis or keratitis referred by the ophthalmologist to the internist and the rheumatologist for systemic and bone assessment. Results. Anterior uveitis was observed in 4, intermediate uveitis in 3, posterior uveitis in 12 (5 with Birdshot retinochoroidopathy), pan-uveitis in 8, keratitis in 5 patients. Granulomatous lesions were observed in 8. A systemic disease was found in 16 patients. Systemic sarcoidosis was diagnosed in 6, spondylarthropathy in 4, Behcet's disease in 2, cicatricial pemphigoid in 3 patients. 31/33 patients received CS at high or medium doses for several months or years. They also received a combination of azathioprine, cyclosporine A, methotrexate or cyclophosphamide. Few significant complications were observed with these drugs. Most side effects were due to CS treatment: Cushing's syndrome in 9, cataract in 14, glucose intolerance in 3, osteoporosis in 20, aseptic bone necrosis in 3. Discussion and conclusion. Patients ocular inflammation have often a systemic disease which is sometimes difficult to define. The immunosuppressive treatments have potential serious side effects. Among them, CS used at doses higher than those used in rheumatic diseases for prolonged period of time appeared as the most deleterious drugs.

81. A MADE IN ONE PIECE SKELETON lN A 22 YEAR OLD MAN WITH SICKLE CELL DISEASE N Dumarey, P Martin, M Jayankura, M Verhas, P Putz, A Peretz. Department of Nuclear Medicine, UVC Brugmann, ULB-VUB, Brussels A 22 year old African man with a known sickle cell disease was referred from Congo to our Hospital in March 1997 with the request to improve his physical ability. When he was admitted to our hospital, he was bedridden and unable to mobilise the vertebral column, hips, knees and ankles. His whole body was stiff like a board. Radiographs of the involved joints showed multiple regions of radiolucency, other regions with osteosclerosis, widening of the medullar cavities and intertrabecular spaces, a biconcave aspect of the vertebrae, flattening of the humeral heads, a bony ankylosis of the hips and of the left femorotibial joint, and a periosteal reaction at the distal metaphyses of both tibias. A CT-scan of the

pelvis showed large sequels of osteonecrosis, more pronounced in the epiphyses of the femoral heads. 99mTc-MDP-bone-scan showed increased tracer-uptake by the skull. There was faintly increased uptake by both hips, the knees, the left shoulder, and both ankles. The diaphyses of both humeri and both femori were diffusely hyperactive. The relatively moderate uptake by bone scan was not in favour of recent infarctions nor osteomyelitis. 99mTc-sulphur-nanocolloids-scan and 99mTc-monoclonal antigranulocyte-antibodies-scan both were suggestive of the presence of active bone marrow in the long bones of the lower limbs neighbouring areas of necrosis; the 99mTc-monoclonal antigranulocyte-antibodies-scan was not consistent with the diagnosis of osteomyelitis. Resection of the right femoral head was performed, and cultures of the resected material remained negative after 6 weeks. Afterwards, the left femoral head was resected, and a hip prosthesis was implanted at this side after negative bacterial cultures of the resected bone tissue. The implant of the right hip prosthesis, which was delayed because of surgical wound infection, was performed one month later. Discussion and conclusions: sickle cell disease is known to be associated with localised areas of bone infarctions, caused by vascular occlusion by sludging of sickle cells in the sinusoids. Such a particular severe disease as in this case with multiple bone necrosis foci including several bony and fibrous joint lesions is rare. The most invalidating lesion, avascular necrosis of the hip, has a high prevalence in patients with sickle cell disease and is more frequently observed with the increasing life expectancy of the patients. Osteonecrosis of the hip and other large joints in patients suffering from sickle cell anemia should be actively sought and treated during infancy, in order to prevent important deformations of this joint leading to a high degree of invalidity in young adults, like in this extreme case.

82.

MULTIDRUG-RESISTANT TUBERCULOSIS SPONDYLITIS

S Cherifi, MP Guillaume, A Peretz. Brugmann University Hospital: Internal Medicine Department, Brussels INTRODUCTION: Multidrug-resistant tuberculosis is a growing problem worldwide. We report a fatal case of multidrug-resistant spinal tuberculosis with epiduritis and paraspinal abscess in a 68year-old black woman. HISTORY: This patient, with hypertension and diabetes had back pain progressively increasing in the lumbar region, which started in 1995 in Africa (Congo). When she arrived in Belgium, with a history of inadequate anti-tuberculosis treatment, she developed progressive neurologic signs. Computed Tomography revealed a major destruction of L3 and ~ vertebrae with a psoas abscess. Magnetic Resonance Imaging showed in addition an epiduritis. A specimen aspirated from the psoas abscess showed on culture a strain of Mycobacterium tuberculosis nominis and on sensitivity test a resistance for Isoniazid, Rifampin, Pyrazinamide and Ethambutol. Chemotherapy with five alternative anti-tuberculosis drugs was administered during four months and the abscess was drained surgically. The patient died, one month after surgical spine decompression. But, post-mortem cultures were negative for Mycobacterium tuberculosis. DISCUSSION: Multidrug-resistant tuberculous spondylitis is still rare in Belgium. Two others cases were reported from 1992 to 1998. The optimal therapy is not standardized and the mandatory duration of treatment is not known. Prompt and vigorous treatment should first be started when the diagnosis is suspected and then individualized according to the susceptibility of the specific strain. This rational approach is justified by the implications of retreatment failure for the patient in terms of poor outcome and for the public in terms of financial and social cost.

452 83. AZATHIOPRINE-INDUCED HEPATITIS IN GIANT CELL ARTERITIS Y Boutsen, S DaIl'Armellina*, W Esselinckx. Department of Rheumatology, Mont-Godinne University (UCL) Hospital, and *N.D. de Grace Gosselies Hosp ital Azathioprine was prescribed, as steroid-sparing drug, to 13 consecutive patients (2 males) suffering from temporal arteritis. All patients, aged from 56 to 85 years, presented with temporal or orbital headache and an erythrocyte sedimentation rate> 70 mml h. Temporal arteries biopsies were positive in 6 out of 10 patients. Time interval between diagnosis and initiation of azathioprine therapy ranged from 12 to 345 days (mean 134). The mean steroid dosage, at the beginning of azathioprine therapy, was 24.3 mg prednisolone (10 to 60mg). The daily dose of azathioprine was 50 mg during the first 2 weeks and progressively increased by steps of 25 mg every 2 weeks to a maximum dosage of 2 mg/kg. Azathioprine had to be discontinued during the first three months in 11 out of the 13 patients because of significant hepatic toxicity. Liver enzyme abnormalities were disclosed by the systematic labo ratory tests monitoring in 10 patients and one patient presented with nausea and jaundice on day 45. Treatment duration prior to diagnosis of hepatic toxicity was 51 ± 19 days (20-73). Results expressed as percent of the upper normal value were: gammaglutamyl transpeptidase 1616 ± 1333% (236 - 4480); alkaline phosphatase 205 ± 117% (54 - 442 ); aspartate amino transferase 437 ± 598% (104 - 1980); alanine amino transferase 884 ± 1871% (183 - 6500). Bilirubin levels were increased in the single patient who presented with jaundice: total bilirubin 2.6 mgl dl; free bilirubin 1.9 mg/dl. Full blood count and differential as well as serum creatinine levels were normal in all patients. Virolog ical screenings for hepatitis (HAV, HBV, HCV, CMV, EBV) were negative. Abdominal echography showed no evidence of extra hepatic obstruction or intrahepatic abnormality. After azathioprine withdrawal, liver enzyme normalisation was observed within 1-2 months and bilirubine levels were normal within four days. Diagnosis of azathioprine-induced toxicity is suggested by the rapid reversibility of biologic disturbances, viral hepatitis and bile duct obstruction being ruled out. Because of the dramatic improvement of biological data we did not perform liver biopsy. The incidence of hepat ic toxicity in this series greatly exceeds the 5% of azathioprine-induced hepatic side effects generally reported in the literature, or occurring in our experience when treating other vascul itides or rheumatoid arthritis. Clinicians probably should be aware of a poss ibly unexpected high risk of azathioprine-induced hepatic toxicity in patients with temporal arteritis. Systematic laboratory monitoring appears mandatory, mainly during the first three months, when azathioprine is prescribed in this condition.

84. TREATMENT OF FIBROMYALGIA: A RANDOMISED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF PAROXETINE, A SELECTIVE SEROTONIN RE-UPTAKE INHIBITOR P Geusens1,2, J Vanhoof", K Declerck" , G Molenberqhs", L Bruckers", J De Wit 4, P Mattelaer", J Raus1.2. 1Dr L WillemsInstituut, Diepenbeek, 2Department of Medicine, Limburgs Universitair Centrum, Diepenbeek, 3Department of Statistics, Limburgs Universitair Centrum, Diepenbeek, 4Smith-KlineBeecham, Brussels

Objectives - The effect of paroxetine, an antidepressant and selective serotonin re-uptake inhibitor, was studied in depressive patients with fibromyalgia (FM). Methods - A randomised, double-blind placebo-controlled study, including 52 patients with FM, treated with paroxetine (20 mg once a day) or placebo for 8 weeks. The effect of treatment was assessed by the patient, the physician and by a study nurse for several dimensions of FM.

Abstracts Results - After paroxetine, a significant amelioration was found in physicians global score, pain score by the patient, morning stiffness and depression scale. No significant differences were found between the two groups. After adjustment for intake of non-steroidal anti-inflammatory drugs (NSAIDs), paroxetine was superior to placebo in improvement of physician's global and pain assessment, morning stiffness and anxiety. Conclusions - After adjustment for intake of NSAIDs, paroxetine was superior to placebo-treatment in ameliorating of physician's global and pain assessment, morn ing stiffness and anxiety.

5. RHEUMATOID ARTHRITIS 85.

EARLY RHEUMATOID ARTHRITIS

PLCM van Riel. University Hosp ital Nijmegen, The Netherlands In the past decade the approach to the treatment of rheumatoid arthritis has changed dramatically. While in the recent past there was a policy of restraint when treating patients with rheumatoid arthr itis with second-line agents , nowadays patients are not only treated as early as possible after the diagnosis has been made but the strategy itself has also been changed. The principal aim is to decrease the disease activity as soon as possible and through this to prevent structural damage. Second-line agents are therefore often given in combination and corticosteroids are frequently given as bridge therapies or as additional treatment. Promising are some of the results with 'anticytokines' like monoclonal antibodies against the cytokine itself, soluble cytokine receptors, cytokine receptor antagonists, antiinflammatory cytokines and monoclonal antibodies against certain T cell antigens. The most promising approach seems to be the suppression of TNFa by different means but also blockade of IL-1 has shown to be effective. The place of these agents in the therapeutic armamentarium needs to be further established in the coming years. Many questions have to be answered like: will it be possible to use these agents in the long-term as single treatments, should they be used in combination with more conventional DMARDs or should combinations of anticytokine treatments be used? Another possibility would be that these treatments are used as short courses to attack exacerbations of the disease or as bridge therapies. These current and future changes in the approach to patients with early rheumatoid arthritis has great impact on the evaluation of the disease process. An accurate monitoring of the disease activity is mandatory for an efficient use of the available secondline agents. As it is not possible to measure disease activity with one single variable a Disease Activity Score (DAS) including the number of swollen joints, a tender jo int count, the erythrocyte sedimentation rate and a general health measure was developed. With the DAS the activity of the disease can be described from no disease activity at all (remission) up' to very active disease. In combination with criteria for change in disease activity individual improvement criteria have been developed: the EULAR response criteria. Both the EULAR response criteria as well as the remission criteria can be used with graded (Ritchie) and non graded, comprehensive and simple (28) joint counts. The validity of these criteria has been shown in several studies.

86.

HLA AND RHEUMATOID ARTHRITIS

F De Keyser. Department of Rheumatology, University Hospital, Gent, Belgium Rheumatoid arthritis (RA) has been linked to a set of class II HLA genes, most of them located in the DR locus. The consensus mot ive between the DR alleles that predispose to RA has been named the shared epitope. This association is important for a double reason. As to the pathogenesis of RA, it may provide crucial insights into the molecular nature of antigens that can be

453

Abstracts presented in the context of RA-associated HLA molecules and eventually induce or perpetuate rheumatogenic T-cell activation. For the clinician, the association can be exploited for early diagnostic purposes. In addition to serum markers, the HLAhaplotype in a patient with joint symptoms compatible with RA may significantly increase the disease probability. It is worth to stress that, unlike some serum markers, the HLA information can be obtained early in relation to the development of joint symptoms, and does of course not change in relation to disease duration and treatment. HLA has been linked, not only to the risk for RA, but also to the disease severity (bone erosions, extra-articular manifestations). It has been suggested that patients double positive but heterozygoous for the shared epitope have the highest risk for the disease and the most severe disease presentation. An estimation of the prevalence of different shared epitope alleles in RA and controls is given in the table . SHARED EPITOPE AND RA DRB1

RA

CONTROLS

01 04 0401 0404 shared epitope single shared epitope double

27% 66% 55% 20% 85% 28%

16% 35% 20% 5% 46% 3%

87. THE TH1/TH2 CYTOKINE BALANCE IN ARTHRITIS P Miossec. Clinical Immunology Unit, Depts of Immunology and Rheumatology, H6pital Edouard Herriot, Lyon, France The contribution of T cells in the pathogenesis of rheumatoid arthritis (RA) has been a matter of debate. That of monocytes through the production of proinflammatory cytokines has been more simple to demonstrate and accordingly IL-1 and TNFet have been selected as important therapeutic targets. Regarding the production of T cell derived cytokines in RA, the low level of expression and production by RA synovium of T cell derived cytokines has been one reason to question the role of T cells. But another way to look at the contribution of T cells in RA regards the analysis of their cytokine profile and the producing subsets. Indeed such subsets have been associated with the development of different disease patterns in mouse and man. More importantly, the modulation of such cytokine profile is now considered as a therapeutic means. Results in mouse then extended to man have classified T cell clones into Th1 clones producing IL-2, TNF~ and IFNy, whereas Th2 clones produce IL-4, IL-6, IL-10 and IL-13 and IL-5. Most clones from RA synovium were found to produce predominantly IFNy, sometimes in combination with low levels oflL-4 and IL-10. In contrast, T cell clones producing predominantly IL-4 were rarely found . Extension of such studies to 1L-17 have indicated that IL-17 is always produced in association with IFNy but not with IL-4, as for a Th1 cytokine. This RA synovium is a good example which reflects the local regulation of cytokines on each other action and production. On one side, staining for IL-10 was positive and endogenous IL-10 was shown to be active as increased production of proinflammatory cytokines was observed when blocking endogenous IL-10. On the other side, isolated synovium T cells do produce significant levels of IFNy. However, IFNy and IL-10 could not be easily detected in the supernatants of synovium pieces . Such result may be explained by the inhibitory effect of these two cytokines on each other. The relative ratio between the two components could then explain the flares observed during the disease course. Conversely addition of exogenous Th2 cytokines was found to have antiinflammatory effects. Such manipulation reflects to some extent clinical situations such as pregnancy now class ified as a Th2 condition, where control of disease activity is commonly observed. Not

knowing the cause of RA remains a major limitation for treatment. The concept of cytokine balance in arthritis is of interest since it may act in a cause independent fashion. Nevertheless th is implies early treatment before joint destruction in patients. In this situation, acting on the endogenous regulatory cytokine balance may represent a more natural way to prevent the consequences of chronic inflammation.

88. UPDATE ON METHOTREXATE IN RHEUMATOID ARTHRITIS H Mielants . Department of Rheumatology, University Hospital, Gent, Belgium Methotrexate (MTX) is at present the disease-modifying antirheumatic drug (DMAARD) most commonly used in the treatment of rheumatoid arthritis (RA). The mode of action in RA is not yet established but different mechanisms have been proposed. MTX inhibits dihydrofolate reductase thus inhibiting proliferation of lymphocytes. MTX polyglutamines are active inhibitors of several enzymatic reactions; one of them (AICAR transformylase) accounts for enhanced extracellular adenosine production. The occupation of adenosine receptors on stimulated neutrophils inhibits production of reactive oxygen metabolites, adhesion to and injury of endothelial cells, synthesis and release of leukotrien B4 and production of tumor necrosis factor (TNFet). Adenosine acting on receptors of macrophages inhibits TNFet, IL-6 and IL-8 production and increases secretion of IL-10. This adenosine release is probably also responsible for peculiar toxicities such as nodulosis (by enhancing giant cell formation) and for diminished renal function. Another possible way of action could be the inhibition of transmethylation reactions which has immunosuppressive effects and diminishes the capacity of lymphocytes to synthetise IL-2, required for further T-cell proliferation. Less than half of the dosis of MTX taken orally, is absorbed and this is not influenced by food intake. Parenteral (1M or SC) administration is therefore preferable, not only for better absorption and compliance, but since this route probably diminishes liver and gastrointestinal side-effects. MTX is without any doubt the most effective DMAARD not only on short term but especially on long term (3-10 years), given in dosages between 7.5 mg to 25 mg in one single dose once weekly. On average 56% of the patients remained on MTX at 5 years, and compared to other DMAARDs, MTX has the best efficacy to toxicity ratio. However, MTX rarely induces remissions in RA. Moreover MTX does not halt erosive joint lesions, although the drug seems to slow the progression of them. Side-effects are not so frequent but can sometimes be life treatening. Liver toxicity is multifactorial and is increased by alcohol consumption, diabetes and other risk factors. Regular monitoring (every 4-8 weeks) of liver tests is mandatory, but liver biopsies are only indicated in risk patients. Alteration of the renal clearance , already induced by the drug itself or caused by other diseases, dehydration or concomittant NSAID or cyclosporine intake, is a major risk factor for severe toxicity, mostly on bone marrow. This toxicity is dose-dependent and can be fatal if not diagnosed. Control of leucocytes, thrombocytes and creatine must be done every 4 to 8 weeks. Hypersensitivity pneumonitis, a dangerous, probably allergic side-effect can appear on any moment; in presence of a nonproductive cough, fever, shortness of breath and absence of proven infection chest radiography is necessary and MTX must be definitely stopped. Nausea is a frequent problem, the incidence of which can be reduced by folic acid supplementation and/or parenteral administration. Nodulosis, present in 8% of the cases can possibly be reduced by simultaneous intake of colchicine. There are no arguments that MTX at the used dosages in RA could induce lymphomas. MTX osteopathy with diffuse osteope nia and associated stress fractures has been documented.

454 Since it is proven that simultaneous administration of folic acid has no effect on the efficacy of the drug, it is mostly accepted to administer folate supplement. Folic acid reduces some toxicities of MTX, including oral ulcers, nausea and cytopenia but seems not to have effect on lung and liver toxicity. Although discontinuation of MTX causes flare-up of the RA after some months, withholding the drug for 2 weeks in the perioperative period of orthopedic surgery is recommended. The last years combination therapy of MTX with other DMAARDs (hydrochloroquine, cyclosporine and especially Sulfasalazine) has shown significantly more efficacy than MTX alone, without increase of side-effects and will probably become more frequently administered.

89. HC GP-;39 IN SYNOVIAL LINING IS CORRELATED WITH JOINT DESTRUCTION IN RA D Baeten, F De Keyser, D Elewaut, AMW Rijnders', GF Verheijden*, AMM Miltenburg', ES Bos", P Steenbakkers', G Verbruggen, AMH Boots', EM Veys. Dept. of Rheumatology, University Hospital Ghent, Belgium, and 'Dept. of Immunology, NV Organon, Oss, The Netherlands Although the physiological function of human cartilage glycoprotein-39 (HC gp-39) is still unknown , there is increasing evidence that it could playa central role in the pathogenesis of rheumatoid arthritis (RA). The induction of a . chronic relapsing arthritis in BALB/c mice by injection of HC gp-39 and the selective recognition of HC gp-39 derived peptides by peripheral blood T cells of RA patients, suggest a role as autoantigen in the initiation of the disease. Moreover HC gp-39 mRNA is detected in inflamed synovium and in cartilage of RA{but not in normal cartilage), and serum levels of HC gp-39 are elevated in RA compared to controls. Here we investigate the local expression of HC gp-39 in synovial samples obtained in RA (n=18) and controls{spondyloarthropathy n=8 and osteoarthrosis n=7). Immunohistochemistry on snap frozen sections reveals clusters of HC gp-39 positive mononuclear cells in the synovial lining, and some solitary positive cells in the sublining layer. Prelimenary results of flowcytometry on synovial cell extracts, suggest a CD14+, HLA DR+ monocytic phenotype. HC gp-39 expression is present in 13/ 18 RA synovia compared to 4/8 in SpA and 1fi in OA. The degree of expression, scored semi-quantitatively, is also higher in RA (p=0.01). Interestingly HC gp-39 expression in RA synovial lining, but not sublining, is clearly correlated with joint destruction as evaluated by X-ray (r=0.76 p=0.0003). Expression in joints with erosions or total destruction is significantly higher than in radiological normal joints (p<0.001). There is no corre lation with other clinical parameters nor with histological features like Iymfocytic infiltration and thickness of the lining. In conclusion we report an increased presence of HC gp-39 expressing monocytic cells in RA synovial tissue, which is clearly correlated with the degree of joint destruction. This may play an important role in the local autoimmune respons leading to chronic synovitis and cartlage destruction.

90. HC GP-39 IS EXPRESSED BY PERIPHERAL BLOOD MONONUCLEAR CELLS IN RA D Baeten, F De Keyser, P Steenbakkers', GF Verheijden', ES Bos", AMW Rijnders', G Verbruggen , AMH Boots', EM Veys. Dept. of Rheumatology, University Hospital Ghent, Belgium, and 'Dept. of Immunology, NV Organon, Oss, The Netherlands HC gp-39 is a human cartilage protein of 39 kD with unknown function, but different facts suggest an important role in the pathogenesis of rheumatoid arthritis{RA): 1) HC gp-39 is secreted by cultured chondrocytes and mRNA is detected in RA cartilage

Abstracts and in inflamed synovium. 2) HC gp-39 protein expressing cells are overrepresented in RA synovium compared to osteoarthritis (OA) and spondyloarthropathies{SpA), and, moreover, the expression in RA synovium correlates with the degree of joint destruction. 3) HC gp-39 derived peptides are dominantly recognized by peripheral blood T cells of RA patients. 4) Injection of HC gp-39 induces a chronic relapsing arthritis in BALB/c mice , which can be suppressed by nasal tolerance. Here we investigate the expression of HC gp-39 by peripheral blood mononuclear cells (PBMC). Immunohistochemistry on PBMC cytospins reveals a strong intracellular staining in monocyte-like cells. These cells are also positive for mRNA on RT-PCR. The number of HC gp-39 expressing PBMC is clearly increased in RA{O.93%) compared to cirrosis{O.32%), SpA{O.05%,p=0.0022) and normals{O.001 %,p<0.00001). Flowcytornetry confirms these data and two different subpopulations of HC gp-39 expressing cells are characterised: 1) a majority of CD14-, CD15++, CD33+,HLA-DR- cells, possibly early myeloid cells. This population correlates with inflammatory parameters. 2) a small population of CD14+, CD15++, CD33++, HLA-DRmonocytic cells, which are overxpressed in RA as well as in SpA, without correlation with inflammation. In conclusion we describe an overexpression of HC gp-39 positive mononuclear cells in RA peripheral blood. The majority of these cells show a myeloid phenotype and are correlated with inflammation, while a fraction of CD14+ cells is present in RA as wei as in SpA. These data confirm that HC gp-39 is a possible target for immunotherapy in RA.

91. NEEDLE ARTHROSCOPY OF THE KNEE WITH SYNOVIAL BIOPSIES IN 150 PATIENTS D Baeten, F Van den Bosch, A Stuer, D Elewaut, EM Veys, F De Keyser. Dept. of Rheumatology, University Hospital Ghent, Belgium Needle arthroscopy is an office-based technique allowing direct visualisation of the knee cavity and selective sampling of the synovial membrane. To assess the balance between technical feasibility, safety and patient comfort on one hand, and the relevance of the obtained macro- and microscopic information for diagnosis and research purposes on the other , we performed needle arthroscopy in 150 patients (rheumatoid arthritis, spondyloarth ropathy, psoriatic arthritis, gout or osteoarthritis) with synovitis of the knee. Relative contraindications were septic arthritis and anticoagulation, but not NSAID intake. After disinfection of the leg and local anesthesia of skin and joint, a 1.8mm or a 2.4mm Hopkins rod lens arthroscope (Karl Storz, Germany) was introduced. Synovial fluid was aspirated and lavage of the joint cavity with isotone saline was performed to allow macroscopic evaluation of hyperaemia and hypertrophy of the synovial membrane. Biopsies were taken at inflamed sites; followed by another lavage to remove blood and debris. The duration of the arthroscopy on its own is 10 min, although the whole procedure takes 45 min. Results: Needle arthroscopy of the knee is a simple and easy to perform technique made particularly attractive by the local aneshesia and the ambulatory setting. It allows good macroscopic evaluation of the synovial inflammation and selective sampling of the synovial membrane. Biopsies are suitable for RNA and DNA extraction, bacterial or lymphocyte culture, and cell isolation. As samples were sometimes too small for representative histology and immunohistochemistry, we switched from a 1.8mm to a 2.4mm arthroscope with good result. In nearly all cases the arthroscopy was very well tolerated. Moreover, some patients reported relief of symptoms and even improvement of mobility after lavage of the inflamed jo int. No complications were noted at all, although arthroscopy was also performed in one patient with Candida Glabrata septic arthritis and one patient with anticoagulation.

Abstracts In conclusion, needle arthroscopy of the knee is a simple, safe and well tolerated technique, with promising perspectives as a diagnostical, scientifical and possibly therapeutical tool in rheumatic diseases.

92. EPITOPE MAPPING OF NATURAL FILAGGRIN LEADS TO THE IDENTIFICATION OF RHEUMATOID ARTHRITISIMMUNOREACTIVE EPITOPES CONTAINING CITRULLINE A Union, L Amerijckx, J Raymackers, M Dauwe, F De Keyser', L Meheus. Innogenetics, Gent, and 'University Hospital, Dept. Rheumatology, Gent, Belgium Anti-filaggrin autoantibodies (AFA) are highly specific for rheumatoid arthritis (RA) and recognize human epidermal filaggrin as well as mouth mucosa cell-derived profilaggrin. Natural filaggrin isolated from human epidermis was resolved by 2-D gel electrophoresis, and the electro-eluted acidic and neutral isoforms were subjected to trypsin digestion. The HPLC-separated peptides were analyzed by a dot spot immunotechnique using RA and control sera, upon which reactive fractions were characterized by microsequencing. The peptide mapping resulted in the identification of several immunoreactive filaggrin sequences that all contained at least one citrulline residue, originating from posttranslational enzymatic modification of arginine. Four synthetic peptides, synthesized according to these findings, were capable of detecting 50% of 75 RA sera in a Line Immuno Assay (L1A). The positive L1A signals observed with the citrulline-containing peptides disappeared completely when tested with the nonmodified counterparts. The peptides were further able to inhibit anti-filaggrin binding of sera in ELISA. These results indicate that citrulline is present in the immunoreactive epitopes of natural filaggrin and that this unusual amino acid is indispensable to obtain appropriate recognition of the filaggrin autoantigen by the AFA antibodies. They also form the confirmation on natural filaggrin of the recent finding of Schellekens et al. (1998. J. Clin. Invest., 101:273) that citrulline is an essential constituent of synthetic peptides recognized by RA-specific antibodies, which was based on the analysis of randomly citrullinated peptides.

93. HLA TYPING AND ANALYSIS OF SERUM MARKERS IN PATIENTS REFERRED TO RHEUMATOLOGISTS WITH A POSSIBLE DIAGNOSIS OF RHEUMATOID ARTHRITIS F De Keyser, F Hulstaert***, I Peene, A Union***; G Mersch***, H Mielants, L Schatteman*, L De Clercq*, S Poriau**, L Meheus***, EM Veys. Departments of Rheumatology, University Hospital Gent; **Elisabeth Ziekenhuis, Sijsele-Damme; *St. Augustinus/St. Camillus Hospital, Antwerpen and ***Innogenetics, Gent, Belgium The predictive diagnostic value of a given test not only depends upon the specificity and sensitivity, but also on the pre-test probability of the diagnosis in the patient population tested. In order to calculate the predictive diagnostic value of the HLA shared epitope and serum markers [rheumatoid factor (RF), antiperinuclear factor (APF), antifilaggrin antibodies] alone and in combination, we studied 350 patients referred to the rheumatologist for a diagnostic work-up, with a clinical presentation justifying rheumatoid arthritis to be included in the differential diagnosis. The patients were included over a 6-month period. Diagnoses were recorded after a follow-up of at least 2 months from the initial rheumatology consultation. HLA typing for HLADRB and -DaB subtypes was performed at the DNA level (INNOLiPA assay, Innogenetics). Classical Waaler-Rose and Latex fixation assays yielded the rheumatoid factor results. For the APF assay, freshly isolated human buccal mucosa cells were used. RF and APF titration were standardized with a reference serum, allowing the transformation into a U/ml format. Detection of antifilaggrin antibodies was based on a Western blotting assay using a human epidermal skin extract as the antigen source.

455 Calculations of the specificity, sensitivity, and diagnostic predictive value of the markers under study will be presented.

94. HIGH SERUM MMP3 LEVELS ARE OBSERVED IN RHEUMATOID ARTHRITIS AND OTHER RHEUMATIC DISEASES C Ribbens, M-J Kaiser, 0 Kaye, 0 Cremer, B Andre, J-M Jaspar, E Louis, 0 De Groote, MG Malaise. Rheumatology Department, University of Liege Introduction. It is suggested that MMP-3 detected in the serum in rheumatoid arthritis (RA) originates from joint sources and could therefore be a sensitive marker of the cytokine-driven local inflammation. Methods. To test the specificity of this hypothesis, we determined serum levels of MMP-3 (ELISA, Biosource) in 138 RA (sero-positive and sero-negative), in 165 non-RA inflammatory and degenerative rheumatic diseases, in 16 inflammatory nonrheumatic diseases (Crohn's disease) as well as in 98 age-and sex-matched controls. Results. Normal values (mean e SEM, median) were 8.7:t 0.3 (8) in 46 females (F) and 15.6 :t 0.8 (14.9) in 52 males (M). The Table shows absolute serum values detected and the percentage of values out of the normal range ( mean + 3 SO: 15 ng/ml in F and 32 ng/ml in M). Diseases

Number (F)

MMP-3 (Mean ± SEM, median)

Number and%> normal range

Fibramyalgia Osteoarthritis GPPD SLE Sjogren MTGD Systemic sclerosis Polymyositis Wegener and PAN Polymyalgia theuma. RA IgM-RFRA IgM -RF+ Grahn 's disease

10 (6) 36 (26) 11 (11) 38 (34) 14 (13) 7 (7) 16 (8) 13 (11) 9 (2) 11 (7) 51 (41) 87 (56) 16 (13)

14.0 ± 3.6 (11.5) 17.5 ± 3.6 (15) 40.4 ± 11.7 (25) 31.1 ± 7.1 (15) 16.9 ± 3.1 (12.8) 31.4 ± 6.6 (32) 29.5 ± 5 (24) 37.0 ± 6.1 (42) 162.0 ± 26 (155) 85.0 ± 22 (58.5) 63.0 ± 9.2 (42) 88.1 ± 8.2 (65) 13.1 ± 1.9 (11.3)

0/10 (0) 12/36 (33%) 7/11 (63.6%) 17/38 (44.7) 3/14 (21.4%) (85.7%) 8/16 (50%) 10/13 (76.9%) 9/9 (100%) 11/11 (100%) 44/51 (86.3%) 82/87 (94.2%) 0/16 (0)

err

(fibromyalgia) and non-rheumatic diseases (Crohn's disease) had normal values; Conclusions: (a) the highest serum values were observed in patients suffering from WG/PAN, polymyalgia rheumatica and RA but abnormally high serum levels were also frequently encountered in other joint diseases; (b) soft-tissue diseases (c) MMP3 serum levels probably reflect the degradation of the matrix, a dominant but not exclusive situation observed in RA.

95. ANTI-TNF-rx ANTIBODIES INDUCE A DIFFERENT CYTOKINE BALANCE IN OKT3- AND LPS-STIMULATED WHOLE BLOOD CELLS IN NORMAL SUBJECTS C Ribbens, B Andre, Y Vrindts, 0 de Groote, MG Malaise. Rheumatology Dept., University of Liege, Belgium Introduction. Since the capture of TNF-rx after treatment with anti-TNF-rx antibodies (Abs) is accompanied by a significant decrease in the serum levels of IL-6, IL-1~ and by an increase in IL-10 serum levels, we tested the hypothesis that this cytokine modulation might be due to direct interactions between Abs and circulating white blood cells (WBCs). Methods. Whole blood was incubated for 48 h with 10 ~g/ml of either a neutralizing anti- TNF-a monoclonal antibody (Mab), a neutralizing anti-IL-1 0 Mab or an isotype control Mab (Biosource), in the presence of 10 ~g/ml soluble OKT3 (Cilag) (lymphocytic trigger) or of 1 ~g/ml LPS (Sigma) (monocytic trigger). TNF-rx, IL1 ~, IL-6, IL-8 (all cytokines ng/ml), GM-CSF (pg/ml) , IL-10 (pg/ml) and IFN-y (Ul/ml) levels were assessed using specific EASIA

Abstracts

456 methods (Biosource). Results (mean ± SEM of 5 experiments) are shown in the Table [* P< 0.05 (anti-TNF-ex vs RPMI); ** P < 0.05 (anti-IL-10 vs RPMI)]. OKT-3 (10 RPMI

TNF-o: IL-1 ~

IL-6 IL-8 IL-10 IFN-y GM-CSF

2.1 % 0.4 0.6 ± 0.06 0.6.0.2 3.5 . 0.7 45:t 13.4 29O:t 68

550:t 45

LPS (1 ~glm l)

~glml)

anti-TNF-ex

anti-IL-l0

RPMI

anti-TNF-ex

anti-IL-l0

0

3.0 ~ 0.7 •• 0.9 e 0.1" 1.3:t 0.3·· 3.9.0.6 0

3.4 ± 0.6 1.6 ~ 0.2 12.2.1.4 11.0.0.7

0

7.2 :t 1.7 ** 3.3 ± 0.3"* 20.9.3.6 19.2 . 3.1" 0 276:t 74· · 309.70"

0.3:t 0.05 *

0.8.0.2 1.2 . 0.2' 103 :t 35.3"

clinical -biological evaluation will later define how much this new tool may help the rheumatologist.

132:t 17.4

1.6:t 0.2

10.8.1.4 10.5:t 1.3

53 :t 8"

144:t 38*

544

84*-

60 :t.13

49 ± 8. 5

295 :t 42*

677.110

58 ± 14

123.42'

:t:

Conclusions: (a) anti-TNF-ex and anti-IL-10 Abs completely blocked the OKT-3- and LPS-stimulated production of TNF-ex and IL-10, respectively; (b) anti-TNF-ex Ab significantly reduced the production of IL1-b, IL-S, IFN-y and GM-CSF, and significantly enhanced that of IL-10, in OKT-3 stimulated WBCs; (c) in LPS-stimulated WBCs, it significantly reduced the production of IL-10 and enhanced that of GM-CSF without any significant changes for all other cytokines tested; (d) in both systems, antiIL-10 Ab significantly enhanced the production of all cytokines tested (except for unchanged levels of IL-S and GM-CSF in OKT-3 WBCs); (e) in addition to their capacity to inhibit TNF-ex, anti-TNF Abs also induce an anti- inflammatory response only in OKT-3 stimulated WBCs. Anti-TNF-ex Abs exert threfore more effects than a mere inhibition of TNF-ex in antigen-driven immune reaction. Application to RA WBCs is under development.

96. GLUCOSE METABOLISM IN RHEUMATOID ARTHRITIS KNEE JOINTS BEFORE AND AFTER INTRA-ARTICULAR METHOTREXATE INJECTION : QUANTIFICATION BY POSITRON EMISSION TOMOGRAPHY: PRELIMINARY RESULTS C Beckers, 0 Kaye, L Mathy, P Rigo, MG Malaise. Department of Nuclear Medicine & Rheumatology, CHU Sart-Tilman, Liege Introduction. Positron emission tomography (PET) allows noninvasive investigation of the physiology of articular structures. [1SF]-f1uoro-2-deoxyglucose (FOG) has been noted to be much higher in inflamed tissues, thus PET with FOG may provide a new imaging modality of inflammation Purpose. To define glycolytic characteristics of rheumatoid arthritis (RA)-inflamed knee joints with PET in basal conditions and after monthly intra-articular methotrexate (MTX) injections. Material and methods: Seven RA patients with clinically active inflammation of knee joints (n=S) were investigated prospectively with PET-FOG. MTX (10-30 mg) was injected in the knee once in 3 patients and twice at four -week interval in 3 patients. PET was recorded 1 month after the injection. From PET images, standard uptake values (SUV) were calculated on the side of painful knees. Results: In all symptomatic knees, a regional FOG increased uptake [SUVs: 3.22 ± 0.7 (mean ± SO) (min: 1.8-max: 4.1)] was localized in tissues surrounding the bony structures of knees but never in bones. In all cases, ultrasonography (US) confirmed the existence of a synov itis. As controls, SUVs of asymptomatic knees were negligible, localized in the soft tissue area, and comparable to those obtained in normal subjects (lower than 1%). After MTX injection, SUVs interestingly reduced in 4 subjects and remained unchanged or increased in 2, mimicking the clinical evolution while US measurements did not change. Conclusions: (a) FOG PET enables non invasive detection of symptomatic synovitis; (b) a transient decrease in SUVs has been observed after intra -articular MTX administration but the adequate dose -regimen still needs to be determined; (c) a systemic survey of parameters obtained by PET-FOG, US and by the

97. DETERMINATION OF INTRACELLULAR INTERLEUKIN-1~ INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR- ex IN MONOCYTES OF RHEUMATOID ARTHRITIS PATIENTS AND RELATIONSHIP WITH OSTEOPOROSIS PARAMETERS A Verbruggen, LS De Clerck, CH Bridts, WJ Stevens. Department of Immunology, Allergology and Rheumatology, University of Antwerp, UIA, Antwerp, Belgium Experimental data suggest that proinflammatory cytokines such as interleukin-1 ~ (IL-1 ~), interleukin-6 (IL-6) and tumor necrosis factor-ex (TNF-ex) are important in the pathogenesis of osteoporosis in rheumatoid arthritis. Therefore we compared the production of these cytokines by monocytes in 10 rheumatoid arthritis patients and 10 age and sex matched controls. Intracellular cytokine levels were related to disease activity parameters, bone mineral density (BMD) corrected for age and sex (Z-scores) and osteocalcin as a laboratory parameter of bone remodelling. Cytokines were determined by a flow cytometrical techn ique. There was a tendency for higher intracellular IL-1 ~ levels in patients, compared to controls. A positive correlation between ESR and spontaneous production of monocytic cytokines was found. Z scores of the lumbar spine showed a negative correlation with spontaneous production of IL-1 ~ and IL-6. Plasma osteocalcin levels were positively correlated with spontaneous production of IL-1~, IL-6 and TNF-ex. In conclusion, the correlation of the levels of these cytokines with parameters of bone metabolism and osteoporosis suggest that especially IL-1 ~ and IL-6 are associated with more pronounced osteoporosis in active rheumatoid arthritis.

98. FLOW CYTOMETRIC DETECTION OF TYPE 1 (IL-2, IFN-y) AND TYPE 2 (IL-4, IL-S) CYTOKINES IN T-HELPER AND T-SUPPRESSOR/ CYTOTOXIC CELLS IN RHEUMATOID ARTHRITIS, ALLERGIC ASTHMA AND ATOPIC DERMATITIS AJ Schuerwegh, LS De Clerck, L De Schutter, CH Bridts, A Verbruggen, WJ Stevens . Departement of Immunology, Allergology and Rheumatology, University of Antwerp, Belgium T-helper 1 (Th1) cytokines (a.o, IL-2 and IFN-y) play an important role in the pathogenesis of rheumatoid arthr itis (RA). On the other hand , IgE mediated diseases such as allergic asthma (AA) and atopic dermatitis (AD) appear to show a Th2 cytokine (a.o. IL-4 and IL-5) profile. This study examined the intracellular production of IL-2, IFN-y, IL-4 and IL-5 of T-Iymphocytes of patients with RA; treated with methotrexate (RAMTxl or salazopyrine (RAszl, AA and AD compared to healthy controls. A f1owcytometric method with three-color analysis was used for cytokine detection in T-helper cells (CD3+CD8-) and T-suppressor/cytotoxic cells (CD3+CD8+). A sign ificantly increased number of IL-2 producing T-helper and T-suppressor/cytotoxic cells was found in RA patients compared to patients with allergic asthma and atopic dermatitis. The IL-4 production of stimulated Tsuppressor/cytotoxic cells of both RA patient groups was higher than in patients with atopic dermatitis or allergic asthma.There was a positive correlation between the number of IFN-y pos itive T-helper cells and disease activity in the RA groups (r=0.48, p=0.02). For IL-S less consistent differences were found . In conclusion: despite therapy Th1 cytokines predominate in RA compared to AA and AD. In addition, cytokine profiles also differ in stimulated T-suppressor/cytotoxic cells between the 3 diseases.

Abstracts 99. PREDICTIVE VALUE OF RHEUMATOID FACTOR AND DRB1 SUBTYPING FOR SEVERITY IN A PROSPECTIVE FOLLOW-UP OF AN EARLY RHEUMATOID ARTHRITIS PATIENT COHORT R Westhovens, G Romanus, A Boonerr", J Tirry, J Joly, M Spaepen', J Dequeker. Depts. of Rheumatology and 'Human Genetics, University Hospitals K.U.Leuven, Belqiurn .vDept. of Rheumatology, University Hospital Maastricht, The Netherlands Predictive factors for RA severity are important in early intensive treatment strategy. Pitfalls in studies are selection biases and their cross-sectional nature. We report on a prospective follow-up of a non-selected early RA patient cohort (n=60, 1 month disease duration) not yet treated with DMARDs and/or steroids at start. All patients but 2 were on DMARDs during follow-up in attempt to lower DAS (Disease Activity Score) below 2.3. X-rays were taken every 6 months and scored (modified Sharp-Vanderheyde method) by two independent observers. HAQ and DAS scores were determined every :!: 4 months. Male/female ratio = 26/34; 51.7% were rheumatoid factor (RF) +. Following DRBl alleles were found more frequently than in a control p~ulation (n=203). DRBl 0401 (OR: 3.61; 95% CI 1.966.8; p<10 ), DRBl 0404 (OR; 4.03; 95% CI1,44-11.10; p<5.10-' and DRBl 0408 (OR 4.39; 95% CI1.01-19.81; p<0.05). X-ray damage score at baseline did not correlate with sex, age, disease duration, DAS, HAQ, RF or shared epitope positivity neither did the change of damage score between week 0 and 56. In a multiple regression model only damage score at week 0 did correlate with the week 0-56 change (p<0.0003). In a similar model, change of damage score between week 0 and 80 did correlate with damage at baseline (p<0.003) and RF+, (p<0.02).In patients with no or minor damage at baseline there was a positive correlation between damage score at week 56 (p<0.05) and week 80 (p<0.01) with RF+. Those starting with .already higher damage score (>5) at baseline did behave similar regardless of RF. In conclusion only X-ray score at baseline and rheumato id factor did predict further damage; RF did so in patients with almost no damage at onset. DRBl subtyping did not predict X-ray damage.

100. COMPARISON OF HLA-DRB1 TYPING BETWEEN RHEUMATOID ARTHRITIS PATIENTS OF AFFECTED SIB PAIR FAMILIES AND SINGLE CASE FAMILIES R Westhovens for ECRAF (The European Consortium on Rheumatoid Arthritis Families). Dept. of Rheumatology, University Hospitals Leuven, Belgium Two different family resources are used to search for new rheumatoid arthritis (RA) susceptibility genes: ASP (affected sib pair) families for linkage analysis to identify susceptibility loci and TDT (single case families with both parents for the transmission disequilibrium test) families for association studies at these loci to identify susceptibility alleles. To test whether the 2 resources are similar for RA genetic factors we compared them for the HLADRB1 typing of RA cases HLA-DRB1 typing was done in RA cases of ASP (1 RA case/ family chosen at random) and TDT families used for the screening (90 ASP and 99 TDT) and for the replication tests (272 ASP and 99 TDT). The frequency of the shared epitope in single and double dose genotypes were compared. In the screening sets we found no significant differences for RA cases with shared epitope single dose, double dose and no dose respectively in ASP versus TDT cases: 45% versus 44%, 36% versus 26%, 19% versus 30%. In the replicat ion sets similar results were found: 53% versus 56%, 23% versus 22%, 24% versus 22%. We conclude that there are no major genetic differences between ASP and TDT cases as far as the shared epitope is concerned. Therefore findings of susceptibility loci in ASP

457 families can be considered of value also for RA patients without affected family members.

101. GELATINASE B IN JOINT DISEASES: MEASURING NET PROTEOLYTIC ACTIVITY OF A METALLOPROTEINASE B Grillet, J Dequeker, G Opdenakker, Y St-Pierre. Dept. of Rheumatology, University Hosp itals, KU Leuven Gelatinase B is a metalloproteinase, like collagenases and stromelysins, involved in the degradation of the extracellular ground matrix of the connective tissue. It is believed to promote the migration of cells involved in inflammation and in cancer. On stimulation, the progelatinase is de novo synthesized by a great number of cells. Neutrophils contain progelatinase B in specific granules, that are emptied on stimulation. Similarly to the other metalloproteinases, progelatinase is activated by proteolysis, once released in the extracellular space. Its net proteolytic activity is inhibited by natural occurring inhibitors. The presence of gelatinase has been documented in inflammatory joint diseases. As the presence of enzyme is not a proof for net proteolytic activity, we sought for net proteolytic activity in the synovial fluid of patients with different joint diseases. Two hundred fifty four synovial fluid samples were analysed for the presence of gelatinase B and for the presence of gelati nolytic activity. Gelatinase B was detected by zymography. Net proteolytic activity was demonstrated by fluorescent activated substrate conversion analysis (FASC analysis). Gelatinase B is found in 94% of the synovial fluid samples, but only in 20% of patients with degenerative joint diseases. Net gelatinolytic activ ity was detected in 60 of the 254 samples (24%). Activ ity was seen in 25% of the rheumatoid arthritis patients and in 23% of the spondylarthropathy patients. It was never found in the patients with degenerat ive joint diseases. The presence of net gelatinolytic activity in the synovial fluid demonstrated that gelatinase B production and activation is not counterbalanced by inhibition in 25% of synovial fluid samples . Net activity was never seen in degenerative joint disorders.

102. POLYMORPHISMS IN THE IL-1 GENE CLUSTER AND SEVERITY. OF RHEUMATOID ARTHRITIS R Westhovens , M Spaepen", A Boonen?", A Cox", NJ Camp'", M Dale", GW DuW'. Depts. of Rheumatology and 'Human Genetics , University Hospitals K.U.Leuven, Belgium and "Division of Molecular and Genetic Medicine University of Sheffield, UK, "'University Hospital Maastricht, The Netherlands Given the central role of the cytokines tumour necrosis factor (TNF) and interleukin-1 (IL-1) in the inflammatory process, the genes encoding for these proteins are reasonable candidates for determining susceptibility and/or severity of rheumatoid arthritis (RA). The genes for IL-1 o; IL-1 ~ and IL-1 receptor antagonist are clustered within 430kb on chromosome 2 (2q13). Polymorphic markers of these genes have previously been found to be associated with other autoimmune and inflammatory diseases. In the present study, four markers (IL1A +4845, 1L1 B+ 3953, IL1B - 511, and IL1RN +2016) were examined in an association study of phenotypic markers of RA: rheumatoid factor (RF) and X-ray damage (modified Sharp-Vanderheyde score). The study group was a prospective non-selected patient cohort of 60 consecutive patients seen in a single centre and not yet treated with DMARDS and/or stero ids. For each marker, association of RF and at least one copy of allele 2 was analysed with 2x2 contingency tables. Association for damage at baseline and further development of damage with carriage of allele 2 was analysed with the Mann Whitney U-test. No statistically significant associations were found, although

458 there were some trends towards increased carriage of allele 2, for example in RF+ patients. In conclusion, despite the prospective follow-up design and our focus on very early RA patients, we were not able to demonstrate significant correlations between carriage of allele 2 of four IL-1 markers and phenotypic expression of the disease defined by rheumatoid factor and X-ray damage, the latter assessed by a method with a reasonable sensitivity to change . However, this preliminary study had relatively low power. The role of the IL-1 gene cluster in RA needs further investigation.

103. CHANGES IN BODY COMPOSITION IN EARLY RHEUMATOID ARTHRITIS R Westhovens, A Boonen*, H Borghs, J Tirry, J Joly, J Dequeker. Depts of Rheumatology, University Hospitals Leuven and *Maastricht Objectives were to assess prospectively bone mineral density (BMD) changes at different body sites as well as changes in body composition parameters [lean body mass (LBM),% body fat, fat distribution ratio (FOR)] in relation to disease activity and severity in a non-selected cohort of 60 newly diagnosed RA patients seen in a single centre and not yet treated at baseline with DMARDs and/or steroids (median disease duration 1 month). All parameters were assessed on a DPX-L scan (Lunar) every 6 months. Disease activity and severity were regularly assessed by HAQ and DAS and erosiveness on X-ray (modified SharpVanderheyde method) was evaluated every 6 mo. We report on 80 weeks of follow-up. BMD data are expressed as Z-scores and % change from baseline. Also body composition data are expressed as % change from baseline and for patients >45 yrs (n=39), a control group was available (n=103). At baseline, Z-scores for BMD (L2-L4 and femoral neck) were not different from controls nor according to the grade of X-ray damage. BMD loss is higher dur ing follow-up according to X-ray damage at baseline as well as to further development of erosions; this for axial- as well as for hip BMD (significance reaching p<0.05).% body fat signif icantly increased over time, especially in females with major erosion development, and compared to healthy controls (p<0.001). LBM decreased over the same 1year period (p
104. A PROSPECTIVE STUDY ON COPING STRATEGIES AND MORBIDITY IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS R Westhovens, G Romanus, G Belis, G Crombez*. Dept. of Rheumatology, University Hospitals K.U.Leuven, and *Dept. of Psychology, K.U.Leuven, Belgium There is considerable variety in how RA patients cope with stressors in life (e.g. disease related stressors). Poor adjustment can lead to poor perceived physical, emotional and social functioning and high RA impact. We looked for correlations between disease activity and different aspects of outcome, and also for different coping styles and their relationship to future morbidity in a prospective study of a non-selected cohort of 60 consecutive newly

Abstracts diagnosed RA patients (median disease duration ± 1 month). Coping styles were assessed at week 0 with the UCL (Utrecht Coping List). Disability, quality of life and disease activity at week o and 56 were assessed by HAQ, IRGL (Invloed van Reuma op Gezondheid en Leefwijze), an adapted and in Dutch translated AIMS and DAS respectively. IRGL measures physical, psychological, social well-being and total RA impact. HAQ and DAS were highly correlated during follow-up and improved over 56 weeks (p
105. DAILY HA~SLES REPORTED BY FIBROMYALGIA / CHRONIC FATIGUE SYDROME PATIENTS IN TERTIARY CARE COMPARED TO RHEUMATOID ARTHRITIS AND MULTIPLE SCLEROSIS E Neerinckx' , R Westhovens 2, B Van Houdenhove", lGrant recipient of the Fund for Scientific Research (FWO) Vlaanderen, 2Dept. of Rheumatology, University Hospital Leuven, 3Dept. of Psychosomatic Rehabilitation University Hospital Leuven, Belgium

Objectives: to gain an insight into the level and the nature of stressors, experienced by patients at the eve of a diagnosis of 'fibromyalgia syndrome' (FM) or 'chronic fatigue syndrome' (CFS). Moreover, links with the symtomatology were investigated. Methods: two hundred twenty nine consecutive patients (180 women, 49 men) attending an interdisciplinary university fatigue and pain clinic completed during their screening a Daily Hassles Scale (Alledaagse Problemenlijst, Vingerhoets & van Tilburg, 1994) and questionnaires measuring fatigue (MFI), pain (MPQ), depression (BDI) and anxiety (STAI). Results were compared with those of 26 multiple sclerosis patients (MS) (20 women , 6 men) and 26 rheumatoid arthritis patients (RA) (21 women, 5 men) with a comparable duration of symptoms. Results: The large majority of CFS/FM pat ients were confronted with high or very high numbers of daily hassles during the last two months preceding the consultation; moreover, the mean emotional impact of these stressors was exper ienced as (extremely) burdening. Analysis as regards contents reveals 3 main themes : (1) frustration (especially about personal capacities), (2) uncertainty about the future, (3) identity and relational problems. On the contrary, MS and RA patients show a significant lower number and lower emotional impact of daily hassles. Moreover, for both groups, contents show a much larger diversity: RA as well as MS patients are clearly less focused on personal deficiency. High correlations are found between (the number and emotional impact of) the stressors and depression and anxiety in CFS/FM. On the contrary, fatigue and pain correlate rather moderately with these. Conclusion: stressors focused on personal failure may playa key role in tertiairy care CFS/FM patients. These findings will be discussed in the light of recent etiological models.

Abstracts 106. SUSCEPTIBILITY FOR RHEUMATOID NODULES IS ASSOCIATED WITH TYPE II COLLAGEN GENE POLYMORPHISM IN PATIENTS WITH RHEUMATOID ARTHRITIS C VandeTer1, J Vanhoof" P Stinissen1,2, K Declerck" JJ Cassiman , J Raus1,2, P Geusens1 ,2. lOr. L Willems-Instituut, Diepenbeek, 2Limburgs Universitair Centrum, Diepenbeek, 3Centrum voor Menselijke Erfelijkheid, K.U. Leuven, Leuven, Belgium Objectives. To investigate whether collagen type II gene (COL2A1) alleles, either alone or in combination with a particular HLA-genotype, are associated with rheumatoid arthritis (RA) or clinical subgroups of RA. Methods. A Pvu II diallelic polymorphism of the collagen type II gene was analysed in 228 patients with RA, and in a group of 497 control subjects. Results. Similar allele frequencies of the COL2A1 dimorphism were observed in RA patients and controls. However, in RA patients manifesting rheumatoid nodules a significant overrepresentation of the PP genotype was observed, resulting in an increased odds ratio (OR) of 4.02 (95% confidence interval (CI): 1.33-12.16) compared to controls. Rheumatoid nodules were found in 38% of the DR4-positive patients with the PP genotype and in 8% of the DR4-negative patients with the pp genotype (OR 11.63, 95% CI: 2.38-56.91). Conclusion. No association of the alleles of the type II collagen gene with RA was found in the whole RA population. However, in the subgroup of RA patients with rheumatoid nodules a positive association with the COL2A1 dimorphism was found, suggesting that this gene polymorphism may playa role in the development of rheumatoid nodules, independent of and additive to the presence of the HLA-DR4 genotype.

459 specific TCR V gene repertoire. The restriction is more pronounced in the early RA population than in the chronic RA populaton and is similar in SF and ST samples of the same patient or in paired SF samples of a patient with bilateral synovitis.

108. IN VITRO EFFECTS OF ALENDRONATE ON T LYMPHOCYTE PROLIFERATION L Celis", P Stinissen1 ,2,P Geusens 1,2, J Raus 1,2. 1 Department of Autoimmune Disease, Dr. L Willems-Instituut and 2Limburgs Universitair Centrum, Diepenbeek, Belgium Bisphosphonates are potent inhibitors of bone resorption. To study the possible immonoregulatory effects of bisphosphonates, we analyzed the in vitro effects of alendronate (4-amino -1hydroxybutylidene-1 ,1-bisphosphonate) on the proliferation of T lymphocytes induced by mitogen (phytohemagglutinin), superantigen (staphylococcal enterotoxin B) and antigen (tetanus toxoid), and on the proliferation of immortalized T cell, B cell and lymphocyte progenitor cell lines. Cell proliferation was measured using a [3Hjthymidine incorporation assay. Alendronate concentrations ranging from 10.5 to 10.4 M significantly inhibited antigen-induced T cell proliferation in a dose-dependent manner. Alendronate did not inhibit T cell proliferative responses induced by mitogen and superantigens. A biphasic response was found on the myelogenous cell line K-562. At concentrations of 10-5 M alendronate increased proliferation, while at concentrations of 5x10· 5 to 10.4 M alendronate suppressed the myelogenous cell growth. No effect was observed on immortalized B cell lines (Daudi and RPMI 1778), while immortalized T cells (Jurkat) were inhibited at 2x1Q-4 M of alendronate. We conclude that alendronate suppresses T cell proliferation induced by antigens, most likely by inhibiting antigen processing and/or presentation of antigen presenting cells.

107. RESTRICTED T CELL RECEPTOR V GENE USAGE IN THE SYNOVIUM OF PATIENTS WITH RHEUMATOID ARTHRITIS A VanderBorght, P Geusens, J Raus, P Stinissen. Dr. L Willems Instituut and Limburgs Universitair Centrum (LUC), Diepenbeek, Belgium Rheumatoid Arthritis (RA) as an autoimmune disease characterized by a chronic inflammation of the synovial tissues of multiple joints. Autoreactive T cells are thought to play an important role in the disease pathogenesis. To study the autoreactive T cell respons in RA we determined the T cell receptor (TCR) Variable M gene usage in the blood and the synovium of RA patients and non-RA controls, using the semiquantitative PCR-ELISA. Variable gene segments of the alpha (AV) and beta chain (BV) of the TCR were PCR amplified using AV and BV region specific primers, and. the PCR amplicons were quantified using an ELISA based method. Over or under representation of particular V gene elements at the site of the disease were determined. Peripheral blood (PB), synovial fluid (SF) and if available .synovial tissue (ST) from 7 early « 1y) and 31 chronic RA patients were studied and compared with 5 Osteoarthritis (OA), 4 Psoriatic Arthritis pat ients (PA) and 5 healthy subjects (NS). A homogeneous expression of all TCR V genes was observed in the PB of RA patients and nonRA control subjects. All synovial cavity samples were characterized by a restricted V gene expression, which varied among patients. Furthermore, the mean number of TCR V genes overrepresented in the synovium of chronic RA patients (AV: 3.50, BV: 3.70) was significantly higher than in the early RA population (AV: 1.60, BV: 2.12). Furthermore, two different synovial samples were available from 9 RA patients, for instance left and right knee SF or SF and ST of the same knee joint. We found a similar TCR V gene profile in all synovial samples of the same patient. Overrepresented TCR V genes are now further characterized for their hypervariable CDR-3 region sequences,which will provide information on their clonal composition We conclude that T cells infiltrating into the synovium of RA patients and non-RA controls have a restricted and patient

109. INTRAVENOUS LOADING DOSE OF AZATHIOPRINE (AZA) IN ACTIVE RHEUMATOID ARTHRITIS (RA) P Durez", JP Desage~, T Appelboorn'. Hopital Erasme, Department of Rheumatology" Universite Libre de Bruxelles, Brussels, and Department of Pharmacology'', Louvain Medical School, Belgium Objective. Azathioprine (AZA), an effective prod rug for RA since 20 years, is limited by a prolonged time to response. This delay may depend on the time to reach a steady-state concentration of the AZA metabolites 6-thioguanine nucleotide (6-TGN) The aim of this study was to determine the safety and utility of an intravenous loading dose of AZA to treat active RA. Methods. Accordingly, patients (n=9, 8 women, age 52±5 yrs, duration of RA: 5±2.2 yrs, RF+ 8/9) suffering from active RA with stable dose of prednisone «10 mg/d) and NSAIDs were enrolled. Patients were given an intravenous infusion of AZA (40 mglkg for 36 hours) followed by oral form (AZA 2 mg/kg/d). Response and tolerance were determined by physical and biological assess ment. Before study entry, erythrocyte concentrations (RBC) of thiopurine methyltransferase (TPMT) was determined and measurement of 6-TGN were performed during the trial by chromatography. Results. 8/9 patients reported a subjective improvement within 2 weeks and 5 of 8 achieved remission. AZA had sign ificant effect on CRP, RF titer and IgG levels. No noticeable difference was observed in lymphocyte subpopulations. Peak concentrations of 6-TGN occurred within 36h and decline with the oral form (329±48 Vs 148.5±30.5 pmol/8 108 RBC at 3 months). No clear correlation with AZA metabolites and clinical response was noted. No side effect was noted. Conclusion. We conclude that a 40 mg/kg intravenous loading dose of AZA for 36 hours is safe and effective in RA and may decrease the time to clinical response.The monitoring of 6-TGN

460 could bring some benefit to better achieve immunosuppression in RA. Further trials should determine the correlation between level of 6-TGN and clinical response.

110. AN ATYPICAL PRESENTATION OF RHEUMATOID ARTHRITIS E Kruithof, A Stuer, H Mielants, EM Veys. Department of Rheumatology, Univ. Hosp. Ghent A 23 year old woman presented with mechanical pain at the left hip region, which started about 5 months before entry. No trauma had occurred. About 6 months before , a son was born, after an uncomplicated pregnancy. Examination of the coxofemoral joints revealed normal mobility, though with a painfull flexium and internal rotation at the left joint and a M.Quadriceps atrophy at this side. Laboratory findings included a slightly elevated ESR of 28 mm/1 h, a C-reactive protein of 0.92 mg%. Serology including RF, APF and ANF was negative. Radiological examination of the left coxofemoral joint revealed a narrowing at the upper external part of the joint without any reactional remodellation. No intraarticular effusion was detected on ultrasonography. The diagnosis of rapidly progressive destruction of the left coxofemoral joint of unknown etiology was made and a treatment consisting in rest for 4 weeks , NSAID and physiotherapy was started. During the follow up period, she had two more pregnancies, during which the NSAID were stopped with relief of symptoms. However during the third postpartal period she developed a symmetric polyarticular involvement of shoulders, hands, knees and feet. Latex fixation and anti-perinuclear factor were both positive. Radiological control however revealed futher narrowing at the upper-external part of the joint with subchondral sclerosis, cystforrnation and signs of remodellation. The diagnosis of Rheumatoid Arthritis was made and a treatment with MTX and NSAID was started. A total hip prothesis was futhermore placed without any complications. This atypical clinical presentation of A.A. with a monoarthritis of the left hip joint for more than 4 years before polyarticular onset is probably caused by disease remission during the 3 consecutive pregnancies; this would also explain the atypical radiological findings of repair in the involved joint.

111. SEPTIC ARTHRITIS WITH LISTERIA MONOCYTOGENES IN A PATIENT WITH RHEUMATOID ARTHRITIS TREATED WITH CORTICOSTEROIDS F Raeman, R Joos, K de Vlam. Dept of Rheumatology, Service of Internal Medicine, AZ Jan Palfijn, Merksem - Antwerpen, Belgium A 60 year old woman with seropositive rheumatoid arthritis was admitted in the hospital on 01/10/1997 with pain at the left hip, subfebrility, nausea and anorexia. At admission she was treated with prednisolone 10 mg; ticlopedine, furosemide, digoxine, Isoten, and celecoxib (a new cox-2 antagonist). Rotation of the left hip was limited as well as the flexion (90°). Laboratory exam showed elevated sedimentation rate (106 mml hr), CRP (11.3 mg%) and normal leukocyte count. X-rays revealed an osteolytic zone at the left ileum. CAT scan illustrated a supra-acetabular cyst in conjunction with the hip joint. Puncture of the left hip showed purulent fluid with 86000 WBC/mm 3 • Listeria Monocytogenes was cultured from the fluid . Treatment was started with cloxacilline 6 x 1 g IV/day during six weeks, followed by an oral treatment of ofloxacin 400 mglday during another six weeks. The hip was drained surgically as soon as the bacteriologic results were known . Evolution was favourable and the patient was discharged from the hospital on 22/111 1997 with a fair hip function.

Abstracts A literature overview shows the reporting of another 16 cases with Listeria Monocytogenes septic arthritis 1 •2 •3 .4. All these patients had an underlying condition compromising their immunity. These cases are discussed and compared with the patient above. References 1.Gispen AG, Alarcon GS, Johnson JJ: Toxicity of methotrexate in rheumatoid arthritis. J. RheumatoI1987:14:74-79. 2.McCambridge MM, Vogelsang SA, Ockenhouse CF: Listeria Monocytogenes in a patient treated with methotrexate for rheumatoid arthritis. Case report. J. RheumatoI1995:22:786-787. 3.Louthenroo W, Schumacher HR:Listeria Monocytogenes osteomyelitis complicating leukemia: report and literature review of listeria osteoarticular infections. 4.Massarotti EM, Dinerman H:Septic arthritis due to Listeria Monocytogenes: report and review of the literature.

112. CHOLESTEROL CRYSTALS PERICARDITIS: A LIFE THREATENING COMPLICATION OF RHEUMATOID ARTHRITIS C Gregoir, C Henuzet, M Piagnerelli, J-S Azagra, P* Delree. CHU A. VESALE, Montigny Ie Tilleul, *IMP Loverval, Belgium According to post-mortem and echographic studies, pericarditis occurs in approximately 40% of rheumatoid arthritis patients. However, clinically apparent rheumatoid pericarditis is unusual. A case of tamponade has been reported in rheumatoid pericarditis conta ining cholesterol crystals and IgE immune complexes (1). We report two cases of severe rheumato id pericarditis containing high levels of cholesterol or cholesterol crystals. An 80 year old woman who suffers of rheumatoid arthritis for 30 years entered the intens ive care unit for acute atrial fibrillation and cardiac failure. The echocardiography revealed pericardial effusion removed by pericardiocentesis. Fluid examination showed a large amount of cholesterol; cultures for mycobacteria were negative. Despite immunosuppressive treatment the pericardial effusion recurs and a surgical drainage was needed; histology confirmed inflammatory fibrinoid pericarditis. 4 years later the patient is still alive. A moderate pericardial effusion was diagnosed in a 71 years old man who suffered of rheumatoid arthritis for 20 years. The initial response to prednisolone and azathioprine treatment was good; but four month later the patient developed acute cardiac and renal failure and died despite pericardial drain and dialysis. At autopsy the pericardium showed multiple deposits of, cholesterol crystals and chronic inflammatory pericarditis; fungi and mycobacteria were negative. The presence of cholesterol in pericardial effusion might be explained by lymphatic circulation obstruction; these two cases suggest that it is of poor prognosis in rheumatoid pericarditis and should lead to surgical drainage to prevent tamponade. (1) Van Offel JF, Clinical Rheumatology; 10: 78-80,1991 .

6. OSTEOARTHRITIS AND CRYSTAL ARTHROPATHIES 113. RELATIONSHIP BETWEEN CALCIUM CRYSTALS AND OSTEOARTHRITIS M Doherty. Rheumatology Unit, City Hospital, Nottingham, UK Observat ions that support an assoc iation between osteoarthritis (OA) and deposition of calcium pyrophosphate (CPPD) and basic calcium phosphate (BCP) crystals with in cartilage include: higher than expected concordance of x-ray chondrocalcinosis (CC) and

Abstracts knee OA in epidemiological studies; the high incidence of postmeniscectomy CC; and premature onset of localised CC at sites of prior joint injury or disease. The negative association between rheumatoid arthritis and CPPD deposition suggests that the tendency to CC relates primarily to the OA process. The view of OA as the inherent repair process of synovial joints helps explain: its evolutionary preservation; the increased metabolic rate and tissue production in OA joints; frequent discordance between symptons and OA structural change; and the generally good outcome of OA. During skeletal growth joint cartilage is characterised by the presence of certain "neo"epitopes, abundant subchondral vasculature, and tendency to calcification. In maturity, neo-epitopes are not expressed, vasculature dim inishes, and cartilage calc ification ceases. However, if the joint experiences insult and needs to produce new tissue (ie "OA") neo-epitopes are re-expressed and angiogenesis and cartilage calcification again are prominent. The mechanisms of CPPD and BCP deposition interrelate and depend on (1) the ionic products of calcium, phosphate and pyrophosphate (PPi), and (2) relative concentrations of tissue inhibitors and promoters of crystal nucleation and growth. In OA there is increase in PPi, reflecting increased cell synthesis and division. However, alteration in tissue factors is probably even more important. Genetic studies of rare, extended families with florid CC, in whom PPi metabolism is normal, may help determine the nature of these tissue factors. Crystal deposition has been used as a marker for OA "subsets", CPPD being linked with "hypertrophic" and BCP with "atrophic" OA. Evidence for such discrete subsets, however, is lacking. The consequences of crystal deposition in OA remain unclear. Shedding of preformed CPPD from cartilage may cause acute synovitis ("pseudogout"), and smaller crystal loads may cause lesser OA "flares". Calcium crystals act as an abrasive at the cartilage surface, but intra-cartilaginous deposition may have beneficial, .as well as adverse mechanical effects, such as absorption of potential toxins (especially by BCP).

114. THE DIAGNOSIS AND MANAGEMENT OF ACUTE CRYSTAL-INDUCED ARTHRITIS

461

115. CLINICAL FOLLOW-UP OF PATIENTS WITH OSTEOARTHRITIS OF THE KNEE. COMPARISON OF LEQUESNE AND WOMAC FUNCTIONAL INDICES G Verbruggen 1 , P Ghosh 2 , D Cullis-Hill'', EM Veys1. 1 Dept. of Rheumatology, Univ Hosp. Ghent. 2Raymond Purves Research Laboratories, University of Sidney. 3Arthropharm Ltd, Bondi Junction, Australia 50 patients suffering from OA of the knee joints were included in a 24-week double-blind, randomized, placebo-controlled trial. The 'SMOAD' effects of Caxylosan-polysulfate were compared with placebo. Medication was given 2 times a week dur ing two 6-week periods. Each period was followed by a 6-week wash-out time. Clinical observation was done at start and after 3, 6, 9, 12, 15, 18, 21 and 24 weeks. Amongst other parameters, clinical variables studied inluded the Lequesne and the WOMAC osteoarthritis functional indices. Both evaluation systems include a number of questions related to subjective complaints e.g. pain and stiffness, and to functional ability. The Lequesne index evaluates pain at night and while standing or walking (3 questions), morning stiffness, and the difficulties associated with some daily act ivities (6 questions). The 10 questions allow to score the patients' subjective and functional status in a scale ranging from 0 to 24 points . The WOMAC osteoarthritis index evaluates pain, stiffness and dysfunction using 5, 2, and 17 questions, respectively. The patient thus evaluates his own clinical condition on 24 '10 mm' visual analogue scales. The 24 results can be combined several ways. It was the authors' option to comb ine the 7 questions related to pain and stiffness to evaluate the subjective complaints, and to combine the 17 questions related to difficulties while conducting routine daily activities to assess functional disability. If the 24 items of the quest ionaire are combined, the WOMAC osteoarthritis index scores the patients' subjective and functional status in a scale ranging from 0 to 2400 mm or points. Patients' changes from baseline levels were recorded after 3, 6, 9, 12, 15, 18, 21 and 24 weeks. The authors looked at an eventual correlation between the changes observed with both systems in each individual after the consecutive clinical observations. Scatter diagrams and regression lines were plotted and correlation coefficients were calculated. Correlation between changes from baseline levels in both clinical scoring systems was highly significant (P<0.00001) after all observation periods. It was concluded that both the Lequesne and the WOMAC osteoarthritis index were equivalent to evaluate changes in the clinics of OA.

P Dieppe, MRC Health Services Research Collaboration, Bristol, UK Attacks of crystal-induced acute synovitis are usually monoarticular, sudden in onset, and short lasting. The three common culprits are monosodium urate monohydrate (the gout culprit), calcium pyrophosphate dihydrate (responsible for pseudogout), and basic calcium phosphates (the cause of acute calcific periarthritis). The characteristic associations. and joint distribution of .each of these three conditions makes diagnosis easy in classical cases. Treatment is also generally straightforward, particularly as the attacks are usually self-limiting. Diagnostic problems arise in atypical cases, which are not infrequent. The correct diagnosis is then critically dependent on the identification of crystals in synov ial fluids. Textbooks of rheumatology often describe the identification of urate and pyrophosphate crystals by polarised light microscopy as a simple reliable test, but it is not. The results of audits of laboratory expertise in crystal identification will be presented, and the need for quality control stressed . A new EULAR quality control activity and reference laboratory are being established and will be described. Management difficulties arise in atypical cases and in patients who get recurrent attacks. In addition, there is still wide variation in practice in the management of simple attacks of acute crystal induced arthritis. Approaches to establishing and implementing evidence based guidelines will be discussed.

116. XYLOSANPOLYSULFATE HAS 'SMOAD'-ACTIVITIES IN PATIENTS WITH INFLAMMATORY FINGER JOINT OA G Verbruqqen", P Ghosh 2, D Culiis-HiII 3, EM Veys1 . "Dept, of

Rheumatology, Univ Hosp. Ghent. 2Raymond Purves Research Laboratories, University of Sidney. 3Arthropharm Ltd , Bondi Junction, Australia Several polysulfated polysaccharides have been shown to stimulate connective tissue cell repair. Amongst these polysaccharides, xylosanpolysulfate (XPS) has been shown to increase serum fibrinolytic activity of patients with osteoarthrosis (OA). This effect may result in an improved microvascularisation and a decrease of the venous congestion in subchondral bone in OA joints. Hence, XPS may reduce pain and improve function of OA finger joints. 50 patients suffering from inflammat ory OA of their finger joints were included in a 24-week double-blind, randomized, placebocontrolled trial. Ca-xylosan-polysulfate (20 mg/kg per os) was given 2 times a week on an empty stomach during two 6-week periods. Placebo was administered at the same frequency. Each

462 period was followed by a 6-week wash-out time. Clinical observation was done at start and after 3, 6, 9, 12, 15, 18, 21 and 24 weeks. Clinical variables studied were VA-scales for global pain, morning stiffness, pain at night and dysfunction while conducting 'heavy' and 'light' daily activities. The Ghent functional index for finger joints was assessed on each visit. Other parameters included the grip -strenght of both the 'most affected' and the 'less or not affected' hand, the 'Ritchie' index (pain on palpation), and a count for analgesic drugs. Both placebo and XPS-treated groups showed improvement of most clinical variables during the second treatment period. This improvement may have resulted from a placebo-effect However, inflammat ory episodes of OA of the finger joints are known to resolve spontaneously in many of the cases. After the second treatment course the placebo group did not show any further change at all, while global pain, morning stiffness, pain at night, dysfunction while conducting 'heavy' and 'light' daily activities, the functional index for finger joints and pain on palpation significantly improved in the XPS-treated group. Grip strength and use of analgesics did not vary in either groups. The 'Disease/Structure modifying' properties in OA joint tissues of xylosanpolysulfate may have caused significant 'Symptom Modifying' effects in this inflammatory osteoarthritic condition.

117. EVALUATION BY IMMUNOCYTOCHEMISTRY AND FLOW CYTOMETRY OF HUMAN ARTICULAR CHONDROCYTE PHENOTYPE DURING DE- AND REDIFFERENTIATION IN VITRO G Verbruggen, L Wang, 0 Elewaut, C Van Der Herten, C Broddelez, EM Veys. Dept. of Rheumatology, Univ Hosp. Ghent Chondrocytes were isolated from human articular cartilage. They were kept as isolated single cells on agarose up to 3 days, or were seeded in Petri dishes or PermanoxR culture slides and cultured in the monolayer condition during 1-2 weeks. In the monolayer condition, the cells were allowed to dedifferentiate while maintained in a semisynthetic medium (Dulbecco's MEM) containing 10% FCS. In order to preserve or to restore the differerentiated phenotype, the chondrocytes were allowed to attach on polylysin-coated PermanoxR culture plates and were cultured in a serum-free medium containing insulin, transferrin and TGF-beta up to 2 weeks. Specific monoclonal antibodies (mAb) against the human aggrecan, type I, II and III collagen, chondroitinsulfate and a fibroblast antigen were used for immunocytochemical staining as well as for flow cytometric analysis to evaluate the phenotype of in vitro cultured cells. Flow cytometric analysis showed that articular chondrocytes, immediately after their isolation, fully expressed the human aggrecan and type II collagen. Type I collagen was present in significant proportions of the cells. Type III collagen was not produced and the fibroblast antigen was not expressed. When attached on polylysine-coated culture dishes and maintained in serum-free cond itions in the presence of TGF-beta, immunocytochemical staining showed full preservation of the chondrocyte phenotype though the cells began to express the fibroblast antigen . The cells characteristically grew in clusters. When maintained in FCS-containing DMEM, the chondrocytes rapidly lost their original morphology. After prolonged culture (subcultures) , increasing proportions of cells failed to produce type II collagen or the chondrocyte-specific human aggrecan. However, other non-chondrocyte-specific proteoglycans probably were synthesized since all the cells continued to express chondroitinsulfate. A number of cells started to synthetise the fibroblastspecific type I and III collagens. All cells became positive for the fibroblast antigen. The loss of the differentiated phenotype dur ing monolayer culture was demonstrated by immunocytochemical staining in situ and by flow cytometric analysis after isolation of the cells from the tissue culture plates.

Abstracts 118. EVALUATION BY IMMUNOCYTOCHEMISTRY OF SV40IMMORTALIZED HUMAN ARTICULAR CHONDROCYTE PHENOTYPE IN VITRO L Wang, G Verbruggen, 0 Elewaut, C Van Der Herten, C Broddelez, P Steenbakkers", EM Veys. Dept. of Rheumatology, Univ Hosp Ghent. #Dept. of Immunology, Organon NV, Oss, The Netherlands Immortalized human articular chondrocytes were obtained after transfection with the SV 40 oncogene. After approx. 15 passages these cells had completely dedifferentiated to fibroblast-like cells. They were seeded in PermanoxR culture slides and cultured in the monolayer condition during 1-2 weeks. The cells were maintained in the dedifferentiated state in a semisynthetic medium (Dulbecco's MEM) containing 10% FCS. In order to restore the differerentiated phenotype, the chondrocytes were allowed to attach on polylysine-coated PermanoxR culture plates and were cultured in a serum-free medium containing insulin, transferrin and TGF-beta up to 2 weeks. Specific monoclonal antibodies (mAb) against the human aggrecan, type I, II and III collagen, chondroitinsulfate and a fibroblast antigen were used for immunocytochemical staining to evaluate the phenotype of in vitro cultured cells. When maintained in FCS-containing DMEM, the chondrocytes were shown to have lost their original phenotype and failed to produce type II collagen or the chondrocyte-specific human aggrecan . However, other nonchondrocyte-specific proteaglycans probably were synthesized since the cells continued to express chondroitinsulfate. A number of cells produced the fibroblast-specific type I and III collagens. All cells were positive for the fibroblast antigen. When attached on polylysine-coated culture dishes and maintained in serum-free conditions in the presence of TGF-beta, the cells characteristically grew in clusters and immunocytochemical staining showed partial reexpression of the orig inal chondrocyte phenotype with the synthesis of type II collagen and variable amounts of cartilage-specific aggrecan. The cells still expressed the fibroblast antigen. The use of specific culture media may be a key factor in controlling the phenotype of isolated chondrocytes in 'in vitro' systems.

119. FLOW CYTOMETRIC ANALYSIS OF THE HUMAN ARTICULAR CHONDROCYTE PHENOTYPE L Wang, G Verbruggen, 0 Elewaut, C Van Der Herten, C Broddelez, EM Veys. Dept. of Rheumatology, Univ Hosp. Ghent Flow cytometry is used as a standard procedure to characterize the phenotype of circulating Iymphomyeloid cells. As a consequence of the effects of any enzymatic digestion procedure on plasmamembrane antigens, the use of the method is somewhat limited with cells isolated from tissues or from culture. When articular chondrocytes are considered, the availability of fluor" escent agents has enabled searchers to use flow cytometry mainly to study cell viability, proliferation and cell cycle characteristics, respiratory activities and free radical production. The availability of specific monoclonal antibodies (Mab) enabled the use of flow cytometry to study some plasmamembraneassociated antigens , e.g. cytokine receptors, cellular adhesion molecules, HLA class I and II antigens, membrane-bound peptidases, ... and intracellular cytokines. Except ionally, flow cytometry has been used to study the synthesis of extracellular matrix molecules. In an attempt to characterize human articular chondrocytes through the synthesis of their matrix macromolecules, chondrocytes obtained from osteoarthritic cartilage were maintained in suspension on agarose in a serum-free medium (OMEM/ insulin/ transferrin/ TGF). After 1 and 3 days, the cells were permeabilized and exposed to Mab directed against aggrecan, type I, II, and III collagen and the fibroblast antigen . Flow cytometric analysis showed that 2 types of chondrocytes had been isolated from

Abstracts osteoarthritic cartilage. One day after their isolation, a prominent population of larger cells synthesized the typical intercellular matrix molecules: articular cartilage aggrecan and type II collagen. Type I collagen was not synthesized by these cells. A minor population of smaller cells produced significant amounts of type I collagen aside of the typical cartilage intercellular matrix products. Three days after isolation, the phenotypical characteristics of these cells were more pronounced.

120. ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR-KB IN HUMAN ARTICULAR CHONDROCYTES C Bassleer, B Piret, V Bours, J Piette, MG Malaise. Laboratory of Rheumatology and Molecular Oncology, Institute of Pathology State University of Liege, Liege, Belgium Introduction. The transcription factor nuclear factor-kB (NF-kB), which is involved in the induction of the expression of a wide range of inflammatory genes (e.g. TNF-o:, IL-1~, IL-6), has been shown to be activated in synovial tissue from both osteoarthritis and rheumatoid arthritis patients. Chondrocyte metabolism is under the control of various cytokines, but it remains unknown whether NF-kB could be also involved. The purpose of the present study was to demonstrate the presence of activated NFkB in human articular chondrocytes. Methods. Human articular chondrocytes, obtained at autopsy (mean men ages: 80 years old), were isolated from the matrix by sequential digestion (hyaluronidase, pronase and collagenase), then cultivated for 24 hours and treated during 20 minutes with TNF-o: (250 U/ml) or IL-1 ~ (100 Ulml) or during 2 hours with LPS (1.25 Ilg/ml) or PDTC (pyrrolidine dithiocarbamate 100%). Nuclear extracts obtained from human articular chondrocytes were examined by electrophoretic mobility shift assay to determine the DNA-binding activity of NF-kB. Results. Markedly high DNA-binding activity of NF-kB was detected in human chondrocytes in basal conditions (= control activity: 100%); moreover, the activity was increased by IL-1 ~ (260%), TNF-o: (200%) and LPS (160%), while virtually no activity was observed in cells incubated with PDTC. Conclusions. Our results suggest that in human articular chondrocytes extracted from 80-years-old men, NF-kB is activated in basal conditions. Further, LPS and the proinflammtory cytokines as TNF-o: and IL-1 ~ markedly enhance its activity while the anti-oxydative product PDTC virtually abrogates it. As the synovial tissue, the cartilage can respond to TNF-o: or to IL-1 ~ through NF-kB activation.

121. BMP SIGNALING IN JOINT MORPHOGENESIS

463 Nature Genet. 17, 18-21 (1997). These chondrodysplasias are characterized by short limbs, the absence of a number of peripheral skeletal elements and defects in joint formation. In addition, we demonstrated the presence of CDMPs in adult human articular cartilage and suggested that these signaling molecules may contribute to the maintenance of the integrity of the joint surface (Er/acher et a/., Arthritis and Rheumatism 41, 263-273 (1998). By in situ hybridisation we are currently analyzing during joint morphogenesis in mice the expression patterns of the known BMPs/CDMPs, their receptors and signal transducing Smad proteins. We explored the functional significance of the relevant BMPs/CDMPs, receptors and Smads by a series of in vitro studies using cell lines, primary cells and transgen ic approaches. These molecular markers will allow us to understand mechanistically reparative processes in the diseased joint , and potentially indicate novel therapeutic targets to slow down joint destruction.

122. ARTHROPATHY IN HEMOCHROMATOSIS A Stuer, E Kruithof, G Verbruggen , H Mielants, EM Veys. Dept. of Rheumatology. Ghent, Belgium In this case report we describe the similar presentation of arthropathy in two relatives (brother and sister) with primary hemochromatosis. A 48-year old man presents with pain at both ankles since approximately 6 years. There is pain at walking and recently pain at night. The diagnosis of primary hemochromatosis has been made approximately 5 years ago; patient is treated with phlebotomy every 2 weeks. Clinical examination reveals tenderness of MCP III joints and an extreme reduction of talar and subtalar motion at both feet. Radiology of the hands shows the typical hook osteophytes on the radial aspect of the second and third metacarpal head bilateral. Radiological evaluation of the feet reveals bilateral marked space narrowing of the talocalcanear and subtalar joints with sclerosis . His sister is known at the gastroenterological department with the diagnosis of primary hemochromatosis since 2 years. She is treated by phlebotomy every 2 months. The reason for consultation in a reumatological service was also pain at both ankles, mainly at the evening, sporadic at night . Clinical examination is within normal limits. Radiological evaluation shows beginning space narrowing of the talocalcanear space joint of the right foot. Interesting in this case report of two relatives is that although the artropathy has not been the presenting symptom of primary hemochromatosis, the articular complaints have a very similar pattern with a mixed mechanic-inflammatory pain at both ankles. The radiological hallmarks are nevertheless different due to a different stage of the arthropathy.

D De Valck, J Peeters, FP Luyten. Laboratory for Skeletal Development and Joint Disorders, KU Leuven, Belgium Tissue destruction during disease processes is always associated with reparative responses. We focus our research efforts on the molecular basis of the regeneration of skeletal tissues, cartilage and bone. Therefore, we are investigating the developmental events leading to the formation of skeletal elements and joint morphogenesis. Major advances have been made in the characterization of the underlying molecular signals leading to the formation of particular skeletal structures. We identified a family of soluble signaling molecules, i.e, the Cartilage-derived Morphogenetic Proteins (CDMPs ; Chang et a/., J. Bio/. Chem. 269, 28227-28234 (1994), that are members of the Bone Morphogenetic Protein (BMP) superfamily and are physiological regulators of the appendicular skeleton. We demonstrated that mutations in the cdmp-1 gene are associated with several human chondrodysplastic syndromes including Hunter Thompson (Thomas et a/., Nature Genet. 12,315-317 (1996), Grebe (Thomas et el., Nature Genet. 17, 58-64 (1997) and Brachydactyly C (Polinkovsky et el.,

123. SYNOVIAL HEMANGIOMA MIMICKING EARLY ONSET PAUCI-ARTICULAR JCA N Van den Bossche*, R Joos*, P Burssens**, J Vandewalle *, EM Veys*. *Centre for Pediatric Rheumatology, University Hospital Ghent ,Belgium, **Department of Orthopedic Surgery, University Hospital Ghent, Belgium A 13-year-old girl presented with low back pain and a history of recurrent inflammatory pain and effusion of the left knee since the age of two . An arthrocentesis at the age of 6 had shown a blood stained synovial fluid. Radiographs and MR of both knees had been normal. History could not reveal any trauma. There were no arguments for hemophilia or other bleeding disorders. The patient's general condition was excellent. At the time of her first visit palpation and range of motion of both knees were within normal range. Slight atrophy of the right quadriceps was noticed. Mobility of the lumbar spine was painful

Abstracts

464 and reduced; SchOberindex 10/13 cm. Skin and nails appeared normal. Laboratory results were normal, except for the presence of ANA. Anti-DNA, ENA and RF were negative. HLA B27 was negative . Radiographs of sacroiliacal joints were normal, those of the lumbosacral regio showed partial sacralisation of L5. The diagnosis of early onset pauci-articular JCA was suspected,but since the presentation was atypical no NSAI or SAARD was started. Oftalmologic control appeared normal. Six months later the girl is admitted with an acute effusion of the left knee. The knee is kept in flexion and palpation and mobilisation is extremely painful. Aspiration of brown-coloured synovial fluid indicated hemarthrosis. Radiographs of the knees showed a thin radio-opaque concrement in the anterior part of the femorotibial jointspace of the left knee. On MR the diagnosis of a hemangioma of the infrapatellar fat was suggested. Resection of infrapatellar fat and anterior synovial membrane was performed. Pathology confirmed a cavernous hemangioma. Conclusion: Recurrent hemarthrosis resulting from intermittent bleeding of a synovial hemangioma can simulate a mono-articular JCA. Furthermore this case illustrates the fact that arthrocentesis is an important diagnostic tool in acute synovial swelling in childhood.

Conclusions. 1) The ultrasonography appears as a very sensitive method to detect shoulder lesions in symptomatic patients, whether diabetic or not . 2) Over half of the diabetic patients studied, had an abnormal ultrasonography of the shoulder, whether symptomatic or not.

125. COMPARISON BETWEEN CLINICAL AND ECHOGRAPHIC EVALUATION OF KNEE HYDARTHROSIS JPh Hauzeur, L Mathy, V De Maertelaer. Hopitaux de BraineL'Alieud et Erasme, U.L.B., Brussels, Belgium Detection of an hydarthrosis is an important diagnostic data for joint disease. The clinical test is the classical reference. But its validity is lacking of evaluation. Such an evaluation can be done by comparing it to a non invasive and "inexpensive" test like an ultrasound test. Method: Hydarthrosis was evaluated clinically and echographically in 103 knees. Results: The correlation between clinical and US tests was poor. False positive and false negative clinical tests were found. For the clinical test, the sensibility is of 57% and specificity 72%. Conclusion: Clinical tests for hydarthrosis have a poor accuracy in comparison with US tests.

124. PAINFUL SHOULDER IN DIABETES MELLITUS EVALUATED WITH ULTRASONOGRAPHY S Daens, C Gillet, J Defrancq, B Brandelet, M Fuss, R Karmali, A Peretz. CHU Brugmann, ULB, Brussels, Belgium Introduction. An association between diabetes mellitus and shoulder periarthritis has been widely reported. However, shoulders abnormalities have been evaluated only with X-rays without a detailed description of the lesions such as the presence of calcifications, rotator cuff tend initis or tears, bicipital tendinitis or acromioclavicular joint alterations. The aim of this study was, using ultrasonography: a) to compare the incidence and the type of lesions found in symptomatic diabetic patients (D) to those seen in non diabetic patients (ND) but having similar complains and b) to evaluate the overall incidence of shoulder lesions in any given diabetic patient. Methods. 103 D were studied, including 38 symptomatic patients which were compared to a similar group of 35 ND patients Results. The type of lesions and their frequencies observed in the D group were as follows: rotator cuff (supraspinatus, subscapularis, infraspinatus and teres minor) and biceps tendinopathies in 87% , calcifications alone in 34%, cuff rotator tears in 34%, bicipital tendinitis in 21%, cuff tend initis without calcification in 18%, lesions in acromioclavicular joints in 11%. In 5%, no abnormalities could be detected. All these results were not statistically different from those seen in the ND group.When all the diabetic patients , whether symptomatic or not, were taken into account, 56% of the patients had an abnormal ultrasonography. From these, 39% did not have any complaints.

126.

INTRADISCAL GAS IN SPINAL INFECTION

C Gregoir, 0 Van Achter. CHU A. Vesale, Montigny Ie Tilleul, Belgium The detection of a vacuum phenomenon within the intervertebral disk usually confirms the diagnosis of degenerative disease. We report a case of gas forming spondylodiscitis caused by gram negative bacilli, Escherichia Coli. A 60 years old man entered the hospital with low back pain and fever. X-rays and Computed Tomography showed severe degenerative disease of the lumbar spine and aftereffects of Pott's disease that occurs 40 years ago. Vacuum phenomenon was present in the last intervertebral disk. Magnetic Resonance Imaging and Tec99m -HMPAO-Leucocyte scintigraphy were in favour of an infectious process. The diagnosis of L5-S1 spondylodiscitis was confirmed by an operative biopsy that yielded Escherichia Coli; Tuberculosis was excluded. IV Quinolones was administered; now the patient is ambulating and has no back pain, imaging shows a regression of intradiscal gas. Spinal vacuum phenomena may accompany different processes : primary intervertebral osteochondrosis, Schmorl node formation , spondylosis deformans or osteonecrosis but also infectious process (1). Causative microorganisms are usually Clostridia, Peptococus or Bacteroides, but gas production may accompany gram negative infections such as Klebsiella and Escherichia Coli. (1) Resnick D., Radiology 139: 341-348 ,1981.