DIAGNOSIS
Dis Manage Health Outcomes 1998 Dec; 4 (6): 315-324 1173-8790/98/0012-0315/$05.00/0 © Adis International Limited. All rights reserved.
Rheumatoid Arthritis Diagnosis and Screening Burkhard F. Leeb, Katharina Weber and Josef S. Smolen Centre for Rheumatic Diseases, Lainz Hospital, Vienna, Austria
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Diagnosis of Rheumatoid Arthritis . . . . . . . . . . . . . . . . 1.1 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Laboratory Parameters . . . . . . . . . . . . . . . . . . . 1.3 Imaging Techniques . . . . . . . . . . . . . . . . . . . . . 2. Screening for Early Rheumatoid Arthritis and Risk Assessment 3. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
315 316 316 317 318 319 321 322
Rheumatoid arthritis is a common inflammatory joint disorder, with a prevalence of about 1% in the general population. It shows high variability with respect to its course and prognosis. In typical cases an insidious onset of symmetrical synovitis of the small joints of the hands and feet occurs, accompanied by symptoms such as morning stiffness, weakness and fatigue. Besides clinical findings, laboratory tests and imaging techniques are other cornerstones for diagnosis of rheumatoid arthritis. Rheumatoid arthritis is anything but a benign disease, potentially leading to disability, chronic pain, morbidity and even early death. Recent studies provide strong evidence that early diagnosis and treatment are crucial for the prognosis of the disease. In recent years, great efforts have been made to detect and establish diagnostic, as well as prognostic, parameters for rheumatoid arthritis. Whereas the reliability of new diagnostic parameters has not been proven conclusively, reliable prognostic factors have been established that may help in identifying patients at high risk for progressive, disabling disease. These risk factors include: high number of joints involved at onset, marked disability, elevated acute phase reactants, a positive finding for rheumatoid factor, female gender, advanced age, presence of certain HLA class II antigens, early x-ray changes, low bone mineral density and job-related physical requirements. As the established classification criteria cover longstanding disease, but not the early stages, it appears necessary to establish a new set of diagnostic criteria for early rheumatoid arthritis. In the case of newly diagnosed rheumatoid arthritis, more attention should be paid to well-known risk factors. This allows a risk profile to be established for individual patients, which may facilitate decisions regarding therapy. A better outcome of rheumatoid arthritis would not only be advantageous for individual patients, but would also result in reduced costs for healthcare systems.
316
Rheumatoid arthritis is the most common inflammatory joint disorder with a prevalence of about 1% in the general population, comparable with that of diabetes mellitus or psoriasis vulgaris, and affecting more women than men. The disease may occur at any age, but has peak incidences between 25 and 40 years and at about 60 years. The onset of disease is highly variable.[1] Commonly, the initial stage of rheumatoid arthritis is subacute or insidious, but acute arthritides are sometimes seen at onset. The clinical course of rheumatoid arthritis is also highly variable. Mild to markedly aggressive courses, the latter sometimes accompanied by extra-articular manifestations and leading to severe functional impairment and early disability, can be observed. About 10 to 15% of patients who experience symmetrical polyarthritis achieve sustained remission after a single flare, whereas another 10 to 15% of the patients have a rapidly progressive and disabling course.[2] 60 to 70% of rheumatoid arthritis patients between 18 and 65 years of age at the time of disease onset are expected to be disabled and unemployed within 5 to 20 years. Indeed, a high degree of functional impairment may even occur within the first 5 years of the disease.[3] Depending on the functional status and the degree of overall disease activity, the life expectancy of rheumatoid arthritis patients is reduced.[4] Thus, rheumatoid arthritis is anything but a benign disease; it is potentially a progressively disabling disorder that reduces not only the quality of life but also life expectancy. Although there is as yet no proof that early initiation of disease-modifying antirheumatic drugs (DMARDs) results in a better long-term outcome in rheumatoid arthritis, it seems evident that early modulation of inflammatory activity, functional capacity and radiological progression would lead to better results, especially with respect to the potentially aggressive course of rheumatoid arthritis during the first years of the disease. [5] There is good evidence that early and adequately aggressive therapeutic intervention may lead to better patient outcomes than are currently © Adis International Limited. All rights reserved.
Leeb et al.
achieved.[6] However, early therapy must be based on a prompt and reliable diagnosis. Therefore it is of great importance to establish criteria for the diagnosis of early rheumatoid arthritis. The theoretical basis for early and aggressive therapeutic intervention in rheumatoid arthritis is: • many patients have a rapidly progressive disease • joint damage starts within the first year of disease • joint damage and functional deterioration are highly correlated with inflammatory activity • inflammatory activity and functional status at onset are correlated with degree of disability • pharmacotherapy can reduce inflammatory activity. In the next few years, our task will be not only to establish better diagnostic systems, but also to increase awareness of the consequence of rheumatoid arthritis among physicians as well as patients. At present, physicians’ willingness to refer rheumatoid arthritis patients seems to rise with increasing patient age and disease duration.[7] Based on results of many epidemiological studies, strategies which could not only increase patients’ quality of life but also lead to economic advantages for society should be considered. In recent years, great efforts have been made to identify parameters of diagnostic, as well as prognostic, value for rheumatoid arthritis. With the goal of diagnosis and therapy of rheumatoid arthritis at as early a stage as possible, the established signs and symptoms of rheumatoid arthritis, as well as these parameters have to be critically considered for their relevance to the course of the disease. 1. Diagnosis of Rheumatoid Arthritis 1.1 Clinical Findings
Rheumatoid arthritis is basically diagnosed according to the American College of Rheumatology (ACR) classification criteria published in 1958 and modified in 1988,[8] (see table I). The criteria clearly show the importance of clinical findings, although patient history, laboratory testing and imaging techniques are also important for differential diagnosis. Dis Manage Health Outcomes 1998 Dec; 4 (6)
Diagnosis and Screening of Rheumatoid Arthritis
Table I. Classification criteria for rheumatoid arthritis:[8] 4 of these 7 criteria have to be fulfilled Morning stiffness lasting more than 1 houra Inflammatory swelling of at least 3 jointsa Involvement of hand/finger jointsa Symmetrical arthritisa Rheumatoid nodules Positive finding for rheumatoid factor Characteristic x-ray changes a
These 4 symptoms must have been present for at least 6 weeks.
Early morning stiffness of at least 1 hour’s duration, constitutional symptoms such as fever, fatigue, weakness and myalgia, and, particularly, reduction of grip strength, may precede the onset of synovitis. The appearance of a palpable joint swelling or effusion is obligatory for the clinical diagnosis of any kind of arthritis.[9] Symmetrical joint involvement can be regarded as one of the most stringent features for rheumatoid arthritis. In typical cases an insidious onset of symmetrical pain and soft articular swelling of the small joints of the hands and feet occurs. Accompanying tenosynovitis of the extensor muscles is often present, but characteristically distal interphalangeal joints are spared. Later, in parallel with, or in rare instances preceding, the involvement of the hands, larger joints such as the knees or shoulder joints can be involved in the disease process, leading to joint effusions and limited range of motion. In the latter, so-called atypical, course of rheumatoid arthritis, however, an oligoarticular, asymmetrical and sometimes acute onset with particular involvement of large joints of the lower extremities may occur that is often accompanied by negative testing for rheumatoid factor. Frequently the vertebral column also becomes involved, usually during the later stages of the disease. In particular, involvement of the cervical spine may constitute a serious complication of rheumatoid arthritis. Nodules, histologically characterised by palisades of giant cells and a central fibrinoid necrosis, com© Adis International Limited. All rights reserved.
317
monly occur quite late in the disease process, usually in regions of high mechanical load such as the elbows, knees or dorsal aspect of the hands and feet.[10] Clinical features of rheumatoid arthritis include:[11] • stiffness of joints (≤98% of patients; especially during rest) • aching joints (sign of disease activity) • fatigue (≤80% of patients; often at onset) • decrease in vitality (almost all patients; dependent on disease activity) • depression (frequent; partly dependent on disease activity) • joint swelling (spindle-like swellings of small joints, often with tenosynovitis) • palmar erythema (frequent) • cool, moist skin (especially hands and feet) • muscular atrophy (rapidly developing in severe courses; especially the interosseous muscles of the hands) • contraction in joints (especially elbows, knees) • rheumatoid nodules (occurs commonly late in the disease) • synovial cysts (especially in knees) • bodyweight loss (rare; unfavourable for prognosis) • fever (sporadic; at the onset of disease and during flares). 1.2 Laboratory Parameters
In addition to clinical features, laboratory parameters (table II) play an important role in the diagnosis, as well as in the prognosis, of rheumatoid arthritis. Routine laboratory tests that should be performed are a complete blood cell count including differential blood count, kidney and liver function tests, and urinalysis. Normochromic anaemia with a low plasma iron and normal serum ferritin and transferrin levels usually occurs in conjunction with an increased platelet count, resulting from inflammatory activity. Changes in the white cell counts may include mild leucocytosis, rarely eosinophilia and, in the case of Felty’s syndrome, leucopenia. Acute phase reactants, such as the erythrocyte sedimentation rate (ESR; which can be Dis Manage Health Outcomes 1998 Dec; 4 (6)
318
Leeb et al.
Table II. Laboratory tests in diagnosis of rheumatoid arthritis Acute phase reactants Erythrocyte sedimentation rate C-reactive protein level
Increased (can be normal in early cases) Increased, (can be normal in early cases); prognostic parameter at onset of rheumatoid arthritis
Serum amyloid-A level
Increased
Ceruloplasmin level
Increased
Fibronectin level
Normal
Fibrinogen level
Increased
Blood-cell count Erythrocytes
(Normochromic) anaemia, low plasma iron, normal ferritin, normal transferrin
Leucocytes
Normal or slightly elevated granulocytes, leucocytosis in severe courses; rarely leucopenia (Feltys Syndrome), eosinophilia in severe courses and vasculitis, normal T and B lymphocyte ratio
Platelets
Increased because of inflammatory activity
Immunological parameters Rheumatoid factor Positive in up to 75% of patients during course of disease. Predictor of severe course of rheumatoid arthritis Antinuclear antibodies
Positive finding in up to 15% of patients at low concentrations
Complement
Normal or slightly increased; may be low sometimes in case of vasculitis
Anti–RA 33; anti–Sa, anti–perinuclear factor; anti–keratin antibodies
Potential diagnostic markers for rheumatoid arthritis
altered by other disorders such as anaemia), Creactive protein (CRP), serum amyloid A and α-2 globulin levels are normally elevated as markers of inflammatory activity, but this may not be apparent in the very early stages of rheumatoid arthritis. The so-called rheumatological laboratory tests include determination of rheumatoid factor and antinuclear antibodies and their subsets. They also occasionally include autoantibodies, which are regarded as diagnostic serological markers for collagen diseases, such as anti–DNA antibodies and compounds of the complement systems. There is overall consensus that a positive finding for rheumatoid factor should be regarded as a risk factor for the development of progressive disease, as well © Adis International Limited. All rights reserved.
as a diagnostic feature of rheumatoid arthritis.[12] However, rheumatoid factor positivity may also be present in a variety of other diseases, such as collagen diseases and infectious disorders. In recent years, essential research has been conducted on rheumatoid arthritis–specific laboratory parameters, including anti–RA 33,[13] anti–Sa,[14] anti-keratin antibodies, and the antiperinuclear factor. Determination of these factors and combination with a positive rheumatoid factor may significantly improve the early diagnosis of rheumatoid arthritis.[15] In addition, genetic markers were shown to be helpful as prognostic parameters for the development of progressive disease, but they have so far not been used for diagnostic purposes. Routine laboratory testing for rheumatoid arthritis should thus include ESR and another acute phase reactant (preferably CRP), liver and kidney function tests, blood cell count and rheumatoid factor, as well as antinuclear antibodies and a urine sample. This combination should provide enough information for routine rheumatological practice, even from an economic point of view i.e. a reasonable cost/efficacy relationship. 1.3 Imaging Techniques
Imaging techniques provide another cornerstone in the diagnosis of rheumatoid arthritis (table III). To date, conventional radiography has constituted the most important technique for visualising bony changes in routine practice. On the other hand, magnetic resonance imaging (MRI) and sonography have provided information about soft tissue changes, allowing detection of even small effusions, synovial swelling and early erosions. Therefore, both techniques provide a reasonable supplement to plain x-rays in giving additional information concerning joints and periarticular soft tissue swelling.[16] MRI may be helpful in the detection of early changes, but it is very expensive and needs highly technical equipment. However, this technique may detect inflammatory and/or destructive joint changes in patients with early arthritis, even those occurring in the absence of clinical symptoms or signs and/or radiographic signs in the examined joint.[17] MRI Dis Manage Health Outcomes 1998 Dec; 4 (6)
Diagnosis and Screening of Rheumatoid Arthritis
plays a pivotal role in the diagnosis of arthritis of the craniocervical junction and its complications,[18] and may constitute an important supplementary tool for detecting early arthritis, as it gives unique insights into soft tissue changes, with the possibility of selecting subgroups of patients for more tailored therapeutic regimens.[19] Ultrasound examinations, however, are becoming increasingly important in routine rheumatological practice. Synovitis, effusion and even bony changes can be visualised by sonography. By using the most advanced techniques, such as Power Doppler, inflammation is able to be detected.[20] Ultrasound is an important instrument for the examining physician, being easily applicable, reproducible even as a bedside procedure or in the rheumatologist’s office and, compared with MRI, much less costintensive and time-consuming.[21] Standardised and validated scores, such as the Larsen-Dale score for x-rays,[22] are still lacking for MRI and sonography. In order to follow disease progression and effects of treatment in particular, standardised ultrasound scoring methods that are able to evaluate small joints in a reproducible manner are required. Finally, scintigraphy can visualise the type of joint involvement, although it lacks the ability to quantify inflammatory activity reliably or to differentiate between types of disease.[23] 2. Screening for Early Rheumatoid Arthritis and Risk Assessment In rheumatology, there are no known diagnostic clinical or laboratory findings peculiar to any one disease. That is why screening for rheumatoid arthritis in a healthy population seems to be an inadequate approach for prevention. For the confirmation of rheumatoid arthritis in symptomatic individuals it is necessary to combine the clinical symptoms and laboratory findings with exclusion criteria to achieve high probability rates. Normally pain within the locomotor system prompts patients to consult a physician. Firstly, differentiation between degenerative, inflammatory or soft tissue rheumatic disorders must be made, © Adis International Limited. All rights reserved.
319
Table III. Imaging techniques in the diagnosis of rheumatoid arthritis Technique
Comments
Plain x-rays
Mainly shows osseous changes, standardised
Ultrasound
Easily applicable; mainly shows soft tissue changes
Magnetic resonance imaging
Expansive, gives exact visualisation of osseous and soft tissue changes
Scintigraphy
Shows type of joint involvement
Bone densitometry
Possibly useful in the detection of early rheumatoid arthritis
based on the patient’s history and clinical findings. If the clinical information is not reliable enough, laboratory, as well as imaging, procedures must be performed. Table IV lists features to look for when attempting to discriminate between inflammatory joint diseases on an empirically-derived basis; this is because no distinct criteria for the diagnosis of early rheumatoid arthritis have been established yet. Because the course of the disease is unpredictable, every symptomatic patient requires careful examination at the earliest possible opportunity for the presence of rheumatoid arthritis. The laboratory tests listed above, together with x-rays of the hands and feet, other affected joints and corresponding contralateral joints, even if these are asymptomatic, would appear to constitute an appropriate approach for diagnosis or exclusion of rheumatoid arthritis. In contrast to many diseases, such as hypertension, infectious diseases, malignant disorders, etc., in which the importance of early diagnosis and therapy is well recognised, rheumatoid arthritis has often been considered a relatively benign disease, where a ‘wait and see’ attitude seemed appropriate. Time was thought to be the main way to discriminate between progressive courses and so-called self-limiting symmetrical arthritides. Some authors consider that these may be two different diseases presenting with similar features.[24] In Austria, as in other countries, a nationwide programme [the Austrian Early Arthritis Action (AEAA)] was instituted in 1996 to establish criteria for early diagnosis of rheumatoid arthritis and to Dis Manage Health Outcomes 1998 Dec; 4 (6)
320
Leeb et al.
Table IV. Relevant features for the differentiation of inflammatory rheumatic diseases. Comments in parentheses indicate that these conditions are facultatively present in the diseases Feature
Rheumatoid arthritis
Family history Gout Psoriasis
Psoriatic arthritis
Reactive arthritis
Septic arthritis
Crystal-induced Collagen arthritis disease Yes
Yes
Patient history Malignant disorder Previous infection Mucosal inflammation UV sensitivity Psoriasis
No No No No No
No No No No Yes
No Yes Yes No No
No No No No No
(Yes) No No No (Yes)
No No Yes Yes No
Joint involvement Monoarticular Oligoarticular Polyarticular Distal interphalangeal joint involvement Symmetry Dactylitis Large joint involvement
(Yes) (Yes) Yes No Yes No (Yes)
(Yes) Yes (Yes) Yes No Yes Yes
Yes Yes No (Yes) No Yes Yes
Yes No No No No No Yes
Yes (Yes) No No No No Yes
No No Yes No Yes No No
Laboratory findings Rheumatoid factor positivity Hyperuricaemia ANA-positivity
Yes No (Yes)
No (Yes) No
No No No
No No No
No Yes No
(Yes) No Yes
X-ray findings Periarticular osteoporosis Erosions Periosteal appositions Enthesiopathies
Yes Yes No (Yes)
(Yes) Yes Yes Yes
(Yes) No No Yes
Yes Yes No No
No (Yes) No No
Yes No No No
No
No
No
Yes
(Yes)
No
Synovial joint count >25/cm3 ANA = antinuclear antibodies.
develop strategies for early treatment of the disease. This was in order to ameliorate the patient’s personal situation and decrease the risk of early disability. One of the greatest difficulties in the early diagnosis of rheumatoid arthritis is to define the term ‘early arthritis’. For the AEAA programme, a limit of 3 months after onset of symptoms was defined as classifying early arthritis. However, in the literature, disease durations of up to 2 years have been accepted for early rheumatoid arthritis.[25] This latter definition is, however, doubtful in view of the above discussion. Furthermore, the ACR criteria were developed to describe established rheumatoid arthritis, but they do not cover the early stages of © Adis International Limited. All rights reserved.
the disease. As with a Japanese patient cohort, a preliminary evaluation of the AEAA revealed that many patients did not fulfil the four essential criteria at the time of first presentation.[26] The decision to initiate disease-modifying therapy in such patients should be taken with respect to the presence of risk factors rather than on the basis of ACR criteria. Therefore, it appears necessary to formulate a new set of diagnostic criteria for patients with early rheumatoid arthritis. From a clinical viewpoint, the number of swollen and tender joints at the onset of the disease can be regarded as the main risk factor for the development of progressive rheumatoid arthritis.[27] This was confirmed in the preliminary evaluation of the Dis Manage Health Outcomes 1998 Dec; 4 (6)
Diagnosis and Screening of Rheumatoid Arthritis
AEAA patients (unpublished observation). Nevertheless, it is difficult to distinguish between socalled self-limiting symmetrical polyarthritis and progressive rheumatoid arthritis at the time of presentation, even when including ESR and rheumatoid factor in the analysis.[28] Measurement of a patient’s functional capacity constitutes one of the most reliable prognostic features. Of the many instruments applied in clinical trials, the Health Assessment Questionnaire (HAQ) has proven to be easily applicable and reliable for predicting patient outcomes.[29] The HAQ score is a sensitive indicator of changes in early disease. The more disabled a patient is at the onset of rheumatoid arthritis, the worse the prognosis for disability, work absenteeism and even life expectancy.[3] There is overall consensus that a positive finding for rheumatoid factor can be regarded as a risk factor for the development of progressive disease.[12] Rheumatoid factor positivity at onset constitutes a sensitive predictor for later joint destruction. Quantitative measurement of rheumatoid factor levels, particularly with repeated determinations to increase prognostic validity, may even allow the possibility of distinguishing between a progressive and a nonprogressive course in early arthritis.[30] In addition, genetic markers were shown to be helpful as relevant parameters for the prediction of progression. HLA-oligotyping of DNA in patients with early rheumatoid arthritis to determine homozygosity versus heterozygosity for the DRB1 susceptibility sequence (HLA-DRB1*04 molecule and its *0401, *0404 subtypes) represents a potential new parameter for the prediction of disease severity.[31] Patients that were positive for rheumatoid factor and HLA Dw 4/Dw 14 were shown to represent a high-risk subgroup for erosive and progressive disease.[32] Prospective studies on patients with early disease show that approximately 75% of patients have joint erosions, which means that these patients had lost at least approximately 30% of their bone density. There is good evidence that bone densitometry may constitute a useful tool for the early detection of early arthritic conditions. Hand bone loss occurs © Adis International Limited. All rights reserved.
321
in early disease, in the absence of detectable systemic disease and before lumbar bone mineral density (BMD) loss. Hand BMD correlates with measures of disease activity, functional capacity, and also with lumbar and femoral BMD. It has the potential to be an outcome measure in early disease.[33] Moreover, when x-rays show rapidly progressing changes in the first years of disease, this is evidence for an aggressive course. Thus, x-rays are essential for risk assessment in an individual patient.[34] The rate of progression, expressed as the number of newly eroded joints or increase in radiographic damage, is highest during the early years of disease, predominantly in the feet. These changes result in early disability and unemployment.[35] Paralleling the radiological changes, mobility and grip strength decrease, which leads to loss of autonomy and therefore may compromise socioeconomic status, in addition to increased disability. Rheumatoid arthritis is a disease that often leads to permanent work disability. In a German study 37% of patients were permanently disabled after 6 years’ disease duration, and the most rapid decline in employment rate was seen within the first 3 years. The patient group with the poorest prognosis was defined by: age >50 years, highly elevated ESR and high degree of disability at the onset of the disease, with job-related physical requirements influencing the degree of work disability.[36] 3. Differential Diagnosis Primarily in so-called atypical cases of rheumatoid arthritis with acute onset or asymmetrical joint involvement, it is crucial that distinctions should be made from other types of inflammatory joint disease, such as reactive arthritis, psoriatic arthritis, other seronegative spondylarthropathies and crystal-induced arthritides, particularly gout and septic arthritis (see table IV). Rheumatoid arthritis, crystal-induced arthropathies and reactive arthritis were the most frequently diagnosed diseases at the first visit in a Dutch early arthritis clinic.[37] The main differential diagnoses to be considered are the seronegative spondylarthropathies (psoriatic arthritis, arthritides accompanying inflamDis Manage Health Outcomes 1998 Dec; 4 (6)
322
matory bowel diseases, reactive arthritis and ankylosing spondylitis with peripheral arthritis); crystalinduced arthritis; osteoarthritis; connective tissue diseases; and (parvo)virus-induced arthritis.[38,39] Involvement of the distal interphalangeal joints often provides an essential differential diagnostic indicator for distinguishing between rheumatoid arthritis and seronegative spondylarthropathies, such as psoriatic arthritis, or arthritides accompanying inflammatory bowel diseases, or reactive arthritis, which often involve finger joints including the distal interphalangeal joints in the form of dactylitis (‘sausage digits’). Furthermore, the type of joint involvement may allow discrimination between several arthropathies. Monoarthritis of large joints commonly occurs in reactive arthritis, osteoarthritis or crystal-induced arthritides, such as gout or chondrocalcinosis. In the latter diseases, the arthritis is of extremely acute onset, with redness, rise in joint temperature and severe pain. In the case of crystal-induced arthritides, the detection of crystals within the cells of synovial fluid is essential for diagnosis. Oligoarthritis, particularly of the lower extremities, constitutes a typical feature of reactive arthritis, psoriatic arthritis, inflammatory bowel disease–arthritis or joint involvement of ankylosing spondylitis, which are, moreover, negative for rheumatoid factor. In rare cases sarcoidosis (Löfgen’s syndrome) may be the reason for oligoarthritis. In psoriatic arthritis, which can be seen as the second most frequent erosive arthritis, a transverse or radiating type of involvement of joints of the hands or feet can be seen. The latter is often accompanied by dactylitis of 1 digit. Distal interphalangeal joint involvement, in contrast to rheumatoid arthritis, is typical in psoriatic arthritis: the predominance of distal interphalangeal joint involvement even represents one subgroup of this disease. In the case of seronegative spondylarthropathies, the vertebral column in part, or even as a whole, is involved, predominantly beginning from the sacroiliac joints. Reactive arthritis is induced by infections (for example Salmonella, Yersinia, Chlamydia, Borrelia, © Adis International Limited. All rights reserved.
Leeb et al.
or Mycoplasma spp., gonococci, or in the case of rheumatic fever, streptococci). Their presence can be confirmed by culture or by serological tests, but these are of limited reliability. Seronegative spondylarthropathies are often associated with HLA B27.[31] If oligoarthritis is present there is a high probability of a joint disorder other than rheumatoid arthritis. However, other diseases must also be considered carefully in the case of symmetrical polyarthritis. Many connective tissue diseases, such as systemic lupus erythematosus, mixed connective tissue disease and vasculitides show symmetrical polyarthralgia, sometimes accompanied by low degree synovitis, as their first symptoms. Discriminating between collagen diseases and rheumatoid arthritis can be difficult at the onset. Serological markers, such as antinuclear antibodies and their subsets, anti–DNA antibodies and others, and clinical features, such as photosensitivity, Raynaud’s syndrome or organ involvement may allow differential diagnosis between rheumatoid arthritis and connective tissue diseases. Moreover, parvovirus-induced arthritis, which often shows a clinical pattern mimicking rheumatoid arthritis but has a much better prognosis, can be confirmed by the detection of IgM antibodies in the serum.[40] 4. Conclusions The onset and early phase of rheumatoid arthritis is a unique and critical stage in the disease process particularly if severe inflammation, clinical features and a high likelihood of radiological progression are present. Decisions regarding therapeutic strategies should be made before irreversible damage and functional deterioration occur.[6] It seems evident, although there is no proof yet, that early intervention with disease-modifying drugs may reduce functional deterioration and improve long-term outcome. Although great efforts have been made to improve the diagnostic possibilities for rheumatoid arthritis, the diagnosis of rheumatoid arthritis must still at present be based on well-known predominantly clinical parameters. Serological markers, however, promise some diagnostic potential, espeDis Manage Health Outcomes 1998 Dec; 4 (6)
Diagnosis and Screening of Rheumatoid Arthritis
cially when they are used simultaneously. From a clinical viewpoint, developing criteria for the diagnosis of early rheumatoid arthritis constitutes an essential challenge for the rheumatological community in the future. The prediction of the course of rheumatoid arthritis, however, can be based on reliable and validated clinical, laboratory and imaging parameters. Stable genetic markers and rheumatoid factor are useful in predicting disease severity and thus in identifying those patients who require early aggressive therapy. Acute phase reactants constitute a valuable marker of disease activity and their suppression is associated with improved outcome. In summary, validated and relevant prognostic parameters for the development of progressive disabling rheumatoid arthritis are: • female gender • advanced age • rheumatoid factor–positivity at onset • highly elevated acute phase reactants (ESR, CRP, serum amyloid A) • genetic predisposition • a high number of swollen and tender joints • low functional capacity (measured by the Health Assessment Questionnaire • low BMD, early erosions on x-rays and rapidly progressive x-ray changes • profession: physical job requirements contribute to the degree of work disability. Given the fact that 52% of the estimated total cost of rheumatoid arthritis in England (£1.256 billions; 1992 values) was regarded to be a result of production loss due to rheumatoid arthritis-related disability and that the prevalence of rheumatoid arthritis rises with age, the socioeconomic importance of early diagnosis and treatment of rheumatoid arthritis becomes unquestionable.[41] The evidence of all these parameters however, is based on statistical data derived from large patient cohorts; therefore it is obviously not possible to predict the outcome for individual patients. However, these parameters may help to establish a risk profile for the patient and also help in planning therapeutic strategies. In patients with confirmed or suspected © Adis International Limited. All rights reserved.
323
rheumatoid arthritis, an individual risk profile should take into account age, gender, occupation, functional capacity, acute phase reactants, rheumatoid factor and x-ray examinations. The last 2 tests should be repeated after 6 months. If applicable, genetic, BMD and sonographic parameters could increase the reliability of this risk profile. The decision to initiate therapy that may induce adverse effects is difficult and should be made cautiously in the light of a possibly self-limiting disease. However, it can be facilitated by concern about the presence of relevant risk factors. Above all, enhanced functional capacity and reduction of inflammation should be the target of primary therapeutic measures. On the basis of current knowledge about rheumatoid arthritis and factors influencing the course of the disease, disease-modifying therapy should be initiated immediately at the time a definite diagnosis of rheumatoid arthritis is made. A step-by-step therapeutic approach, beginning with nonsteroidal anti-inflammatory drugs (NSAIDs) and initiating DMARDs after unsuccessful NSAID therapy according to the traditional ‘pyramid’ approach, cannot be regarded acceptable in the light of current understanding.[42] Moreover, early detection of inflammatory joint diseases with subsequent follow-up may lead to new, perhaps individually utilisable, prognostic parameters and, possibly, differentiated and better treatment. All these efforts should bring us nearer to the goal of making rheumatoid arthritis a curable disease. References 1. Zvaifler NJ. Etiology and pathogenesis of rheumatoid arthritis. In: McCarty DJ, Koopmann WJ, editors. Arthritis and allied conditions. 12th ed. Philadelphia: Lea & Febiger, 1993: 723-36 2. Young A. Short-term outcomes in recent-onset rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl. 2: 79-86 3. Pincus T. The case for early intervention in rheumatoid arthritis. J Autoimmun 1992; Suppl. A: 209-26 4. Pincus T, Callahan LF, Vaughn WK. Questionnaire, walking time and button test measures of functional capacity as predictive markers for mortality in rheumatoid arthritis. J Rheumatol 1987; 14: 240-51 5. Egsmose C, Lund B, Borg G, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year follow-up of a prospective double blind placebo controlled study. J Rheumatol 1995; 22: 2208-13
Dis Manage Health Outcomes 1998 Dec; 4 (6)
324
6. Emery P. Early rheumatoid arthritis: therapeutic strategies. Scand J Rheumatol 1994; 23 Suppl. 100: 3-7 7. Glazier RH, Dalby DM, Badley EM, et al. Management of the early and late presentations of rheumatoid arthritis: a survey of Ontario primary care physicians. Can Med Assoc J 1996; 155 (6): 679-87 8. Arnett FC, Edwarthy SM, Bloch DA, et al. The American rheumatism association revised criteria for the classification of rheumatoid arthritis. Arthr Rheum 1988; 31: 315-24 9. Moder KG, Hunder GG. Examination of the joints. In: Kelley WW, Ruddy S, Harris E, et al., editors. Textbook of rheumatology. 5th ed. Philadelphia: WB Saunders, 1997: 313-70 10. Athanasou NA, Quinn J, Woods CG, et al. Immunohistology of rheumatoid nodules and rheumatic synovitis. Ann Rheum Dis 1988; 47: 398-403 11. McCarty DJ. Clinical picture of rheumatoid arthritis. In: McCarty DJ, Koopmann WJ, editors. Arthritis and allied conditions. 12th ed. Philadelphia: Lea & Febiger, 1993: 781-809 12. van Zeeben D, Hazes JMW, Zwinderman AH, et al. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis 1992; 51: 1029-35 13. Hassfeld W, Steiner G, Studnicka-Benke A, et al. Autoimmune response to the spliceseosome. Arthr Rheum 1995; 38: 777-85 14. Despres N, Boire G, Lopez-Longo FJ, et al. The Sa system: a novel antigen-antibody system specific for rheumatoid arthritis. J Rheumatol 1994; 21: 1027-33 15. Cordonnier C, Meyer O, Palazzo E, et al. Diagnostic value of anti-RA33 antibody, antikeratin antibody, antiperinuclear factor and antinuclear antibody in early rheumatoid arthritis: comparison with rheumatoid factor. Br J Rheumatol 1996; 35 (7): 620-4 16. Leeb BF, Machold KP. Ultrasonography in rheumatology (the sound of arthritis). Rheumatol Eur 1997; 26 (3): 85 17. Forslind K, Larsson EM, Johansson A, et al. Detection of joint pathology by magnetic resonance imaging in patients with early rheumatoid arthritis. Br J Rheumatol 1997; 36 (6): 683-8 18. Stiskal M, Neuhold A, Szolar DH, et al. Rheumatoid arthritis of the craniocervical region by MR imaging: detection and characterization. Am J Radiol 1995; 165 (3): 585-92 19. Kainberger F, Trattnig S, Czerny C, et al. MRI in assessment of the systemic manifestations of rheumatological disease. Br J Rheumatol 1996; 35 Suppl. 3: 40-4 20. Kainberger F, Machold KP, Liskutin J, et al. Ultrasonography of the locomotor system: recent developments and trends. Rheumatol Eur 1997; 26 (3): 86-8 21. Leeb BF, Stenzel I, Czembirek H, et al. Radiologic vignette: diagnostic use of office-based ultrasound. Arthritis Rheum 1995; 38: 859-61 22. Larsen A. How to apply Larsen score in evaluating radiographs of rheumatoid arthritis in longterm studies. J Rheumatol 1995; 22: 1974-5 23. Dieppe P, Cushnaghan J, Young P, et al. Prediction of the progression of joint space narrowing of the knee by bone scintigraphy. Ann Rheum Dis 1993; 52: 557 24. Devlin J, Gough A, Huissoon A, et al. The acute phase and function in early rheumatoid arthritis: C-reactive protein levels correlate with functional outcome. J Rheumatol 1997; 24 (1): 9-13 25. Machold KP, Eberl G, Leeb BF, et al. Early arthritis: rationale and current approach. J Rheumatol 1998; 25 Suppl. 53: 13-9 26. Yamamoto S, Nobunaga T, Kashiwazaki S. Study on Japan Rheumatism Association diagnostic criteria for early rheumatoid arthritis: 1. Application of the American Rheumatism Association diagnostic criteria to Japanese patients with early rheumatoid arthritis. Ryumachi 1993; 33 (4): 354-62
© Adis International Limited. All rights reserved.
Leeb et al.
27. van Gestel AM, van Riel PL. Evaluation of early rheumatoid arthritis disease activity and outcome. Baillieres Clin Rheumatol 1997; 11 (1): 49-63 28. Tunn EJ, Bacon PA. Differentiating persistent from self-limiting symmetrical synovitis in an early arthritis clinic. Br J Rheumatol 1993; 32 (2): 97-103 29. Callahan LF, Smith WJ, Pincus T. Self-report questionnaires in five rheumatic diseases: comparison of health status constructs and associations with formal education level. Arthritis Care Res 1989; 2: 122-31 30. Paimela L, Palosuo T, Leirisalo-Repo M, et al. Prognostic value of quantitative measurement of rheumatoid factor in early rheumatoid arthritis. Br J Rheumatol 1995; 34 (12): 1146-50 31. Arnett FC. Histocompatibility typing in the rheumatic diseases: diagnostic and prognostic implications. Rheum Dis Clin North Am 1994; 20 (2): 371-90 32. Gough A, Faint J, Salmon M, et al. Genetic typing of patients with inflammatory arthritis t presentation can be used to predict outcome. Arthritis Rheum 1995; 38 (6): 1166-70 33. Devlin J, Lilley J, Gough A, et al. Clinical associations of dualenergy X-ray absorptiometry measurement of hand bone mass in rheumatoid arthritis. Br J Rheumatol 1996; 35 (12): 1256-62 34. van Leeuwen MA, van Rijswijk MH, Sluiter WJ, et al. Individual relationship between progression of radiological damage and the acute phase response in early rheumatoid arthritis: towards development of a decision support system. J Rheumatol 1997; 24 (1): 20-7 35. Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl. 2: 74-8 36. Mau W, Bornmann M, Weber H, et al. Prediction of permanent work disability in a follow-up study of early rheumatoid arthritis: results of a tree structured analysis using RECPAM. Br J Rheumatol 1996; 35: 652-9 37. Speyer I, Hazes M, Breedveld FC. Recruitment of patients with early rheumatoid arthritis-the Netherlands experience. J Rheumatol 1996; 24 Suppl. 44: 84-5 38. Arnett FC. Seronegative spondylarthropathies. Bull Rheum Dis 37: 1-12 39. Keat A, Rowe I. Reiters syndrome and associated arthritides. Rheum Dis Clin North Am 1991; 17: 25-42 40. Nikkari S, Roivainen A, Hannonen P, et al. Persistence of parvovirus B19 in synovial fluid and bone marrow. Ann Rheum Dis 1995; 54 (7): 597-600 41. McIntosh E. The cost of rheumatoid arthritis. Br J Rheumatol 1996; 35 (8): 781-90 42. McCarty DJ. Suppress rheumatic inflammation early and leave the pyramid to the Egyptians. J Rheumatol 1990; 17: 1115-8
About the Author: Dr Burkhard F. Leeb is Senior Consultant at the Second Department of Medicine, Lainz Hospital, Vienna, Austria. He is presently Co-Chairman of the Austrian Early Arthritis Action and the Polymyalgia Rheumatica subgroup of the EULAR standing committee for clinical trials including therapeutic trials. His current clinical research interests are anti-TNF-α antibody treatment of rheumatoid arthritis and therapy of osteoarthritis. Correspondence and reprints: Dr Burkhard F. Leeb, Second Department of Medicine, Center for Rheumatic Diseases, Lainz Hospital, Wolkersbergenstrasse 1, A-1130 Vienna, Austria.
Dis Manage Health Outcomes 1998 Dec; 4 (6)
