PHARMACOECONOMICS

Drugs & Aging 7 (5): 338-346, 1995 117o-229X/95/0011-0338/SQ4,5Q/O

© Adts tnternationollimited All rights reselVed.

Pharmacological Intervention in Older Patients with Rheumatoid Arthritis Quality of Life Aspects Preben Bendtsen, Ingemar Akerlind and Jan-OIDf Hornquist Department of Community Medicine, University of Linkoping, Sweden

Contents Summary , , , , , , , , , , , , , , , , , . , 1, Course of Rheumatoid Arthritis (RA) , , , , 2, Quality of Life (QOL) Studies in RA Patients 2,1 QOL Studies in Older Patients , , , , , 3, Time Aspects in the Assessment of Pharmacological Interventions 4, Pharmacological Interventions in Older Patients with RA , 4,1 QOL Assessment " " " " " 5, Scaling of Items in QOL Questionnaires 6, Conclusion " " , , , , , , , , , , , ,

Summary

338 339 339 340 340 342 343 344 344

Despite the rather pessimistic outlook regarding the long term effects of pharmacological treatment of patients with rheumatoid arthritis (RA), there is no doubt that drug interventions can affect quality of life (QOL). The disease has a significant impact upon physical, psychological and social function, and QOL optimisation should cover all these dimensions, Swelling of joints and pain are important manifestations in assessing RA since these may result in sleep disturbances as well as depressed mood. This might be particularly significant for older persons with RA. Outcome parameters of RA can be divided into short, intermediate and long term. The long term results are quite disappointing with regard to disability and premature death, However, more intermediate outcome measures related to QOL might improve after pharmacological interventions. Patient preferences and expectations with regard to the outcome of pharmacological interventions are important parameters to assess. When assessing older patients with RA with QOL instruments, it is recommended that questionnaires are fairly short and easy to complete. Adverse effects of pharmacological interventions are important factors to monitor in QOL assessment in older patients with reduced remaining life span.

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QOL and Rheumatoid Arthritis

The cause of rheumatoid arthritis (RA) is unknown and still remains a puzzle to modern medicine. The disease is chronic and is characterised by joint pain, swelling and stiffness, accompanied by structural damage and deformity of the joints.[1-4] Individuals with RA experience various degrees of limitation in personal functioning and may develop psychological disturbances.[5.6] As for other chronic diseases, no cure is yet available. Instead, treatment interventions are aimed at relieving symptoms and improving functional performance. From this perspective, it is quite obvious that both physical and psychosocial aspects of health need to be included in outcome assessments of RA.l 7.8] The WHO definition of health some decades ago as a state of physical, mental and social well-being has stimulated the development of new measurements in the area of outcome assessment of chronic diseases such as RA.[9] Consequently, the focus of outcomes studies in chronic diseases has changed from a technical and biological preoccupation towards a more patient-concerned psychosocial perspective. The biological and serological abnormalities may provide information about the disease activity, but it is the physical, social and psychological improvements that make the difference between adequate and inadequate treatment.[IO] This article explores practical pharmacological treatment recommendations, in older patients with RA, with regard to monitoring the effect of treatment on quality of life (QOL).

1. Course of Rheumatoid Arthritis (RA) Since remission is rare, most patients with RA have life-long disease, inevitably leading to disability and premature death. Prevention of disability and death would seem to be the ultimate goal of treatmentofRA.[4,II,12] However, a number of studies have shown a rather pessimistic effect of treatment with regard to these 2 parameters.l4,II,13-15] In most cases the disease leaves the individual with a certain amount of disability despite treatment interventions, [16] On the other hand, there seems to be no doubt © Adis International Limited. All rights reseNed.

that patients with RA, despite the lack of a cure, can benefit from therapeutic interventions when outcome is considered from a QOL perspective. This includes reduction of pain and ability to live a normal life according to personal preferences,[13,16-18] When considering the effects of treatment in older patients with RA, it is important to have in mind the correlation between age and duration of the disease. In line with other studies, we have demonstrated an increasing disability with longer disease duration.l 17 ,19-22] Physical disability would not be expected to show a dramatic improvement after a clinical pharmacological intervention in older individuals who have had RA for many years, but pain and joint swelling might improve. Tissue damage is permanent unless surgical intervention is performed.l 23 ] The normal aging process (rather than ill health) might also complicate outcome assessment since health status after treatment might be blurred by lowered expectations upon physical performance in generaI.l24]

2. Quality of Life (QOL) Studies in RA Patients Rheumatoid arthritis has a significant impact upon QOL.l 25 ] Mason et al.[26] compared QOL in RA with 5 other chronic diseases and found RA to be associated with most negative health status and ranked as one of the most morbid chronic diseases. In particular, physical activity, social activity and pain were impaired in comparison with diabetes, pulmonary disease, hypertension, cancer and cardiac disease. Each chronic disease had its own profile.[26] In a comparative study of 9 chronic diseases, clearly worse physical, social and psychological functioning were identified for all the diseases when compared with the absence of chronic conditions. However each chronic condition had a unique profile with regard to the various components of present health status,l27] While there is no universally accepted definition of QOL, there seems to be a consensus about the inclusion of at least 3 dimensions: physical, psychological and social. Furthermore, some measureDrugs & Aging 7 (5) 1995

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Table I. Specific age'related factors to consider in quality of life assessment in older patients with rheumatoid arthritis Factor to consider 1. Normal aging process vs ill health 2. Cognitive functioning reduced 3. Sleeping disturbances in combination with depression and pain 4. Functional disability might be permanent 5. Potential conflicts with family members due to dependency and physical restrictions 6. Social isolation due to comorbidity in spouse 7. Adverse effects of pharmacological therapy

ments of pain should be applied. A variety of definitions of QOL have been proposed and many of these focus on subjective measurements depending upon personal preferences or the ability to act in order to satisfy vital goals.[25.28.30 l Several different types of QOL questionnaires are available and we have previously reviewed some of theseP 5l The Arthritis Impact Measurements Scale (AIMS) is one of the most commonly used in outcome studies of RA disease, together with the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) and the Health Assessment Questionnaire (HAQ)J31.32 1 The clinical relevance of information from such questionnaires has been substantiated in a number of studiesJ21. 31 l In an editorial, Bellamy stated that the most powerful predictor of prognosis is loss of function as measured by HAQ, AIMS or similar instruments)32l The psychometric properties of QOL instruments have been extensively studied and in most cases found to be reliable and sensitive to important clinical changes in health status.[17. 25 1 2.1 QOL Studies in Older Patients

QOL measurements in older patients with RA have certain limitations due to specific age-related factors, as displayed in table I. All sensory systems become less efficient with increasing age and this might affect cognitive functioning in some individuals. Where pharmacological treatment for RA involves educational and informational aspects, this might require awareness of such an impairment. Drug compliance in older patients is generally © Adis International limited. All rights reserved.

Comments Assessment should focus upon disease·specific symptoms Short and easy questionnaire Include assessment of pain and psychosocial well·being Focus on function as perceived by the patients rather than exact measurement Include a questionnaire to dependent other/spouse Include items about the family members' social status Include items on adverse effects of drug therapy

claimed to be lower than that in younger persons but some authors argue that older persons appear to try harder to comply with medication)33l Dependence on external support is another factor that might be valued differently in older individuals)34l Dependence may be considered as something negative in the younger age groups but for the older age group it is regarded as more tolerable and to a certain extent 'normal'. Therefore, dependence may not have the same importance for older RA patients as for younger ones when considering QOL and the beneficial effects of pharmacological interventions. Wegener[34 1 has pointed out the importance of sleep disturbances in older persons in general. Individuals with RA have been reported to have sleep disturbances associated with depression and pain. These parameters should be included in QOL assessment in response to pharmacological treatmentJ 341 Most individuals with RAlive within families and, since increasing disease duration correlates with increasing functional disability, the responsibility upon the family and especially the spouse might increase over timeJ22,351 This constitutes a potential risk for creating conflicts between family members. Family factors are therefore considered important when measuring QOL in older individuals.[3 4 1

3. Time Aspects in Assessment of Pharmacological Interventions The ideal treatment for RA should be effective both with regard to short term effects, such as relieving pain and increasing mobility, and long term Drugs & Aging 7 (5) 1995

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effects, such as preventing disability and death. In addition, the treatment should be cost effective and easy to administer.! 151 Before evaluating effects of clinical pharmacological interventions, one must decide whether all or only some of these aspects should be included in the assessment. Outcome parameters measuring successful treatment could be divided in several different ways, as shown in table II. Some consensus appears with regard to short term effects (which seem to be process oriented, i.e. laboratory improvements) and to long term effects (as measured by a comprehensive QOL questionnaire including physical, psychological and social parameters). In this respect, short term refers to a time span of a few months up to as long as 5 years, whereas long term is generally considered to be more than 5 years.! I II Since the time span between short and long term evaluations is rather long, a more practical time frame would be to consider treatment effects with reference to 3 levels of improvement: immediate, intermediate and ultimate (i.e. short, intermediate and long term). On the immediate level, laboratory variables may be improved, while on the intermediate level, disability, pain and QOL might be improved for periods of time.!161 Long term effects, such as sustained remission, is a more ultimate variable to be monitored in a life-long perspective. Although an intervention might have immediate and intermediate effect, the more long term benefits might be hampered by lack of therapeutic effect after some months of treatment. Pincus and Callahan[41 stated in a recent review that the long term results regarding remission were disappointing due to a loss of efficacy after 3 to 12 months in most patients. They also observed that many clinical trials were too short to demonstrate any long term effect on disability and QOU 41 In addition, Wolfe claims that much of the prognosis literature has been confusing with regard to definition of outcome. He suggests that process and outcome evaluation should be kept apart. Where process measures reflect the inflammatory component of RA, outcome measurements refer to the more long term consequences of the disease, such as structural © Adis International Limited. All rights reserved.

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Table II. Focus of outcome measurements used in clinical trials Author Tugwell & Bombardier36] Liang, Cullen & Larson[17] Wrigh~16]

Focus Objective and subjective Proximal and distal Immediate, intermediate and ultimate Short and long term

Spector14] Pincus & Callahan l4] Wolfel13]

Process and outcome

Bombardier 12]

Clinical and patient-orientated

Long & Scottl37]

Impairment, disability and handicap

Short and long term

changes to the joints, functional disability, pain, social and psychological aspects and mortality. According to Wolfe, we have failed to measure the real benefits of therapy. We have focused upon either the immediate or the ultimate consequences of RA instead of a more intermediate assessment.[ 13 1 Supporting the application of more intermediate outcome assessment, Biljsma et al.[ 301found that laboratory measures are process rather than outcome measures and as such correlate poorly with selfreported indices. Some correlations were found between self-reported mobility and psychological measures in relation to one laboratory measure, ESR. However, no correlation was found between social factors and any other objective or subjective measure. The authors concluded that physical, psychological and social aspects of health are independent and should be measured independently.[301 In summary. the outcome of clinical trials should not only be evaluated with regard to proximal outcome, as measured by joint swelling and range of motion, and more distal outcome, such as disability and death, but also in a more intermediate perspective as measured by QOL assessments. The first outcome measurements should be applied shortly after a clinical intervention; QOL demands a somewhat longer time span, several months or even years, before the effect of an intervention can fully be assessed.[13·14.17.29. 361This mixture of short term and more intermediate effects was also included in the suggestions of the American College of Rheumatology subcommittee on clinical trials regarding the following outcome measures to use in clinical trials: Drugs & Aging 7 (5) 1995

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• swollen joint count • physical disability • pain • tender joint count • patient global assessment • acute phase reactant • physician global assessment • x-ray studies (trials> I year duration). Swollen joint count was considered the most credible outcome measure of clinical trials, although this is a rather short term variable.[ 121 This article focuses on practical recommendations with regards to more intermediate outcome measurements. This is of great relevance for the patient's ability to live a normal life within his or her own preferences. Due to a possible lack of effect after some months of treatment, it is important to continue measuring QOL aspects several years after clinical pharmacological interventions have been initiated. If a particular study only measures the effect of a pharmacological intervention on the immediate effect on mobility and pain, this time frame does not need to be considered)41

4. Pharmacological Interventions in Older Patients with RA Medical treatment in the older patient in general has been shown to be related to a poorer QOL, perhaps as a consequence of related morbidity, but drug adverse effects cannot be ruled out.[38) As part of an evaluation of a clinical drug intervention in RA, consideration must be given to monitoring the adverse effect of drugs. This is especially important in the elderly. Drugs used in treating RA are potentially toxic and adverse effects are often experienced which quite often leads to discontinuation of the particular drug)4.13) All drugs used in RA therapy have adverse effects, particularly the second-line drugs. Toxic reactions to gold salts and penicillamine have been reported to occur more often in patients over the age of 60 years, although this has not led to a recommendation to abstain from treatment.[ 391In general, gold is very toxic and about 20% of patients will discontinue the drug because of this)I) © Adis International limited. All rights reserved.

Bendtsen et al.

Premature death has been associated with adverse drug reactions. Mutru et aI.l40) studied 500 men and women over a lO-year period with a matched control population. The overall mortality was significantly higher in the RA group. Infections and renal disease appeared to be the main cause of death in patients with RA. The authors raised the question as to whether gold and penicillamine have renal adverse effects. [40) Other studies have not given a clearer picture of the relationship between RA drugs and malignancy.[2) Wolfe[13) claims that adverse reactions to intramuscular gold injections, corticosteroids and methotrexate have received too little attention. He also adds a time aspect to adverse effects of drug therapy: dyspepsia occurring daily for 3 years might be unacceptable to the patient whereas this has minor importance in a short clinical trial. He suggests long term follow-up of adverse effects.[ 13 1 In an earlier study of medical records in a cohort of individuals with RA from a healthcare district,[25) we found a high percentage of drug discontinuation due to adverse effects. The group consisted of 222 men and women with a mean age of 64 years. Around 1 in 4 patients discontinued second line drugs due to adverse effects.[25) In contrast to our findings, Fries et al.[41) reported a relatively high continuation of drug therapy with disease-modifying agents after 9 months of therapy. In a prospective descriptive study conducted with 737 consecutive new users of 11 prescribed drugs, around 70% were still undergoing treatment after 9 months)4l) In general, compliance with pharmacological treatment has not been sufficiently studied in RA.[42) Patients with RA might feel forced to 'try' a potentially toxic drug in order to avoid further progression of disability, although this cannot be guaranteed with any drug. Previous studies have shown that RA patients were prepared to accept a 27% likelihood of death in order to have a chance of full recovery.l15) Compliance is the single most important judgement of the patient indicating effectiveness or noneffectiveness of the pharmacological intervention. If the patient feels or believes that the drug is effective, he/she will continue to Drugs & Aging 7 (5) 1995

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take it. Noncompliance on the other hand, might indicate that a patient found that the risk or adverse effects of the drug exceeded the benefits.l 42 ]

Table III. Quality of life-related parameters included in intermediate assessment in studies of rheumatoid arthritis Parameter 1. Short and easy questionnaires

4.1 QOL Assessment Scrutiny of previous clinical trials which used QOL assessment can assist in identifying items to be included in future QOL assessments, as shown in table III. Although the study populations in many of the cited studies include both younger and older patients, the mean age of patients in most of the studies is approximately 60 years of age or more.[4.12.14.16.17.36] Several authors suggest that assessment measurements of pain, disability and stiffness should be included in outcome studies of interventions in RA.[16.19.54] For example, 55 patients responded to a questionnaire about the importance of various aspects of an arthritis treatment programme. The caregivers and the patients both agreed about the importance of pain relief.l 54 ] Furthermore, in a qualitative study, van Lankveld et al.l46 ] asked 14 patients to list their problems: pain, physicallimitations and dependence were most often reported as stressors. Tugwell and Bombardier[36] underline the importance of physical and social functioning since many activities within these dimensions are affected by RA. The patient should identify the most important symptoms and functional restrictions due to arthritis in order to be able to measure improvement in these areas. Patient preferences and expectations need to be taken into consideration when measuring pharmacological optimisation of QOL in older patients. An individual might value functional status differently in comparison with the doctor or other patients in similar situations. A patient's expectations of a certain drug therapy might also influence the perceived result of the intervention. If patients have unrealistic expectations, the specific drug therapy might be evaluated incorrectly.l36.37] Tugwell et aI)55] among others, have displayed how QOL can be included in a clinical trial, providing important and valuable information. In an l8-week trial of methotrexate treatment in patients © Adis Intemational Um~ed . All rights reserved.

2. Outcome parameters important to the patients

Study Stewart et al.(27) Borstlap et al. (29) Long et alP7) Stewart et al.(27) Tugwell et al.(43)

3. Pain measurement

Anderson et al.['9) Wright['6) Buckelew et al.(44) Keefe et al. (20) Young l4S) van Lankveld et al.[461 Hurst et al. [471

4. Stiffness. mobility and functional status

Anderson et al.(19) Wright['6) Bellamy(32) Wolfe & Pincus(3') van Langkveld et al. (46) Anderson('9) Parker et al. (48) Reisine et al.(49) Tugwell et al.(43) van Langkveld et al. (46)

5. Social functioning including household and recreational activities

6. Social support including family

situation and dependency

7. Well-being including anxiety. depression. self-esteem

8. Adverse effects of drugs

Fritz patrick et al. (SO) Parker et al.l48) Lambert et al.(S'1 Resine et al.(49) Smith & Waaiston lS2) van Langkveld et al.l461 Anderson et al.('9) Young(45) Smith & Waa[ston(52) van Langkveld et al. (46) Hurst et al. (47) Krol et al. (53) Wright(16) Anderson et al.['9) Wolfe(13)

with RA, 189 patients were studied with regard to clinical parameters as well as improvements in QOL experiences. Previous studies had shown improvement in clinical parameters only, but the study in question even showed effects on QOL. The authors included the MACTAR questionnaire in which patients are asked to identify and rank important activities according to personal preferences. The patients identified the following areas of importance: walking, housework, lifting, dressing, sewing, dancing, shopping, working, going to church and sport activities. Similarly, in an earlier Drugs & Aging 7 (5) 1995

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Table IV. Checklist for quality of life (OOL) monitoring of pharmacological interventions in older persons with rheumatoid arthritis Item 1. Short and easy questionnaire

2. Comprehensive QOL assessment should include items on physical, social and psychological functioning

3. Pain

4. Allow the patients to give their preferences and expectations concerning areas to be irnproved

5. Include registration of adverse effects of drug in relation to cornpliance with therapy

6. The questionnaire should be repeated with certain intervals exlending at least a year or two from the start of the intervention in order to monitor more sustained effects

study using the MAC TAR questionnaire, 50 consecutive patients referred to a medical outpatient clinic ranked their preferences as follows: walking, housework, cooking, sewing, gardening, working, going to church and sport activitiesJ43]

5. Scaling of Items in QOL Questionnaires In an earlier review we discussed the essential psychometric properties of a QOL instrumentJ25] With regard to this, one must consider the nature of the scaling of a questionnaire. A nominal scale identifies the existence of a certain phenomenon at a particular time (i.e. 'yes/no' options) whereas an ordinal/interval scale quantifies the magnitude of a phenomenon over a certain time span (i.e. 'worse/unchangedlbetter' options).125] We find it more meaningful to apply answer options in an ordinal or interval scale rather than a nominal scale. For example, instead of asking 'are you able to dress yourself' , an ordinal scale could provide the following answer options to the question 'how has © Adis International Limited. All rights reserved.

Reason for inclusion In clinical trials some longer questionnaires might be included but in daily clinical practice this might not be applicable. Remember cognitive functioning may be reduced Functional status measurement similar to the Health Assessment Questionnaire should be included l211 as well as swollen joint count. Furthermore, questions on depression, anxiety, self-esteem and social functioning and support should be included A graphic scales-of-pain measurernent should be applied at certain time intervals depending upon the nature of the study. Reduction of pain is an essential expected effect of treatment in older patients with relevance for sleep and mental well-being The patients should identify some areas important to their preferences in which improvement is expected as a result of the pharmacological intervention, i.e. the medicine should improve the function of my right knee What degree of adverse effects due to the therapy are patients willing to accept in order to accomplish the expected benefits of the treatment? In older patients immediate adverse effects might be more important than more long term risks. Expected length of pharmacological treatment, temporary or life-long, makes a difference and must be taken into consideration Although pharmacological treatment might have an immediate effect on pain and stiffness, sustained QOL improvement as such might not be detected until a year later

your ability to dress yourself changed since the start of the drug therapy' : 'much improved / somewhat improved / unchanged / somewhat deteriorated / much deteriorated'. This scaling technique has been shown to be useful and relevant in QOL measurement in patients with RA.[28]

6. Conclusion In table IV, a checklist for QOL monitoring pharmacological interventions in older persons with RA is presented. This should offer some guidance in choosing the most relevant items in the assessment of a pharmacological intervention. No single outcome measurement or questionnaire has yet been proven to cover all important aspects under all circumstances.[25,37] In the absence of one single satisfactory scale it has been suggested that a battery of well-tested scales measuring different aspects of interest should be used.125 ] The specific purpose of a particular drug intervention should guide the number of assessment items to be included. Drugs & Aging 7 (5) 1995

QOL and Rheumatoid Arthritis

In clinical practice, a fairly short questionnaire is probably the most applicable. For comparison and standardisation purposes, existing instruments are most easily applied in older patients with RA. A combination of a short functional disability questionnaire and a somewhat longer psychosocial instrument have been shown to be a good basic combination. [21,31,32] Furthermore, it is recommended to include some areas of daily functioning in which the patients expect improvement due to the drug intervention. Repeated measurements must be applied in order to assess improvement within the areas defined by the patients. Compliance with the therapy as well as adverse effects gives important information about QOL during the drug intervention. If a more prolonged improvement in QOL is to be assessed, the questionnaire should be repeated a year or more after the start of the intervention. The effect of a drug intervention on QOL is a combination of all the above factors. If there are more positive effects on the included areas, QOL must be considered to have improved.

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32. Bellamy N. Prognosis in rheumatoid arthritis [editorial]. J Rheumatol 1991; 18: 1277-9 33. James MA, Potter JE The effect of antihypertensive treatment on the quality of later years. Drugs Aging 1993; 3: 26-39 34. Wegener ST. Cognitive, behavioral and psychological issues in the rheumatological care of elderly. Scand J Rheumatol 1989; Suppl. 82: 39-49 35. Bendtsen P, Bjurulf P, Trell E, et al. Cross-sectional assessment and subgroup comparison of functional disability in patients with rheumatoid arthritis in a Swedish health-care district. Disabil Rehabil1994; 17: 94-9 36. Tugwell P, Bombardier e. A methodological framework for developing and selecting endpoints in clinical trials. J Rheumatol 1982; 9: 758-62 37. Long AE. Scott DL. Measuring health status and outcomes in rheumatoid arthritis within routine clinical practice. Br J Rheumatol 1994; 33: 682-5 38. Jensen E, Dehlin 0 , Hagberg B, et al. Medical, psychological, and sociological aspects of drug treatment in 80-year-olds. Z Gerontol 1994; 27: 140-4 39. Terkeltaub R, Esdaile J, Decary F, et al. A clinical study of older age rheumatoid arthritis with comparison to a younger onset group. J Rheumatol 1983; 10: 418-24 40. Mutru 0, Laakso M, Isomiiki H, et al. Ten years mortality and causes of death in patients with rheumatoid arthritis. BMJ 1985; 290: 1797-9 41. Fries JF, Spitz PW, Mitchell DM, et al. Impact of specific therapy upon rheumatoid arthritis. Arthritis Rheum 1986; 29: 620-7 42. Liang MH. Compliance and quality of life: confession of a difficult patient. Arthritis Care Res 1989; 2: 71-4 43. Tugwell P, Bombardier C, Buchanan WW, et al. The MACTAR patient preference disability questionnaire. An individualized functional priority approach for assessing improvement in physical disability in clinical trials in rheumatoid arthritis. J Rheumatol 1987; 14: 446-51 44. Buckelew SP, Parker Je. Coping with arthritis pain. Arthritis Care Res 1989; 2: 136-45

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Correspondence and reprints: Dr Preben Bendtsen, University of Linkoping, Faculty of Health Sciences, Primary Health Care and General Practice, 5-581 85 Linkoping, Sweden.

Drugs & Aging 7 (5) 1995