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The Use of Disease Modifying Antirheumatic Drugs In Postgraduate Medical Journal (1989) 65, 905 - 912 Postgrad Med J: first published as 10.1136/pgmj.65.770.905 on 1 December 1989. Downloaded from Difficult Decisions The use ofdisease modifying antirheumatic drugs in the management ofrheumatoid arthritis Lawrence E. Hart and Peter Tugwell Departments ofClinical Epidemiology andBiostatistics and Medicine, McMaster University, The Rheumatic Disease Unit, Chedoke Division, Chedoke-McMaster Hospitals, P.O. Box 2,000, Station 'A', Hamilton, Ontario L8N 3Z5, Canada. Introduction Lack of predictability in the clinical course of agents on both the natural history of RA and the rheumatoid arthritis (RA) is but one of several factors radiographic manifestations of joint destruction. that challenge our ability to treat this condition effectively. A further consideration is the aetio- The impact of DMARD therapy on the natural history pathogenesis of the disease which, for all practical of rheumatoid arthritis purposes, remains obscure. While several strands of evidence point to an infectious agent as a likely Because the natural history of RA is characteristically no micro- unpredictable, attempts at prognostication in indivi- mediator of joint inflammation, specific Protected by copyright. organisms have ever been unequivocally linked to the dual patients are often difficult. However, some causation of RA.'"2 Immune mechanisms almost cer- generalizations are possible. Disease remissions, tainly play a role in the initiation and perpetuation of should they occur, are most likely within a year of rheumatoid synovitis, but a convincing unifying disease onset. Women tend to have more severe hypothesis that accounts for all of the disparate disease than men, and the presence of subcutaneous elements of the process is still awaited.2'3 nodules or radiographic evidence ofjoint erosions at The disease modifying antirheumatic drugs the time of diagnosis are recognized indications of a (DMARDs), or slow acting antirheumatic drugs, are poor outcome.5 6 About 10% of patients with RA will so named because it is thought that they modify the experience an unrelenting and aggressively destructive progression of RA by (i) favourably altering the polyarthritis that leads very rapidly to cartilage de- natural history of the disease, or (ii) slowing the struction, bone erosion, and unsightly deformities. development ofjoint erosions or joint destruction, as For most of the remainder, cyclical exacerbations of measured on joint radiographs.4 These agents are a active disease will be interspersed with variable diverse group of compounds that produce a common periods of disease quiescence, though, eventually, a pattern of clinical response when used to treat RA. majority ofpatients will be considerably incapacitated http://pmj.bmj.com/ They can be broadly divided into two groups. In group by their disease.6 Moreover, several studies have 1 are such agents as the antimalarials, gold salts, demonstrated a higher death rate in patients with RA D-penicillamine and sulphasalazine. Although these than in age and sex matched controls in the general DMARDs do exert some effect on the immune population. response, the actual mechanism of their immunosup- In perhaps the most comprehensive long term study pressive action is poorly understood. The second of RA, Scott et al.7 found that patients tended to a more second decade of group of DMARDs have well documented capa- deteriorate rapidly during the on September 28, 2021 by guest. bility for suppressing immunity, but they also have their disease than during the first 10 years following recognized cytotoxic properties. Medications in this their diagnosis. All of the 112 patients who were group include methotrexate, azathioprine, cyclophos- entered into the study were aggressively treated with phamide and chlorambucil. DMARDs. During the first 10 years, there was a Before treating patients with a DMARD, it is significant fall in the number of patients with ele- important to appreciate the likely impact of these vations oftheir erythrocyte sedimentation rate (ESR); initially 33% had an ESR of over 50 mm/h and by 10 years, only 12% had such high readings. In addition, Correspondence: Lawrence E. Hart, M.B.B.Ch., M.Sc., the functional capacity of these patients showed a F.R.C.P.C., F.A.C.P. general improvement during the 10 year follow-up. Received: 24 July 1989 Initially, only 23% of cases were in classes I and II for The Fellowship of Postgraduate Medicine, 1989 906 L.E. HART & P. TUGWELL Postgrad Med J: first published as 10.1136/pgmj.65.770.905 on 1 December 1989. Downloaded from functional capacity (according to the Steinbrocker recent study, 50 patients with RA were followed for a Criteria8), but by 10 years, 67% of cases were in these minimum of 10 years.2 In 48 cases the total joint score classes. As patients entered the second 10 year period deteriorated (a mean increase in maximal damage of oftheir disease, the acute phase reaction fell much less 13%), regardless of treatment. During the 10 year frequently and functional improvement was rarely period, most progression occurred in the wrists, knees seen, as the number of severely disabled cases rose.7 and metacarpophalangeal joints, but also there was a Seventeen deaths occurred during I to 10 years from highly significant correlation between scores in these presentation and 20 between 10 and 20 years. Deaths joints and those in all other joints. were due to infections (septicaemia/abscess/ Evidence supporting an improved outcome in pneumonia) or renal failure in 13 patients. Many ofthe shorter term studies has been similarly disappointing. other deaths were attributed, at least in part, to Pullar et al. followed 47 patients on gold and D- rheumatoid disease. While none of the deaths was penicillamine over a period of 24 months.'5 Hand directly linked to the use ofDMARDs, corticosteroids radiographs of all patients showed a statistically may have been a contributing factor in the mortalities significant deterioration (when compared to controls) associated with infection or coronary heart disease. and, although there did appear to be a trend towards a In other studies that have examined the prognosis of slowing ofthe rate oferosions in the DMARD treated RA, Ragan and Farringdon9 followed up 500 patients groups, healing of erosions was very unusual. In this for up to 16 years. At entry, 82% were in Steinbrocker study, it was demonstrated that radiological changes functional classes I and II, while at 16 years only 45% showed a steady progression, and that fewer than one were in these categories. Similarly Rasker and Cosh'0 third of patients did not progress by at least one found that, of 100 patients seen within one year of (Steinbrocker) functional class. A detailed examin- onset of RA, 35 were dead and 8 in Steinbrocker class ation of radiographic progression showed that only IV at 15 years. Such declines were not only attributed 7 patients (8% of cases) did not have significant joint to the progress of a pathological mechanism but were destruction by 10 years; of these 4 were consistently Protected by copyright. thought also to have been influenced by socio- seronegative for rheumatoid factor and 3 of these economic factors. Pincus and Callahan," in a study of never had a raised ESR. By implication this was an 75 RA patients, showed that educational status atypical group with mild disease who may not have influenced prognosis. Death or a 50% reduction in warranted DMARD therapy in the first place. In more functional capacity occurred in 79% of patients typical patients it was exceptional not to have educated only at grade school, in 43% who had radiological changes by 10 years. attended high school, and in only 20% of those with a lannuzzi's review of controlled trials since 1960 college education. came to the conclusion that gold and cyclophos- phamide were the only agents where the weight of evidence indicated retardation of radiographic pro- 4 Impact of DMARD therapy on the radiographic gression. manifestations ofjoint destruction An approach to the management ofrheumatoid There has been ongoing debate over whether arthritis DMARDs actually slow the progression of joint http://pmj.bmj.com/ erosions. Several studies have addressed this issue,'2 16 When managing patients with RA, we are faced with a but, to date, there has been little agreement on the chronic, inflammatory, multisystem disorder in which impact of these drugs. Luukainen et al.17 have sug- causation, pathogenesis, course and outcome are gested that gold therapy is effective in slowing the rate incompletely understood. As a result treatment of radiological deterioration, but their study groups strategies have had to evolve empirically and have, for were not comparable and the observed differences the most part, been directed at (i) pain relief, (ii) were small. Although other studies have suggested reduction or suppression of inflammation, (iii) preser- on September 28, 2021 by guest. that disease severity, assessed clinically or by acute vation of muscle and joint function, (iv) minimization phase responses at a specified point in time, is related of drug side effects, and (v) return of the patient to a to the extent ofradiological progression,'21'8"9 they fail desirable and productive lifestyle.22 to show that such progression is favourably influenced When planning a treatment programme for patients by DMARDs over a period of time. with RA, it is essential to set specific objectives and In a study by Sharp et al.20 mean radiographic prospective time limits for the various therapeutic scores, when plotted against years after diagnosis of options. This approach should be clearly explained to RA, showed no deviation from the straight line the patient. In pursuing a comprehensive, though determined by a regression equation, implying that, prudently individualized protocol for the patients with when RA is fairly well established, progression ofjoint RA, a stepped care or staged approach (e.g.
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