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J. R. Kirwan Effects of long-term glucocorticoid therapyin rheumatoid arthritis
unterscheidet, geben diese neueren Stu-dien zustzlich Einblicke in die derKrankheit zugrundeliegenden patho-physiologischen Prozesse. Die Ergeb-nisse dieser therapeutischen klinischenStudien untersttzen die Sicht, dassEntzndung und Gelenkdestruktionparallele Prozesse sind, welche durchdie dahinter stehenden Ursachen derRA nur lose verbunden sind, sich aberin einem gewissen Umfang unabhngigvoneinander entwickeln. Es ist interes-sant zu spekulieren, ob diese verschie-denen Effekte der Glukokortikoide sichauf unterschiedliche Mechanismen,dargestellt an anderer Stelle auf diesemSymposion, beziehen knnten.
Schlsselwrter Rheumatoide Arthri-tis Glukokortikoide radiologischeProgression
Summary Radiographic erosionsdevelop in about two thirds of patientswith rheumatoid arthritis (RA). Gluco-corticoids offer rapid and substantial
control of the symptoms of inflamma-tion in the short and medium term.Data are reviewed which suggest thatthis benefit may not last into the longerterm (more than 1 year). However,recent studies provide unequivocal evi-dence that joint destruction can behalted in this disease. Also, by separat-ing the short-term anti-inflammatoryeffect from a more prolonged suppres-sion of joint destruction, these studieshave shed light on the underlyingpathological processes. The evidencefrom these therapeutic clinical trialsstrengthens the view that inflammationand joint destruction are parallelprocesses, loosely linked by the under-lying cause of RA, but progressing tosome extent independently. It is intrigu-ing to speculate that different effects ofglucocorticoids might relate to theirdifferent modes of action outlined else-where in this symposium.
Key words Outcome long-term disease assessment X-rays pathology radiographs
J. R. Kirwan (Y)Rheumatology UnitUniversity of Bristol Division of MedicineBristol Royal InfirmaryBristol BS2 8HW, UKE-mail: John-Kirwan@Bristol.ac.uk
Effekte der Langzeittherapie mitGlukokortikoiden bei rheumatoiderArthritis
Zusammenfassung Zwei Drittel allerPatienten mit rheumatoider Arthritis(RA) entwickeln im Laufe ihrerErkrankung radiologisch nachweisbareErosionen. Glukokortikoide habenkurz- und mittelfristig zunchst eineschnelle und nachhaltige Wirkung aufdie Symptome der Entzndung. Eswerden Daten vorgestellt, welche einenlangfristigerer Effekt nahelegen (lngerals ein Jahr). Neuere Studien belegeneindeutig einen retardierenden Effektauf die Gelenkdestruktion bei RA.Indem man die Kurzzeiteffekte der Ent-zndungshemmung von den Langzeit-wirkungen auf die Gelenkdestruktion
Rheumatoid arthritis (RA) is an inflammatory disease withgreat variability within and between patients. It is a relativelycommon condition and the prevalence of RA in Europe rangesfrom 13 % (1). RA is the most common disease treated byrheumatologists, and comprises up to 25 % of all referrals torheumatology clinics and 75 % of follow-up work (2). There
currently is no cure for RA and treatment of the most commonclinical presentation is directed at the control of pain, swellingand stiffness caused by the inflammatory synovitis. To thisend, most patients are treated with non-steroidal anti-inflam-matory drugs (NSAIDs) and specific anti-rheumatoid drugs(SARDs, also known as disease modifying antirheumatic
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drugs, DMARDs). About two thirds of patients with RAdevelop destructive lesions of the bone and cartilage seen onradiographs as erosions (3). Much debate has focused onwhether or not it is possible to reduce the rate progression ofjoint destruction and hence modify the natural history of RA(4, 5). This is a difficult question to answer because of thechronic, variable nature of the disease.
Glucocorticoids have been used to treat RA since their dis-covery in 1948 (6). Glucocorticoids offer rapid and substan-tial control of the symptoms of inflammation in the short andmedium term. Compared with placebo and over a period of afew weeks, they show effect sizes (improvements expressed asa proportion of the standard deviation of the parameter beingmeasured) of 1.31 for joint tenderness and 1.75 for joint pain(7), both of which are substantial. They are also significantlybetter than the values achieved by NSAIDs (7). There havebeen relatively few randomised, controlled trials of medium-and long-term use of glucocorticoids in RA, but a recent
review estimated that low doses of glucocorticoids over 6 months are more effective than placebo and NSAIDs fortender joints, swollen joints, pain and function (8). The broadconclusion by the end of the 1950s was that glucocorticoidshave a powerful anti-inflammatory effect but this may not beprolonged for more than a year or so. However, there was someindication that glucocorticoids might have an additional effectnot shared by NSAIDs, namely to reduce the rate of jointdestruction in RA. The data were particularly suggestive in astudy by West (9), which was not well known and went essen-tially unrecognised for many years (10).
In 1986 a re-analysis (11) of early results (9, 12) concludedthat there was a case to be made for exploring the diseasemodifying potential of glucocorticoid therapy. The authorsproposed conducting a new randomised, double blind, placebocontrolled trial of a fixed dose of glucocorticoids (7.5 mgprenisolone daily) designed specifically to test the hypothesisthat glucocorticoids can suppress erosive progression (11).
Fig. 1 Mean (95 % CI) Larsenscore after log transformation for75 patients with complete dataover 3 years in the ARC Gluco-corticoid Study Group trial ofprednisolone 7.5 mg daily (14).The difference between groups issignificant at 1, 2 and 3 years.
Fig. 2 Mean (95 % CI) articularindex for 75 patients with com-plete data over 3 years in the ARCGlucocorticoid Study Group trialof prednisolone 7.5 mg daily (14).The difference between groups issignificant at 3 months only.
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That study, conducted in patients with early, active diseasewho were also treated with conventional NSAIDs and SARDs,has since been undertaken and the results have been published(13, 14). The trial was conducted over two years, and a blindedfollow-up of patients was continued for a further year. Therewas a clear-cut reduction in the rate of radiological progres-sion of the disease (Fig. 1). However, symptomatic benefit overand above that achieved with NSAIDs and SARDs (reducedpain, joint swelling and tenderness and improved function)was relatively short lived and lasted only three to twelvemonths (Fig. 2). There are several important observations to bemade by comparing Figs. 1 and 2. First, patients treated withNSAIDs and SARDs but no prednisolone showed the symp-tomatic improvement which might be expected from patientsstarting treatment with these agents. Second, there was a fasterbut no greater improvement in symptoms in the prednisolonetreated patients, and the placebo patients eventually achievedthe same level of improvement. Third, the placebo-treatedpatients had a progressive increase in their erosion score
throughout the period of treatment, while the prednisolonetreated patients showed little or no progression throughout thetreatment period. Fourth, there was no deterioration in thepatientsclinical status when glucocorticoids were withdrawn,but radiological progression re-commenced (14). Fifth, therewas a dissociation between the short-term additional benefitfrom glucocorticoids for symptom control, and the continuinglonger-term benefit in terms of preventing joint destruction.
Since then, a further study (15) has been published in fulland two more reported in abstract form (16, 17). The results ofthese studies taken together with the original MRC study (12)are shown in Fig. 3 for radiographic change and Fig. 4 forassessments of joint inflammation. All the studies point to thesame conclusion that a fixed daily low dose of glucocorticoid(equivalent to about 7.5 mg of prednisolone) can substantiallyreduce the rate of radiological progression over 2 years inpatients with early RA who are taking concomitant treatmentwith other second line agents. In addition, they confirm theimportant observation of the dissociation between the short-term, unsustained response of joint inflammation and the con-tinuing effect of suppression of radiological joint destruction.This suggests that these aspects of RA, clinical inflammatorysymptoms and radiological joint destruction, are differentfrom each other (or at least are controlled differently).
As well as providing the first unequivocal evidence thatjoint destruction can be halted in this disease, these studieshave shed light on the underlying pathological processes. Theassumption in the past has been that the joint destruction thatoccurs in RA is caused by the same process of inflammationthat causes the symptoms and signs. However, clinicians havesuspected for some time that this model of RA is not consis-tent with clinical experience (3, 18). The evidence from thesetherapeutic clinical trials strengthens the view that inflamma-tion and joint destruction are parallel processes, loosely linkedby the underlying cause of RA, but progressing to some extentindependently (19). Indeed, it has been known for some time
Fig. 3 Proportionate (%) change from baseline of erosion scores for fiverandomised, controlled trials which compared glucocorticoids to placebo.Kirwan et al. (13) and Hickling et al. (14): 7.5 mg prednisolone daily for2 years (plus non-steroidal anti-inflammatory drugs and specific anti-rheumatoid drugs) using the Larsen score (25); Boers et al. (15): pred-nisolone 60 mg daily reducing to 7.5 mg daily over 6 weeks then 7.5 mgdaily for 28 weeks plus methotrexate 7.5 mg weekly (plus non-steroidalanti-inflammatory drugs and specific anti-rheumatoid drugs) for 40 weeksusing a modified Sharp score (26); Wassenberg et al. (16): 5 mg pred-nisolone daily (plus non-steroidal anti-inflammatory drugs and specificanti-rheumatoid drugs) for 2 years using an erosion score; van Everdin-gen et al. (17): 10 mg prednisolone (plus non-steroidal anti-inflammatorydrugs and specific anti-rheumatoid drugs) for 2 years using the Sharpscore (26); and the MRC and Nuffield Foundation trial (12): prednisolone20 mg daily gradually reducing to a mean of 10 mg daily compared tohigh dose aspirin over 2 years using standardised radiographic grades(12).
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that, in those patients who do develop radiographic changes,the correlation between the symptoms and signs of inflamma-tion and erosive progression explains only 50 % of their vari-ance (20, 21). This view is also supported by findings in animalmodels of arthritis (22), in histological studies in humans (23,24), and in epidemiological studies and community basedinvestigations (18). If more than one different pathologicalprocess is occurring in RA joints, then it is easier to imaginehow different treatments might effect these processes differ-ently. It is intriguing to speculate that different effects ofglucocorticoids might relate to the different modes of actionof these agents outlined elsewhere in this symposium.
Fig. 4 Proportionate (%) change from baseline of articular index scoresfor four randomised controlled trials which compared glucocorticoids toplacebo. Kirwan et al. (13) and Hickling et al. (14): 7.5 mg prednisolonedaily (plus non-steroidal anti-inflammatory drugs and specific anti-rheumatoid drugs) for 2 years using an articular index of swollen and ten-der joints (27); Boers et al. (15): prednisolone 60 mg daily reducing to7.5 mg daily over 6 weeks then 7.5 mg daily for 28 weeks plus methotrex-ate 7.5 mg weekly (plus non-steroidal anti-inflammatory drugs andspecific anti-rheumatoid drugs) for 40 weeks using a swollen joint count;Zeidler et al. (28) (same study as Wassenberg et al. (16): 5 mg pred-nisolone daily (plus non-steroidal anti-inflammatory drugs and specificanti-rheumatoid drugs) for 2 years using an articular index of swollen andtender joints (27); and the MRC and Nuffield Foundation trial (12): 20mg daily gradually reducing to a mean of 10 mg daily compared to highdose aspirin over 2 years using standardised joint swelling grades (12).
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