British Journal of Rheumatology 1998;37:

Transcription

1 British Journal of Rheumatology 1998;37: PROGRESSION OF JOINT DAMAGE IN EARLY ACTIVE SEVERE RHEUMATOID ARTHRITIS DURING 18 MONTHS OF TREATMENT: COMPARISON OF LOW-DOSE CYCLOSPORIN AND PARENTERAL GOLD H. K. ZEIDLER,* T. K. KVIEN, P. HANNONEN, F. A. WOLLHEIM, Ø. FØRRE, H. GEIDEL,** I. HAFSTRÖM, J. P. KALTWASSER, M. LEIRISALO-REPO, B. MANGER, L. LAASONEN,*** E. R. MARKERT, H. PRESTELE and P. KURKI *Medizinische Hochschule Hannover, Division of Rheumatology, Hannover, Germany, Oslo City Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway, Department of Medicine, Central Hospital of Middle Finland, Jyväskylä, Finland, Department of Rheumatology, Lund University Hospital, Lund, Sweden, The National Hospital, University of Oslo, Oslo, Norway, **Department of Rheumatology, Dresden University Central Hospital, Dresden, Germany, Department of Rheumatology, Huddinge University Hospital, Huddinge, Sweden, Department of Medicine III, Johann Wolfgang Goethe University, Frankfurt, Germany, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland, Department of Medicine III and Institute of Clinical Immunology, University of Erlangen, Erlangen, Germany, ***Department of Radiology, Surgical Hospital, Helsinki University Central Hospital, Helsinki, Finland, Department of Clinical Research and Development, Novartis Pharma GmbH, Nürnberg, Germany, Department of Clinical Research and Development, Novartis Pharma AG, Basel, Switzerland and Department of Clinical Research and Development, Novartis Pharma AG, Helsinki, Finland SUMMARY Objective. This study compared the progression of joint damage in patients with early active severe rheumatoid arthritis ( RA) treated with cyclosporin or parenteral gold. Methods. In this open, randomized, multicentre study with a blinded radiological endpoint, 375 patients who had suffered from active severe RA for <3 yr were randomized to be treated for 18 months with low-dose cyclosporin or parenteral gold. The groups were stratified with regard to corticosteroid use. Primary efficacy variables were numbers of erosions, erosion score and the Larsen Dale joint damage score. Results. Joint damage progressed at similar rates in both treatment arms. In both groups, patients receiving corticosteroids had less X-ray progression. Rheumatoid factor positivity, high swollen joint count, high erythrocyte sedimentation rate and pre-existing X-ray abnormalities predicted progression of joint damage. Although numbers of serious adverse events were similar, more gold patients (n = 65) than cyclosporin patients (n = 45) withdrew from study medication because of adverse events. Conclusion. Cyclosporin was comparable to parenteral gold in retarding progression of joint damage and was better tolerated in terms of adherence to therapy. The open label design should be kept in mind when assessing this difference. KEY WORDS: Rheumatoid arthritis, Disease modification, Cyclosporin, Parenteral gold, Joint X-rays, Long-term safety. FOR most patients, rheumatoid arthritis ( RA) is a chronic, disabling disease, characterized by the rapid development of irreversible joint damage, often within the first 2 yr [1 3]. Initiation of anti-rheumatic therapy is advocated at an early stage to prevent the occurrence of erosions and to retard the progression of any previous erosive damage [ 4, 5]. Several anti-rheumatic drugs may decrease the rate of progression of structural joint damage [6]. To date, parenteral gold has been considered to be one of the most effective agents for retarding joint damage in RA, and is one of the recognized standards for treatment comparisons [7 9]. Clinical trials conducted over the past 10 yr have demonstrated that cyclosporin is effective in active severe and refractory RA [10 14], and a double-blind, placebo-controlled study suggested that cyclosporin may be capable of retarding joint destruction in active severe RA [12]. The patient populations recruited to Submitted 2 July 1997; revised version accepted 9 April Correspondence to: H. K. Zeidler, Division of Rheumatology, Department of Internal Medicine and Dermatology, Medizinische Hochschule Hannover, Zentrum Innere Medizin und Dermatologie, Carl-Neuberg-Straße 1, Hannover, Germany. these studies were characterized by advanced disease of long duration, where the prevention of joint damage has been limited. The primary objective of this study was to compare the ability of low-dose cyclosporin to prevent or to retard the progression of joint damage in early active severe RA with that of parenteral gold. The secondary aim was to compare the safety and tolerability of these agents in an RA patient population with a short disease duration. PATIENTS AND METHODS Patients Patients aged between 18 and 65 yr, with a diagnosis of RA as defined by the 1987 ARA criteria, with onset of disease after 16 yr of age, were eligible for inclusion in the study. Under these criteria, active RA is defined as unremitting disease for at least 6 months, accompanied by three or more of the following characteristics: (i) six or more tender joints; (ii) three or more swollen joints; (iii) early morning joint stiffness lasting for at least 1 h (average during the past week); (iv) an erythrocyte sedimentation rate ( ESR) of at least 28 mm at British Society for Rheumatology

2 ZEIDLER ET AL.: CYCLOSPORIN AND GOLD COMPARED IN SEVERE RA h ( Westergren) or C-reactive protein (CRP) of at patient recruitment. All patients gave written or oral least 20 mg/l. Early severe RA is defined as RA with informed consent before being accepted into the study. a duration of < 3 yr with juxta-articular erosions visible on X-ray, or disease failing to respond to a second- Study design line anti-rheumatic drug ( 4 months of treatment), or Patients who met the entry criteria were assigned to two of the following characteristics: (i) a positive assay treatment with either cyclosporin or parenteral gold for rheumatoid factor; (ii) an ESR of >40 mm/h on a 1:1 basis, using a minimization technique [15]. or CRP of >40 mg/l; (iii) anaemia ( haemoglobin This randomization technique was used to avoid imbalance <110 g/l; bleeding and haemolysis excluded). in the following criteria: previous joint erosion, Patients were excluded if they had received previous concomitant corticosteroid use, age, country and time cyclosporin or parenteral gold therapy; had impaired since diagnosis. The participating physicians and renal function as determined by haematuria, pro- patients were not blinded for treatment. The assessor teinuria (>0.2 g/24 h), or abnormal creatinine clearance; of the joint X-rays was blinded to the treatment exhibited hypersensitivity or other adverse allocation. reactions to gold compounds; had impaired liver function (bilirubin greater than the upper limit of the Drug administration normal range, aspartate aminotransferase, alanine The initial cyclosporin dose was 3 mg/kg day; if this aminotransferase and alkaline phosphatase greater proved ineffective, it could be increased from week 4 than twice the upper limit of the normal range); had onwards to a maximum dose of 5 mg/kg day. The elevated blood pressure (diastolic blood pressure dose was to be decreased if the serum creatinine level >90 mmhg; systolic blood pressure >160 mmhg); rose to >50% above the baseline, if the serum potashad a history of or current anti-hypertensive therapy sium level rose above the upper limit of normal, if or malignant disease; had uncontrolled infections; had diastolic blood pressure was >95 mmhg on consecu- leuco- or thrombocytopenia; had hereditary angio- tive visits, or if there were other intolerable side-effects. edema; had epilepsy; had gastrointestinal ulcer or malabsorption Parenteral gold therapy was initiated with an i.m. syndrome; or were alcohol or drug abusers. 10 mg test dose of sodium aurothiomalate. The dose Women who were pregnant, or who were capable of was then increased to a weekly injection of 50 mg. becoming pregnant and not practising an approved Weekly injections continued until a cumulative dose of method of contraception, and women who were breast 1 g was reached. Thereafter, patients were given injec- feeding, were not allowed to participate. Fifty-eight tions every 2 4 weeks. Minor modifications could be centres in Austria, Finland, Germany, Iceland, Norway made to these guidelines, to enable the therapy to be and Sweden participated in the study. adjusted according to local practice and to improve tolerability and efficacy. Patients who were withdrawn from the trail medica- Concomitant medication tion could be treated with other anti-rheumatic drugs, The use of non-steroidal anti-inflammatory drugs but not with cyclosporin or parenteral gold. (NSAIDs) was permitted during the study. Oral corticosteroid therapy beyond the first 2 months was Efficacy evaluation allowed only in patients who were pre-stratified into The primary efficacy parameters were derived from corticosteroid therapy. Daily concomitant cortico- X-rays of hands, wrists and feet taken from all patients steroids were limited to 10 mg/day of prednisolone (or at baseline, month 10 and month 18, regardless of equivalent) and the mean dose of corticosteroid over whether they were still receiving trial medication. the corticosteroid treatment period was limited to Radiological evaluations were performed on batches 7.5 mg/day of prednisolone (or equivalent). Intracontaining complete sets of X-rays from individual articular corticosteroid injections were allowed, but patients. The sequence of X-rays, but not the treatment were restricted in frequency to a maximum of four allocation, was known to the radiologist who perinjections per joint (except for joints of the hands, formed the evaluations. Three X-ray scores were wrists or feet, in which injections were restricted to derived: number of juxta-articular erosions; number of two per joint) and timing relative to disease activity eroded joints (= erosion score) (possible score 0 32); assessments (i.e. not within the 2 weeks before the and joint damage score (possible score 0 200), accordassessment of disease activity). Concomitant treatment ing to Larsen and Dale [16]. For the analysis of with other anti-rheumatic drugs was not permitted and cyclosporin and parenteral gold responder profiles, the use of concomitant medication was recorded at patients with progression of 3 points in the joint each visit. damage score between baseline and endpoint were classified as responders, and patients with progression Ethics and good clinical practice of 13 points in joint damage score at either 10 or 18 The study was conducted in accordance with the months were regarded as non-responders. Declaration of Helsinki and the guidelines of the The secondary efficacy parameters were assessed at European Community for Good Clinical Practice. baseline, and at months 3, 6, 12 and 18, and included The study protocol was approved by the local ethics a Health Assessment Questionnaire ( HAQ) for activcommittee and institutional review boards before ities of daily living [17], number of swollen joints

3 876 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 37 NO. 8 (maximum 22), modified Ritchie articular index ( RAI; population, which included all patients who had derived from 29 joints, maximum score 87) and received at least one dose of study medication and had patient s assessment of pain using a 100 mm visual provided at least one post-baseline safety evaluation. analogue scale, grip strength and duration of early Two-sided statistical tests were performed using a morning joint stiffness ( EMS), together with ESR and 5% significance level. The only confirmatory analysis CRP. It should be noted that for the swollen joint was planned for the change from baseline of the count and RAI, metatarsophalangeal, metacarpo- Larsen Dale joint damage score of the ITT population phalangeal and proximal interphalangeal joints were at month 18. According to power considerations before assessed as one unit each at one side (instead of five the start of the study, and based on the limited data or four assessments). At the end of treatment (after 18 available, the study was able to detect a difference of months or at the time of withdrawal ), both the patient five in the mean change from baseline with a power of and the investigator assessed the change in disease 76%. No adjustments of the significance levels were activity, relative to baseline, using a five-point verbal undertaken for further comparisons. Standard statisrating scale: 1 = much better; 2 = moderately better; tical techniques including Fisher s exact test and the 3 = no change; 4 = moderately worse; 5 = much Wilcoxon rank sum test were used to summarize the worse. Investigator assessment of disease activity was study data. The primary efficacy analysis was based based on a combination of parameters ( joint damage on the Larsen Dale joint damage score, the total score, erosion score, treatment failure, presence of number of erosions and the erosion score (number of positive rheumatoid factor and inflammmatory eroded joints) in the ITT population. The joint damage activity). score and the total number of erosions were compared at 10 and 18 months between the two treatment groups Safety evaluation by a two-way analysis of covariance (ANCOVA), with Adverse events were recorded at all visits on the the baseline value as a covariate and the change from basis of spontaneous reports by the patient, general baseline as the response variable, including country questioning, physical examination and laboratory and treatment-by-country interaction in the linear assessments. The investigators classified adverse events model. For the erosion score, a corresponding twoaccording to severity, causality and duration. Vital way analysis of variance (ANOVA) was used for the signs were recorded at all scheduled visits and physical changes from baseline 0 (i.e. for the number of examinations were performed at baseline, and at newly eroded joints). ANCOVA was also applied for months 6, 12 and 18. Overall tolerability was assessed analysis of the secondary efficacy variables (clinical by the investigator at the time of withdrawal from parameters) at the scheduled visits for these items. The study medication, or on completion of the 18-month same methods were applied for the efficacy analyses of trial period. Chest X-rays were taken at baseline and the VCC population. at month 18. Laboratory safety assessments included a complete blood count, serum potassium, magnesium, creatinine, uric acid, cholesterol, high-density lipopro- RESULTS tein ( HDL) cholesterol, serum glutamic oxaloacetic Of the 375 patients recruited, 187 were randomized transaminase, serum glutamic pyruvic transaminase, to receive cyclosporin and 188 to receive parenteral total bilirubin, alkaline phosphatase, urinary protein gold. The baseline characteristics presented in Table I and haemoglobin. demonstrate that the treatment groups were well bal- anced. There was also a relatively high proportion of Compliance patients with a positive test for rheumatoid factor in Patients were questioned about compliance with both groups. One hundred and seventy-seven patients study medication at each visit and a record was made in the cyclosporin group and 183 patients in the of used and unused medication. Blood cyclosporin parenteral gold group received at least one dose of levels were also used to assess compliance. trial medication and had at least one subsequent ( X-ray) efficacy assessment ( ITT population). Various Statistical analysis reasons were reported for those patients who were Two populations were identified for the efficacy centrally randomized but not treated, e.g. withdrawal analyses: an intention-to-treat ( ITT ) population and of informed consent, or protocol violation due to a valid-compliant-completer ( VCC) population. The newly occurring events. One hundred and four patients ITT population included all patients randomized to (56%) in the cyclosporin group and 87 patients (46%) treatment who had received at least one dose of study in the parenteral gold group completed at least 15 medication and had provided at least one post-baseline months of therapy and had joint X-rays taken at efficacy value. The VCC population included patients month 18. Kaplan Meier graphs displaying the adher- randomized to treatment who had received trial medi- ence of patients to therapy are presented in Fig. 1. cation at least up to month 15 and had joint X-rays This figure shows that a higher withdrawal rate was taken at month 18. In addition, patients were excluded found among gold-treated patients during the first 6 from the VCC population if they violated protocol months. Thereafter, the withdrawal rate was similar in requirements that were liable to influence the efficacy both treatment groups. The anti-rheumatic treatment outcome. The safety analyses were based on the safety after withdrawal from the study medication was similar

4 ZEIDLER ET AL.: CYCLOSPORIN AND GOLD COMPARED IN SEVERE RA 877 TABLE I Baseline characteristics of the intention-to-treat patient population Cyclosporin Gold Characteristic (n = 177) (n = 183) Age* 48.2 (± 11.4) 48.7 (± 10.8) Female sex (%) Years since diagnosis* 0.94 (± 0.80) 1.02 (± 0.86) Rheumatoid factor positive (%) Previous therapy with any slow-acting anti-rheumatic drug (%) Oral gold (%) 9 11 Antimalarials (%) Sulphasalazine (%) Other slow-acting anti-rheumatic drugs (%) Joint damage score* 22.9 (± 20.3) 23.1 (± 20.7) Erosion score* 3.9 (± 5.2) 3.7 (± 5.1) Number of patients with/without erosions 107/60 114/59 CRP (g/l)* 37.4 (± 39.7) 32.7 (± 35.2) ESR (mm/h)* 48.1 (± 5.5) 42.0 (± 24.1) Number of swollen joints* 8.6 (± 3.5) 8.7 (± 3.6) RAI* 18.5 (± 8.1) 18.2 (± 10.2) Disability index (HAQ)* 1.2 (± 0.6) 1.1 (± 0.6) *Mean (± S.D.). Data based on investigators assessment of X-rays available before randomization. Only patients with valid baseline X-ray evaluations are shown. FIG. 1. Probability of adherence to treatment. in both groups: the most common anti-rheumatic drug was methotrexate, followed by sulphasalazine. The mean initial cyclosporin dose was 2.97 mg/kg/ day; this increased to 3.36 mg/kg/day at month 5 and declined slightly to 3.19 mg/kg/day at month 18. The mean cumulative parenteral gold dose reached 1 g at month 6. Only four of 93 patients still receiving therapy at month 15 failed to reach the 1 g cumulative dose. 31% of parenteral gold patients had progression of <3 points (subgroup data not shown). Effect of corticosteroids Patients receiving oral corticosteroid therapy in both arms of the study had significantly less progression in all X-ray parameters than patients who did not receive corticosteroids after the first 2 months (Table III). At baseline, these groups did not differ significantly in their mean X-ray scores, but patients in the corticosteroid group had significantly higher mean HAQ scores, Ritchie indices and tender joint counts. Subgroup analysis of patients who used oral cortico- steroids did not reveal any differences between the cyclosporin and parenteral gold groups (data not shown). Actual exposure to intra-articular cortico- steroids during the study did not differ between treat- ment groups. Prognostic factors In the total patient population, significant predictors of rapid X-ray progression were rheumatoid factor Progression of joint damage positivity (P < 0.001), high baseline swollen joint count Analysis of the ITT population revealed no (P = 0.004), high ESR (P < 0.001) and high baseline statistically significant differences between the treat- joint damage score (P < 0.001). ment groups in terms of primary efficacy variables ( Table IIA), in particular not for the main con- Secondary efficacy parameters firmatory item, the Larsen Dale joint damage score All clinical secondary efficacy parameters improved (P = 0.424). In the VCC population, however, the in both treatment groups ( Table IV ). No significant progression of erosion score was statistically significantly differences were found beween the groups, except for lower in the cyclosporin group than in the ESR, which showed a greater mean reduction in the parenteral gold group (P = 0.041) ( Table IIB). parenteral gold group. The improvement in secondary Considering the progression of the joint damage efficacy parameters was maintained throughout the 18- score, in the ITT group, 30% of cyclosporin patients month treatment period in patients who adhered to and 34% of parenteral gold patients had progression the therapy. At the end of the therapy (after 18 months of <3 points in the joint damage score at month 18. or at the time of withdrawal ), 69% of patients in the In the VCC group, 39% of cyclosporin patients and cyclosporin group and 72% in the parenteral gold

5 878 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 37 NO. 8 TABLE IIA Progression of joint damage and erosion scores (ITT) Cyclosporin Gold Variable Time n Mean Median Range n Mean Median Range 95% CI P* Larsen Dale Baseline joint damage Change at month to to , score Change at month to to , Erosion score Baseline Change at month to to , Change at month to to , Number of erosions Baseline Change at month to to , Change at month to to , *Two-way ANCOVA for joint damage score and number of erosions; two-way ANOVA for erosion score. Mean at/mean change from baseline; ITT = intention to treat. 95% CI: 95% confidence interval for the difference in adjusted means of cyclosporin minus gold. TABLE IIB Progression of joint damage and erosion scores ( VCC) Cyclosporin Gold Variable Time n Mean Median Range n Mean Median Range 95% CI P* Larsen Dale Baseline joint damage Change at month to to , score Change at month to to , Erosion score Baseline Change at month to to , Change at month to , Number of erosions Baseline Change at month to , Change at month to , *Two-way ANCOVA for joint damage score and number of erosions; two-way ANOVA for erosion score. Mean at/mean change from baseline; VCC = valid compliant completer. 95% CI: 95% confidence interval for the difference in adjusted means of cyclosporin minus gold.

6 ZEIDLER ET AL.: CYCLOSPORIN AND GOLD COMPARED IN SEVERE RA 879 TABLE III month 18, respectively. The corresponding changes in Effect of per-oral corticosteroid therapy* on the progression of joint diastolic blood pressure were 5.3 and 0.1 mmhg at damage month 6, and 4.9 and 2.0 mmhg at month 18, respectively. With Without Twenty-nine per cent of patients in the cyclo- corticosteroids corticosteroids sporin group and 9% of patients in the parenteral gold Parameter (n = 132) (n = 192) P group started anti-hypertensive medication. In the gold Joint damage score group, the most common reasons for withdrawal were Baseline 25.2 (24.9) 22.2 (17.1) skin reactions (40 patients), which were rare in the Change from baseline cyclosporin group (three patients). at month (12.1) 12.3 (12.2) Twenty patients were withdrawn from the cyclo- Erosion score sporin group because of renal disorders (mainly Baseline 4.3 (5.9) 3.9 (4.7) Change from baseline increases in serum creatinine), whereas nine patients at month (3.7) 3.5 (3.7) were withdrawn from the gold group (mainly because Number of erosions of proteinuria and/or albuminuria). From baseline to Baseline 9.8 (17.3) 7.7 (10.6) month 18, the mean serum creatinine levels increased Change from baseline at month (10.2) 8.8 (10.7) by 24% in the cyclosporin group and by 10% in the parenteral gold group. Three patients in each group *Only patients who had X-ray evaluations at baseline and month had an increase in serum creatinine of 100% during 18, and who adhered to the pre-stratification, are included in the study. Changes in serum cholesterol and HDL this analysis. cholesterol were similar in the treatment groups. At the final visit or at the time of premature withdrawal group had improved from baseline, according to the from therapy, the investigator rated tolerability to be investigator s overall assessment. The corresponding good or very good in 68% of cyclosporin patients and figures for patient s overall assessment were 64 and in 64% of gold patients, although significantly more 73%, respectively. patients withdrew from parenteral gold treatment than from cyclosporin treatment overall (54% vs 42%; Adverse events, vital signs and laboratory P = 0.021). abnormalities The numbers of serious adverse events, including DISCUSSION malignant tumours and infections, were similar in the This study has demonstrated that the overall efficacy cyclosporin (n = 26) and parenteral gold (n = 24) and tolerability of cyclosporin in the treatment of early groups. One patient in the cyclosporin group developed active severe RA are comparable to those of parenteral non-hodgkin s lymphoma; this patient had previously gold. The study was planned to detect clinically signi- received methotrexate therapy. Sixty-five patients in ficant differences in efficacy between the two treatment the parenteral gold group were withdrawn because of arms and its duration was sufficient to enable changes an adverse event, compared with 45 patients in the to be detected in joint X-rays [6, 18 20]. The cyclosporin group ( Table V ). Most adverse eventrelated main outcome measure, radiological progression, was withdrawals in both groups took place during assessed in a blind fashion and X-rays were taken at the first 6 months, although a tendency for earlier the same time points irrespective of the treatment. withdrawals was found in the parenteral gold group. The increase in erosion score, i.e. the number of The most frequently occurring adverse events in the eroded joints in the hands, wrists and feet, was used cyclosporin group were elevation of serum creatinine as a semi-quantitative measure of joint damage. This and hypertension. The mean changes in systolic blood endpoint is logical because juxta-articular erosion is pressure in the cyclosporin and gold groups were 9.4 the hallmark of the joint destruction in RA, and joint and 0 mmhg at month 6, and 6.9 and 5.1 mmhg at damage in the hands and wrists also reflects damage TABLE IV Effect of therapy on secondary efficacy parameters: endpoint analysis Baseline/change from baseline Treatment difference at endpoint Parameter Cyclosporin Parenteral gold (P) Disability index (HAQ) 1.1/ / RAI 18.1/ / Number of swollen joints 8.6/ / Pain (visual analogue scale) 53.6/ / EMS (min) 119.0/ / Grip strength (mmhg) Left hand 234.3/ / Right hand 239.8/ / ESR (mm/h) 48.1/ / 16.1 <0.001 CRP (g/l ) 37.6/ /

7 880 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 37 NO. 8 TABLE V Serious adverse events and withdrawals due to adverse events* Withdrawals from study due to adverse events Serious adverse events Cyclosporin Gold Cyclosporin Gold Number of patients Number of events Number of events by type Renal Neoplasms Infections Gastrointestinal disorders Skin disorders Hypertension Red and white cell disorders Thrombocytopenia Central and peripheral nervous system Liver and biliary system Other *Note that some patients had more than one serious adverse event or reason for withdrawal. in other joints [21]. The number of eroded joints damage by corticosteroids [ 23]. Concomitant medication reflects the spreading of the disease into new joints, with low-dose corticosteroids was permitted but not the quantity of joint damage in individual during this study, but the intended use of corticosteroids joints. Joint damage was quantified using the was a pre-stratification parameter and the Larsen Dale joint damage score [16], which has been groups became well balanced. Evaluation of the combined used extensively in clinical trials [9, 19] and is one of treatment groups revealed slower radiological the best documented methods for scoring joint progression in corticosteroid-treated patients, despite X-rays [6 ]. a more active disease at baseline. These findings suggest Two analyses were performed: the first was based that corticosteroids may also retard radiological progression on all patients who received at least one dose of study in severe early RA when used with background medication ( ITT). This approach is open to bias second-line drugs. because of withdrawals and rescue therapy, but Approximately half of the patients were withdrawn reflects the randomized population and the possible from both treatments, mainly because of adverse delayed effects of study medication. The second events. This is not surprising and is in line with the analysis was based on a VCC population and hence therapeutic survival study published previously [24]. was free from the interference of other therapies. A typical profile of adverse events was observed for Nevertheless, it can be argued that patients remaining cyclosporin; similarly, the adverse-event profile for on therapy no longer represent the randomized population. parenteral gold was as expected. The most common Together, however, these complementary analyses reason for withdrawal of patients from cyclosporin constitute a rational approach to the study of the treatment was an increase in serum creatinine. This progression of joint damage in RA. was a requirement of the study protocol and was based Joint damage progressed at similar rates in both on the recognition of renal dysfunction as a risk factor treatment arms. In addition, in the ITT population of cyclosporin nephropathy [25]. It has been established there was no significant progression of joint destruction that the risk of cyclosporin nephropathy is small in a comparable proportion of patients in each treat- when the serum creatinine level is monitored [26] and ment arm (cyclosporin 30%; parenteral gold 34%). A the cyclosporin dose adjusted accordingly. The study recent study of similar size compared cyclosporin with has been extended to 3 yr, in order to observe renal a variety of conventional second-line anti-rheumatic function in the long term. The frequency of serious drugs, including parenteral antimalarials and gold, in adverse events, including infections and neoplasms, early active RA [22]. The results demonstrated a was similar between treatment groups, but more paren- statistically significant difference in favour of cyclo- teral gold patients than cyclosporin patients were withdrawn sporin in terms of control of radiological progression. from study medication because of adverse The difference between the arms was not observed in events. Most withdrawals because of adverse events the current study, possibly because patients had a more took place during the first 6 months of therapy in both severe disease and showed poorer adherence to cyclo- treatment groups, although early withdrawals were sporin therapy. However, the Italian study [22] was more frequent in the gold group. not stratified for corticosteroid use. One patient in the cyclosporin group developed The issue of whether corticosteroids can influence a non-hodgkin s lymphoma. The contribution of the radiological progression of RA is controversial. cyclosporin is difficult to estimate because of the rarity However, recent evidence indicates retardation of joint of the event, the possible role of preceding events and

8 ZEIDLER ET AL.: CYCLOSPORIN AND GOLD COMPARED IN SEVERE RA 881 the increased incidence of lymphomas in RA in general followup of a prospective double blind placebo controlled [27 30]. However, the development of non-hodgkin s study. J Rheumatol 1995;22: lymphoma in immunosuppressed patients must be 5. Weinblatt ME. Rheumatoid arthritis: treat now, not borne in mind when patients are treated with cyclo- later! Ann Intern Med 1996;124: Scott DL, Adebajo AO, Badaway SE, Kirwan J, van de sporin for RA. Putte LBA, van Riel PLCM. DC-ART: preventing or In conclusion, this study, albeit with a relatively low significantly decreasing the rate of progression of power, has shown that cyclosporin was comparable to structural joint damage. J Rheumatol 1994;21 (suppl. the established treatment, parenteral gold, retarding 41): progression of joint damage in early active severe RA. 7. Iannuzzi L, Dawson N, Zein N, Kushner L. Does drug Although overall tolerability was similar between the therapy slow radiographic deterioration in rheumatoid treatment groups, more patients in the cyclosporin arthritis? N Engl J Med 1983;309: group adhered to therapy. 8. Rau R, Herborn G, Karger T, Menninger H, Elhardt D, Schmitt J. A double blind randomized parallel trial of ACKNOWLEDGEMENTS intramuscular methotrextate and gold sodium thiomalate in early erosive rheumatoid arthritis. J Rheumatol This study was supported by a grant from Novartis 1991;18: Pharma AG. The following investigators participated 9. Paulus HE, Bulpitt KJ. DC-ART classification: review in the study by treating patients and collecting the of relevant clinical studies. J Rheumatol 1994;21 (suppl. 41):8 20. clinical data: R. Alten, Germany; E. Apostoloff, 10. Dijkmans BA, van Rijthoven AW, Goei Thé HS, Germany; T. D. Astor, Norway; D. Becker-Capeller, Boers M, Cats A. Cyclosporine in rheumatoid arthritis. Germany; A. Bjelle, Sweden; O. 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