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Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension

T K Kvien¹, H K Zeidler², P Hannonen³, F A Wollheim⁴, Ø Førre⁵, I Hafström⁶, J P Kaltwasser⁷, M Leirisalo-Repo⁸, B Manger⁹, L Laasonen¹⁰, H Prestele¹¹, P Kurki¹²

¹ Oslo City Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
² Department of Internal Medicine and Dermatology, Medizinische Hochschule, Hannover, Germany
³ Department of Medicine, Central Hospital of Middle Finland, Jyväskylä, Finland
⁴ Department of Rheumatology, Lund University Hospital, Lund, Sweden
⁵ Centre of Rheumatic Diseases, The National Hospital, University of Oslo, Oslo, Norway
⁶ Department of Rheumatology, Huddinge University Hospital, Huddinge, Sweden
⁷ Department of Medicine III, Johann Wolfgang Goethe University, Frankfurt, Germany
⁸ Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland
⁹ Department of Medicine III and Institute of Clinical Immunology, University of Erlangen, Erlangen, Germany
¹⁰ Department of Radiology, Surgical Hospital, Helsinki University Central Hospital, Helsinki, Finland
¹¹ Department of Clinical Research and Development, Novartis Pharma, Basel, Switzerland
¹² National Agency for Medicines, Helsinki, Finland

Correspondence to:
Correspondence to:
Professor T K Kvien, Oslo City Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vinderen, N-0319 Oslo, Norway;
t.k.kvien{at}ioks.uio.no

Objective: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment.

Methods: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure.

Results: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%.

Conclusion: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

Keywords: rheumatoid arthritis; cyclosporin; gold; clinical trial

Abbreviations: DMARDs, disease modifying antirheumatic drugs; HAQ, Health Assessment Questionnaire; ITT, intention to treat; NSAIDs, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis

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