Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis

doi:10.1016/S0140-6736(96)90535-8

The Lancet

Volume 347, Issue 8998, 10 February 1996, Pages 347-352

https://doi.org/10.1016/S0140-6736(96)90535-8 Get rights and content

Abstract

Summary

Background A favourable benefit/risk ratio for treatment of rheumatoid arthritis (RA) with second-line drugs has been established only in short-term studies. The present investigation addresses the question of whether RA patients with a good response to long-term treatment with second-line drugs benefit from continuation of such treatment.

Methods A 52-week randomised double-blind placebo-controlled multicentre study was conducted to assess the effect of stopping second-line therapy in 285 RA patients with a good long-term therapeutic response. The patients either continued the second-line drug (n=142) or received a placebo (n=143). The endpoint was a flare, defined as recurrence of synovitis.

Findings At entry into the study median duration of second-line drug therapy was 5 years (range 2-33). At 52 weeks the cumulative incidence of a flare was 38% for the placebo group and 22% for the continued therapy group (p=0·002). The risk of a flare was 2·0 times higher for patients receiving placebo than for those continuing the second-line drug (95% Cl 1·27 to 3·17). The same trend was found for each second-line drug separately, with the exception of d-penicillamine. Side-effects that necessitated dose reduction or discontinuation occurred in 2 patients in each group.

Interpretation Second-line drugs continue to be effective in RA patients who have responded well to initial treatment.

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Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission.
In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18–80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed.
Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69–88%) were flare-free in the stable-dose group, compared with 57% (41–71%) in the half-dose group and 38% (22–53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6–41%, p=0·010) in the half-dose group and 40% (22–58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication).
Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making.
Research Council of Norway and South-Eastern Norway Regional Health Authority.
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Citation Excerpt :
However, most of these RCTs compared either different biological DMARD tapering or stopping strategies, or different strategies of remission maintenance after stopping biological DMARDs.6,24–29 One trial evaluated tapering or stopping treatment in patients receiving conventional synthetic DMARDs only.30 Only two trials included an intervention arm aiming at DMARD-free remission.6,29
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Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3–90·0) in the continue group, 58·6% (49·2–70·0) in the taper group, and 43·3% (34·6–55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69–5·40; p=0.0003) for the taper group and 4·34 (2·48–7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9).
Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis.
None.
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Citation Excerpt :
The 2019 updated EULAR recommendations state that conventional synthetic DMARDs in monotherapy, if they are tolerated, should not be discontinued but that dose reduction can be considered.2 This recommendation is based on a double-blinded, placebo-controlled study from 1996,44,45 in which patients with longstanding, mostly erosive rheumatoid arthritis and stable low disease activity were randomly assigned to continuation or discontinuation of the conventional synthetic DMARDs of the time. The cumulative incidence of flares was higher in the discontinuation group (53 [37%] of 143) compared with the continuation group (30 [21%] of 142).44
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Citation Excerpt :
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ArticlesRandomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis

Abstract

Mayo Clin Proc

J Clin Epidemiol

Am J Med

Chloroquine and hydroxychloroquine therapy in rheumatoid arthritis

Arthritis Rheum

A controlled trial of gold salt therapy in rheumatoid arthritis

Arthritis Rheum

Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial

Ann Intern Med

Sulfasalazine in early rheumatoid arthritis. A 48-week double-blind, prospective, placebo-controlled study

Arthritis Rheum

Efficacy of low-dose methotrexate in rheumatoid arthritis

N Engl J Med

Azathioprine in rheumatoid arthritis: a double-blind, cross over study

Arthritis Rheum

Clinical trial of penicillamine in rheumatoid arthritis

Arthritis Rheum

Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone

J Rheumatol

Are the results of controlled clinical trials and observational studies of second line therapy in rheumatoid arthritis valid and generalizable as measures of rheumatoid arthritis outcome: analysis of 122 studies

J Rheumatol

Long-term second-line treatment: a prospective drug survival study

Br J Rheumatol

Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis

J Rheumatol

Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1917 consecutive starts

J Rheumatol

Outcome of second line therapy in rheumatoid arthritis

Ann Rheum Dis

Long-term azathioprine in rheumatoid arthritis: a double-blind study

Ann Rheum Dis

Low dose, long-term treatment of rheumatoid arthritis with azathioprine

South Med J

Articles
Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis