NIHR Signal Stopping biological drugs for rheumatoid arthritis can lead to twice the relapse rate

Published on 24 January 2018

It seems safer to reduce the dose of biological drugs, rather than to stop them if people with rheumatoid arthritis and their doctors want to avoid relapse. Stopping these powerful drugs caused the disease to recur in 58% of people compared with 29% who continued them. Reducing the dose also led to more relapses for people in remission, but did not cause those with low-grade disease activity to worsen.

Rheumatoid arthritis is a chronic disease which causes pain, swelling and stiffness in the small joints of the hands and feet. It can cause more widespread inflammation. The disease has episodes of improvement and deterioration so judging the effects of treatment can be difficult. Drug treatments suppress the immune system, putting people at higher risk of infection.

This review should help inform shared decisions on optimal drug doses to balance the risk of side effects with the risk of relapse for those wishing to reduce their dose.

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Why was this study needed?

Rheumatoid arthritis affects an estimated 400,000 people in the UK. It affects young adults and about one-third of people stop work because of the disease within two years of onset. The total cost of the disease in the UK, including indirect costs and work-related disability, has been estimated at between £3.8 and £4.75 billion per year. About 10 to 25% of this cost is for the medication.

Early treatment with disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is recommended to prevent and limit joint damage. Newer biological drugs (bDMARDs) are more targeted against the immune system. They are very effective at reducing disease activity and often lead to remission. However, it is important not to remain on them at high doses due to infection risk and side effects.

This review aimed to address the actual risk of relapse if stopping or reducing the dose of biological drugs.

What did this study do?

This systematic review and meta-analysis pooled the results of 15 randomised controlled trials and two non-randomised trials. It included 2,855 adults who had rheumatoid arthritis for less than a year to 13.6 years. Four trials were multinational and nine European including one from the UK.

The trials compared either stopping or lowering the dose of bDMARD with continuing on the same dose that achieved either remission or low disease activity. The bDMARDs included abatacept, adalimumab, etanercept and tocilizumab. Most people were also taking methotrexate.

The non-randomised trials had a high risk of bias, and there was wide clinical variation between them including type, dose and length of treatment with a bDMARD. This reduces our confidence in the pooled results.

What did it find?

For people who were in remission:

  • Relapse occurred in 57.2% of those who stopped taking bDMARDs during a year of follow up compared to 28.8% of those who continued taking them (relative risk [RR] 1.97; 95% confidence interval [CI] 1.43 to 2.73; 926 participants, seven trials).
  • Continuing bDMARDs on a tapered lower dose led to a in 33.1% of people compared to 25.7% who continued treatment (RR 1.23, 95% CI 1.06 to 1.42; 1,512 participants, nine trials).

For people with low disease activity:

  • Stopping bDMARDs led to an increase in disease activity in 49.9% of people compared to 21.1% of those who continued (RR 2.24, 95% CI 1.52 to 3.30; 1,760 participants, seven trials).
  • Tapering to a lower dose led to a similar proportion of people developing higher disease activity, 26.6% versus 25.1% who continued on the usual dose (RR 1.02, 95% CI 0.85 to 1.23; 1,107 participants, seven trials).

Recurrence of active rheumatoid arthritis for people in remission

What does current guidance say on this issue?

NICE 2015 guidelines on rheumatoid arthritis recommend starting two disease-modifying drugs such as methotrexate or sulfasalazine plus short-term steroids. If this regime is not effective, they recommend adding a bDMARD. Alternatively, a bDMARD can be started on its own if the other drugs are not tolerated.

According to the NICE 2016 technology appraisal, the bDMARD should only be continued beyond six months if there is at least a moderate response. When there is good control of the disease, the drug doses can be cautiously reduced. If there are any signs of a flare-up, the drug doses should be rapidly increased back to the disease-controlling level.

What are the implications?

This review backs the guidance to only consider reducing the dose of bDMARDs rather than stopping in people who are in remission or have low disease activity.

For patients willing to try this approach, these results should help shared-decision making when weighing up the pros and cons of the different strategies.

The review does not cover other important aspects of management, for example, whether the original non-biological disease-modifying drugs should be reduced first or instead. This is likely to depend on individual circumstances and tolerability of the particular DMARDs.

Citation and Funding

Henaux S, Ruyssen-Witrand A, Cantagrel A, et al. Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis. Ann Rheum Dis. 2017. [Epub ahead of print].

No funding information was provided for this study.

Bibliography

NICE. Rheumatoid arthritis in adults: management. CG79. London: National Institute for Health and Care Excellence; 2009 (updated 2015).

NICE. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. TA375. London: National Institute for Health and Care Excellence; 2016.

Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960-77.

Why was this study needed?

Rheumatoid arthritis affects an estimated 400,000 people in the UK. It affects young adults and about one-third of people stop work because of the disease within two years of onset. The total cost of the disease in the UK, including indirect costs and work-related disability, has been estimated at between £3.8 and £4.75 billion per year. About 10 to 25% of this cost is for the medication.

Early treatment with disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is recommended to prevent and limit joint damage. Newer biological drugs (bDMARDs) are more targeted against the immune system. They are very effective at reducing disease activity and often lead to remission. However, it is important not to remain on them at high doses due to infection risk and side effects.

This review aimed to address the actual risk of relapse if stopping or reducing the dose of biological drugs.

What did this study do?

This systematic review and meta-analysis pooled the results of 15 randomised controlled trials and two non-randomised trials. It included 2,855 adults who had rheumatoid arthritis for less than a year to 13.6 years. Four trials were multinational and nine European including one from the UK.

The trials compared either stopping or lowering the dose of bDMARD with continuing on the same dose that achieved either remission or low disease activity. The bDMARDs included abatacept, adalimumab, etanercept and tocilizumab. Most people were also taking methotrexate.

The non-randomised trials had a high risk of bias, and there was wide clinical variation between them including type, dose and length of treatment with a bDMARD. This reduces our confidence in the pooled results.

What did it find?

For people who were in remission:

  • Relapse occurred in 57.2% of those who stopped taking bDMARDs during a year of follow up compared to 28.8% of those who continued taking them (relative risk [RR] 1.97; 95% confidence interval [CI] 1.43 to 2.73; 926 participants, seven trials).
  • Continuing bDMARDs on a tapered lower dose led to a in 33.1% of people compared to 25.7% who continued treatment (RR 1.23, 95% CI 1.06 to 1.42; 1,512 participants, nine trials).

For people with low disease activity:

  • Stopping bDMARDs led to an increase in disease activity in 49.9% of people compared to 21.1% of those who continued (RR 2.24, 95% CI 1.52 to 3.30; 1,760 participants, seven trials).
  • Tapering to a lower dose led to a similar proportion of people developing higher disease activity, 26.6% versus 25.1% who continued on the usual dose (RR 1.02, 95% CI 0.85 to 1.23; 1,107 participants, seven trials).

Recurrence of active rheumatoid arthritis for people in remission

What does current guidance say on this issue?

NICE 2015 guidelines on rheumatoid arthritis recommend starting two disease-modifying drugs such as methotrexate or sulfasalazine plus short-term steroids. If this regime is not effective, they recommend adding a bDMARD. Alternatively, a bDMARD can be started on its own if the other drugs are not tolerated.

According to the NICE 2016 technology appraisal, the bDMARD should only be continued beyond six months if there is at least a moderate response. When there is good control of the disease, the drug doses can be cautiously reduced. If there are any signs of a flare-up, the drug doses should be rapidly increased back to the disease-controlling level.

What are the implications?

This review backs the guidance to only consider reducing the dose of bDMARDs rather than stopping in people who are in remission or have low disease activity.

For patients willing to try this approach, these results should help shared-decision making when weighing up the pros and cons of the different strategies.

The review does not cover other important aspects of management, for example, whether the original non-biological disease-modifying drugs should be reduced first or instead. This is likely to depend on individual circumstances and tolerability of the particular DMARDs.

Citation and Funding

Henaux S, Ruyssen-Witrand A, Cantagrel A, et al. Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis. Ann Rheum Dis. 2017. [Epub ahead of print].

No funding information was provided for this study.

Bibliography

NICE. Rheumatoid arthritis in adults: management. CG79. London: National Institute for Health and Care Excellence; 2009 (updated 2015).

NICE. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. TA375. London: National Institute for Health and Care Excellence; 2016.

Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960-77.

Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis

Published on 1 December 2017

Henaux, S.,Ruyssen-Witrand, A.,Cantagrel, A.,Barnetche, T.,Fautrel, B.,Filippi, N.,Lukas, C.,Raffeiner, B.,Rossini, M.,Degboe, Y.,Constantin, A.

Ann Rheum Dis , 2017

OBJECTIVES: To assess the risk of losing remission, low disease activity (LDA) or radiographic progression in the case of (1) discontinuing or (2) tapering doses of biological disease-modifying antirheumatic drugs (bDMARDs) compared with continuation of the initial treatment regimen in rheumatoid arthritis (RA) patients with remission or LDA. MATERIALS AND METHODS: A systematic literature analysis was carried out through May 2017 on the PubMed, Embase, Cochrane and international congress databases, selecting controlled trials comparing bDMARDs discontinuation/tapering versus continuation in RA patients with remission or LDA. The meta-analysis assessed the risk ratio (RR) and 95% CI of losing remission or LDA and the risk of radiographic progression after (1) discontinuing and (2) tapering doses of bDMARDs versus continuing the initial treatment. RESULTS: The meta-analysis comparing bDMARDs discontinuation versus continuation performed on nine trials showed an increased risk of losing remission (RR (95% CI)=1.97(1.43 to 2.73), P<0.0001) or LDA (RR (95% CI)=2.24(1.52 to 3.30), P<0.0001) and an increased risk of radiographic progression (RR (95% CI)=1.09(1.02 to 1.17), P=0.01) in case of bDMARD discontinuation. The meta-analysis comparing bDMARDs tapering versus continuation performed on 11 trials showed an increased risk of losing remission (RR (95% CI)=1.23(1.06 to 1.42), P=0.006) but no increased risk of losing LDA (RR (95% CI)=1.02 (0.85 to 1.23), P=0.81) nor any increased risk of radiographic progression (RR (95% CI)=1.09(0.94 to 1.26), P=0.26) in case of bDMARD tapering. CONCLUSION: Discontinuation of bDMARDs leads to an increased risk of losing remission or LDA and radiographic progression, while tapering doses of bDMARDs does not increase the risk of relapse (LDA) or radiographic progression, even though there is an increased risk of losing remission.

Expert commentary

Can we save money, and improve safety, through smarter use of biologic therapies?

By suppressing the immune system, these treatments can transform the quality of life for people with painful, disabling rheumatoid arthritis. Spend on biologic therapies is high and rising, heading towards £1 billion annually by the NHS in England. Reducing the dose would not only save cash but reduce the risk of infections due to immunosuppression.

Stopping these treatments risks disease flares with irreversible damage to joints, but lowering the dose appears relatively safe. If lower doses are cheaper and safe, can we afford to ignore this?

Dr Benjamin Ellis, Senior Clinical Policy Adviser, Arthritis Research UK