Prescribing Methotrexate with Anti-TNFs May Only Benefit Some RA Patients

Prescribing methotrexate with anti-TNFs may only benefit some rheumatoid arthritis patients

Combining methotrexate with TNF inhibitors may only be worthwhile for rheumatoid arthritis patients who are seropositive, the results of a small study suggest.

The results of the study published as a letter in the Annals of Rheumatic Diseases found that seropositive patients had a significantly lower rate of anti-TNF withdrawal for ineffectiveness if on methotrexate, while withdrawal rates were unexpectedly higher in seronegative patients on methotrexate. Conversely in patients not on methotrexate, anti-TNF discontinuation rates due to ineffectiveness were far greater in seropositive patients than in seronegative.

Combining methotrexate with a tumor necrosis factor inhibitor is common practice, with the American College of Rheumatology 2015 guidelines on rheumatoid arthritis recommending that biologic therapy is combined with methotrexate because the combination has superior efficacy to monotherapy.

However, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) status have not always been taken into account in studies looking at the benefits of the combination, and there is increasing doubt about the value of combining methotrexate with anti-TNF therapy in psoriatic arthritis.[i],[ii]A group of UK researchers therefore decided to look more closely at use of the combination in patients with rheumatoid arthritis by analysing withdrawal rates in patients taking etanercept or adalimumab combined with methotrexate.

“When it was proposed that methotrexate should be given with anti-TNF, the initial justification was that it would reduce the antibody response to the anti-TNF monoclonal,” explained Professor Michael Ehrenstein of the Center for Rheumatology, UCL, London, UK.

The production of anti-drug antibodies in response to monoclonal antibodies such as adalimumab is believed to be an important mechanism underlying therapeutic failure and loss of response over time in rheumatoid arthritis However, etanercept is thought to be less immunogenic because a similar effect correlating drug response and anti-drug antibody formation has not been observed.[iii]

“There is also the idea that methotrexate improves the outcome with anti-TNF because it is also effective for RA by itself,” Ehrenstein added.

However, the results did not show any difference between these two types of anti-TNF with respect to methotrexate influencing.

Treatment durations for adalimumab or etanercept were analysed for 301 patients with rheumatoid arthritis treated at a single centre. All had started adalimumab or etanercept as a first-line biologic from 2003 onwards.

After five years 52 patients had withdrawn from therapy due to adverse events and ten for other reasons. One hundred and six patients were still on anti-TNFs after five years, and 60 remained on anti-TNF but had not completed five years of therapy.

Kaplan-Meier plots revealed seropositive patients had a significantly lower rate of withdrawal for ineffectiveness if on methotrexate at anti-TNF initiation while rates were unexpectedly significantly higher in seronegative patients on methotrexate. The researchers conceded that the number of patients in the study was small, but the pattern was replicated in a separate group of 534 patients at two other hospitals. However, in patients not on methotrexate, discontinuation of anti-TNF due to ineffectiveness was far greater in seropositive patients than in seronegative patients (p=0.002, and p=0.001 in the validation cohort).

Cox regression highlighted seropositive status and methotrexate as significant factors in discontinuation, but not anti-TNF type. When the impact of anti-CCP and RF were considered separately, both were found to have a significant individual impact.

The researchers concluded that their findings support the coprescription of methotrexate for patients with rheumatoid arthritis with both adalimumab and etanercept but for only for seropositive patients.

Ehrenstein said that the findings were surprising, “particularly the fact that methotrexate appeared to increase the chance of stopping anti-TNF for ineffectiveness in seronegative rheumatoid arthritis, i.e. the opposite result compared to seropositive rheumatoid arthritis.”

The researchers said that the reasons for this were unclear but speculated that it might be due to specific mechanisms of disease response to the combination methotrexate and TNF inhibitors dependent on RF or CCP status.

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REFERENCE

Greenwood M, Shipa M, Yeoh S, et alMethotrexate reduces withdrawal rates of TNF inhibitors due to ineffectiveness in rheumatoid arthritis but only in patients who are seropositive. Annals of the Rheumatic Diseases Published Online First: 28 May 2020. doi: 10.1136/annrheumdis-2020-217725

[i] Behrens F, Koehm M, Arndt U, et al. Does concomitant methotrexate with adalimumab influence treatment outcomes in patients with psoriatic arthritis? data from a large observational study. J Rheumatol 2016;43:632–9.

[ii] Mease PJ, Gladman DD, Collier DH, et al. Etanercept and methotrexate as monotherapy or in combination for psoriatic arthritis: primary results from a randomized, controlled phase III trial. Arthritis Rheumatol 2019;71:1112–24.

[iii] Jani M, Barton A, Warren RB, et al. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology 2014;53:213–22.