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New Use for Methotrexate in Spondyloarthritis?

— In combination with adalimumab, immunogenicity lowered by half in patients with axial SpA

MedpageToday

Adding methotrexate to adalimumab (Humira) in axial spondyloarthritis was associated with reduced immunogenicity, as shown by a lower rate of developing antidrug antibodies, French researchers reported.

In a group of 107 patients with spondyloarthritis, 25% of those given methotrexate along with adalimumab developed antidrug antibodies by week 26 compared with 47.3% of those who received adalimumab as monotherapy, for a relative risk of 0.53 (95% CI 0.31-0.91), reported Denis Mulleman, MD, PhD, of the University of Tours, and colleagues.

And in a follow-up extension study, treatment duration with adalimumab was 98.6 weeks in patients without antidrug antibodies compared with 56.9 weeks in those who developed the antibodies (P=0.015), the researchers reported online in .

Tumor necrosis factor (TNF) inhibitors such as adalimumab and infliximab (Remicade) can be effective for spondyloarthritis, but up to one-quarter of patients stop the therapy within a year because of primary or secondary loss of efficacy. In some cases it is due to the development of antidrug antibodies, which can have a negative influence on pharmacokinetics.

Methotrexate is not approved for use in axial spondyloarthritis because it has not demonstrated symptomatic benefits. However, in rheumatoid arthritis, using methotrexate in combination with a TNF inhibitor has been shown to lessen the immunogenicity that can develop with the use of biologics.

Despite the lack of regulatory approval for methotrexate in spondyloarthritis, the drug is often used among patients who have peripheral disease manifestations. Mulleman's group noted that in retrospective studies, were seen among patients with spondyloarthritis receiving infliximab in combination with methotrexate.

To explore the possibility that co-administration of methotrexate with a TNF inhibitor could lessen the likelihood of development of antidrug antibodies and loss of treatment efficacy, the researchers recruited adult patients with spondyloarthritis in 2013 and 2014 from the network of Western France University Hospitals.

This randomized, open-label study had patients receiving 40 mg subcutaneous injections of adalimumab every other week with or without subcutaneous weekly 10 mg injections of methotrexate.

Along with antidrug antibody detection, patients were assessed for clinical response according to the (ASDAS) at weeks 4, 8, 12, and 26.

Patients' mean age was 42, the sexes were equally represented, and disease duration was 2.5 years. Mean ASDAS at baseline was 3.1.

Adalimumab concentrations were higher among patients also given methotrexate, and adalimumab concentrations were lower for those who developed antidrug antibodies by week 26 (1.43 µg/mL vs 8.66 µg/mL, P<0.05).

Clinical responses were similar in the two groups, with median ASDAS being 1.6 at week 26. The percentages having inactive disease at that time point were 37% in the methotrexate group and 40% in the adalimumab monotherapy group (P=0.9).

Safety also was similar in the two groups, with two serious adverse events occurring in each group. In the adalimumab monotherapy group, one patient developed psoriasis pustulosa and another had drug-induced liver toxicity associated with prophylaxis for tuberculosis, while in the combination therapy group, one patient developed pneumonia and lower limb ischemia, and another developed nausea, diarrhea, and liver enzyme abnormalities associated with methotrexate and tuberculosis prophylaxis.

In the extension study, median follow-up was 210 weeks, and median duration of adalimumab use was 88 weeks. Univariate analysis of the extension study found that having antidrug antibodies at 6 months was associated with lower adalimumab survival, and in a multivariate analysis, being treated with methotrexate beyond week 26 was associated with half the risk of discontinuing adalimumab (HR 0.46, 95% CI 0.22-0.95). Being male also lowered the risk (HR 0.51, 95% CI 0.31-0.85).

"In this prospective randomized trial, we demonstrate that methotrexate significantly reduced the immunogenicity and ameliorated adalimumab concentration, as a surrogate of drug exposure, in axial spondyloarthritis patients," the investigators wrote. "This result is of importance because immunogenicity to monoclonal antibodies is an unwanted outcome responsible for loss of response and treatment discontinuation in chronic inflammatory diseases."

They noted that the relatively low 10 mg/week dosage of methotrexate may have contributed to the finding that 25% of the combination therapy group did develop immunogenicity, and that higher or weight-based dosing could have minimized this.

Further studies will be needed to identify potential mechanisms by which methotrexate influences the development of antidrug antibodies.

A limitation of the study was the small number of patients included.

Disclosures

The authors reported financial relationships with multiple companies, including Roche, UCB, Bristol-Myers Squibb, AbbVie, Novartis, Pfizer, Sanofi, Janssen, Merck Sharp & Dohme, Amgen, Expanscience, Eli Lilly, Chugai, Shire, Boehringer Ingelheim, Biogaran, and Hospira.

Primary Source

RMD Open: Rheumatic & Musculoskeletal Diseases

Ducourau E, et al "Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: A multicentric randomized trial" RMD Open 2020; DOI: 10.1136/rmdopen-2019-001047.