Methotrexate Lowers Immunogenicity to Adalimumab in Axial Spondyloarthritis

Adding methotrexate to adalimumab (Humira, AbbVie) in axial spondyloarthritis was associated with reduced immunogenicity, and prolonged co-medication was associated with long-term maintenance of adalimumab, say researchers recently writing in RMD Open: Rheumatic & Musculoskeletal Diseases.

Around 25 percent of patients with spondyloarthritis discontinue the use of tumor necrosis factor inhibitors (TNFi) beyond the first year, mostly because of primary failure or secondary loss of efficacy. Anti-drug antibodies can develop in some cases, resulting in drug withdrawal due to loss of efficacy, and reducing immunogenicity to TNFi would improve drug concentration, clinical outcomes and long-term maintenance.

Adalimumab is a monoclonal antibody to TNF approved in spondyloarthritis, but about 30 percent of patients may be positive for anti-drug antibodies after 24 weeks of treatment, leading to low or undetectable adalimumab concentrations and poor clinical response. Methotrexate is a disease-modifying drug largely used in rheumatoid arthritis, peripheral forms of spondyloarthritis and psoriatic arthritis. In axial spondyloarthritis, methotrexate does not improve symptoms and is therefore not recommended. However, methotrexate has been shown to be associated with a reduced proportion of patients with detectable anti-drug antibodies in rheumatoid arthritis, and reduced anti-drug antibodies to infliximab, another monoclonal antibody to TNF. No randomized study has investigated the potential benefit of methotrexate added to adalimumab in preventing immunogenicity in axial spondyloarthritis.

“We randomized axial spondyloarthritis patients to receive adalimumab alone or with methotrexate and examined the rate of anti-drug antibodies detection during a 26-week period,” wrote the authors, led by Denis Mulleman, M.D., Ph.D., of the University of Tours in France. “In a follow-up study, we sought to identify the factors associated with adalimumab maintenance in the long term.”

This randomized, open-label study included 107 patients with axial spondyloarthritis who received 40 mg subcutaneous injections of adalimumab every other week with or without subcutaneous weekly 10 mg injections of methotrexate. Antidrug antibody detection and adalimumab serum concentration were assessed at weeks four, eight, 12, and 26. The primary outcome was the proportion of patients with antidrug antibodies at week 26. Four years after the study completion, adalimumab maintenance was analyzed in relation with methotrexate co-treatment duration.

Results showed that 25 percent of patients given methotrexate along with adalimumab developed antidrug antibodies by week 26 compared with 47.3 percent of those who received adalimumab alone (p=0.03). Adalimumab concentration was significantly higher in patients who received methotrexate than in those who received adalimumab as monotherapy at all time points. The two groups did not differ in adverse events or efficacy.

“Methotrexate decreases anti-drug antibodies development and improves adalimumab pharmacokinetics,” the authors 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."

In the follow-up study, methotrexate co-treatment for longer than 26 weeks versus less than 26 weeks or no methotrexate was significantly associated with adalimumab long-term maintenance (p=0.04).

“Prolonged co-medication of methotrexate with adalimumab is associated with long-term maintenance of adalimumab,” the authors wrote. “These results rise the potential interest of methotrexate in combination with adalimumab in axial spondyloarthritis.”

REFERENCE

Emilie Ducourau, Theo Rispens, Marine Samain, et al. “Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.” RMD Open. January 9, 2020. doi: 10.1136/rmdopen-2019-001047