Ankylosing Spondylitis: Combinations Up Anti-TNF Responses

Janis C. Kelly

March 04, 2015

Combining a conventional disease-modifying antirheumatic drug (DMARD) with a tumor necrosis factor inhibitor (TNFi) was more effective than a TNFi alone in patients with ankylosing spondylitis (AS) or undifferentiated spondyloarthritis (uSpA), according to a nationwide prospective study published online February 20 in the Annals of the Rheumatic Diseases. However, the beneficial effect might not be large enough to justify changing current treatment guidelines, experts caution.

Elisabeth Lie, MD, from the Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway, and colleagues found that among 1365 patients with AS and 1155 patients with uSpA, those who started treatment with a TNFi plus a conventional DMARD (csDMARD, most commonly methotrexate) were significantly more likely to still be taking the TNFi after 5 years (described as "TNFi drug survival"), compared with those who started on a TNFi alone.

In the case of patients with AS, 40.8% used both TNFi and csDMARD comedication at baseline. In multivariable Cox regression analyses, at 5 years after the start of therapy, those patients were 30% more likely to continue receiving TNFi than patients with AS who did not also take csDMARDs (hazard ratio, 0.71; 95% confidence interval, 0.59 - 0.85; P < .001). The multivariable analysis adjusted for age, sex, baseline csDMARD comedication, TNFi type, prescription year, and covariates representing frailty and socioeconomic status.

Similarly, 50.3% of patients with uSpA used both TNFi and csDMARD comedication at baseline. At 5 years after the start of therapy, those patients were about 20% more likely to continue receiving TNFis than were patients with uSpA who did not also take csDMARDs (hazard ratio, 0.82; 95% confidence interval, 0.68 - 0.97; P = .020).

Most TNFi discontinuations were for lack or loss of efficacy, according to the researchers. They suggest that one possible mechanism of action might be formation of anti-TNFi antibodies, which have been associated with clinical nonresponse to infliximab and to adalimumab in other studies.

Spondyloarthritis specialist Muhammad Asim Khan, MD, MACP, FRCP, from Case Western Reserve University, Cleveland, Ohio, told Medscape Medical News that the current standard approach in North America to treating patients with AS with axial disease is TNFis without concurrent conventional DMARDs. Dr Khan, who was not involved in the study, said, "Lie et al correctly state that the current [Assessment in SpondyloArthritis international Society/European League Against Rheumatism] recommendations recommend against routine use of concomitant DMARD and anti-TNF therapy in AS patients with axial disease."

Walter P. Maksymowych, MD, FRCP, who worked on the development and validation of Canadian spondyloarthritis magnetic resonance imaging criteria, told Medscape Medical News, "A puzzling aspect of the results is that the effect of DMARD therapy was significant even in those patients that stopped DMARD therapy at the time of starting an anti-TNF. A major concern with such observational data is the issue of confounding by indication. For example, patients with active inflammatory disease tend to be the best responders to anti-TNF therapy. However, these patients are often prescribed a DMARD before starting anti-TNF precisely because they have active disease. So the improved survival on anti-TNF using DMARD cotherapy could reflect a more active level of inflammation, which predicts a better treatment response to anti-TNF. While the authors adjusted for inflammation parameters, they state there was a good deal of missing data." Dr Maksymowych, who was not involved in the study, is consultant rheumatologist and professor of medicine, University of Alberta, Edmonton, Canada.

Dr Maksymowych also noted that TNFis are often used for treating patients with AS with active disease who have failed treatment with at least two nonsteroidal anti-inflammatory drugs and that a trial of DMARD therapy (typically either methotrexate or sulfasalazine) is often used in patients with concomitant peripheral synovitis, but there is scant evidence that these agents are effective for axial disease, and they have only limited efficacy in peripheral involvement.

"I do not think that clinicians are likely to start coprescribing DMARDs to patients on anti-TNF because these agents lack efficacy for axial disease. I am not convinced that the results reflect an effect of combination DMARD-anti-TNF therapy, as opposed to the identification of a more responsive phenotype of disease. This will require randomized trials that include a combination therapy arm," Dr Maksymowych said.

The ARTIS Study Group conducts scientific analyses using data from the Swedish Biologics Register run by the Swedish Society for Rheumatology and has received funding from Merck, Bristol-Myers Squibb, Pfizer, AbbVie, SOBI, UCB, Astra Zeneca, and Roche for the maintenance of this register. Dr Lie reported consulting and/or receiving speaker honoraria from AbbVie, Bristol-Myers Squibb, Hospira, Pfizer and UCB. Other coauthors reported consulting and/or receiving speaker honoraria from AbbVie, Merck Sharp & Dohme, Pfizer, Roche, and UCB. Dr Khan has disclosed no relevant financial relationships. Dr Maksymowych reported receiving consulting honoraria from Abbvie, Amgen, Eli-Lilly, Janssen, Merck, Pfizer, and UCB.

Ann Rheum Dis. Published online February 20, 2015. Abstract

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