Five TNF inhibitors (TNFi) (infliximab, etanercept, adalimumab and golimumab) have been proven highly efficacious in reducing signs and symptoms of ankylosing spondylitis (AS) and are approved for this indication. However, a proportion of patients either fail to respond adequately, experience adverse events that necessitate discontinuation, or lose response after initially having shown good response to treatment. Currently, no other DMARDs have been shown to be effective in patients with axial spondyloarthritis (SpA) who have failed TNFi therapy. Thus switching to a second, and even a third, TNFi has become common practice in many countries. The various available TNFi differ in terms of pharmacodynamics, ligand specificity and the qualitative and quantitative characteristics of their interaction with soluble and membrane-bound TNF-α, and production of anti-drug antibodies can occur with time and reduce efficacy. In RA, the effectiveness of switching to a second TNFi has been extensively studied in several observational studies and even a couple of randomised controlled trials, and overall the efficacy is somewhat lower than for the first TNFi. In axial SpA including AS, the evidence of the value of switching to a second TNFi still is limited. The published studies have for the most part been small and retrospective. However, the RHAPSODY study was a large 3-month prospective study on the effect of adalimumab in active AS, and 326 of the 1250 patients included had previously been treated with etanercept and/or infliximab [1, 2]. These patients achieved lower response rates than patients who were TNFi naïve (e.g. ASAS 40 response rate of 38% vs. 59%), and TNF naivety was an independent predictor of treatment response in multivariate logistic regression analyses.
A case series showing benefit of treatment with a second TNFi in AS was first published in 2005. Several small observational studies have followed: Most studies included less than 25 patients with AS/axial SpA who switched to a second TNFi, and they generally resported favourable results and a response in the majority of patients. However, the study methodology was heterogeneous and the chosen response definitions differed considerably. In a retrospective study from France, Paccou et al reported a 41% BASDAI response rate (50% or 20 mm improvement) at 3 months among 56 patients with AS who switched to a second TNFi, and 80% had improved according to “expert opinion”. In a Norwegian study of 77 AS patients who switched to a second TNFi we found superior drug survival and response rates for the first TNFi vs. the second, with estimated drug survival rates of 76% vs. 65% at 1 year and BASDAI 50 response rates of 47% vs. 28% at 3 months.
The efficacy of the second TNFi according to reason for switching has been even less studied in AS/axial SpA. The main reasons are adverse events and lack of efficacy, with the latter often being subdivided into primary lack of efficacy and secondary loss of efficacy. In the RHAPSODY study the efficacy of adalimumab in the 247 patients who had previously received one of the two other TNFi (etanercept or infliximab) was analysed in detail according to the reason for discontinuation of the first TNFi. BASDAI 50 response rates were 26% for patients with primary lack of efficacy, 42% for patients with secondary loss of efficacy, and 46% in patients with intolerance to the first TNFi. Results from smaller observational studies as well as the RA literature also suggest that better results with the second TNFi can be expected if the reason for secondary loss of efficacy. Data from a few studies in RA have also indicated that the reason for discontinuing the first TNFi influences the reason for discontinuation of the second TNFi.
The current lack of other effective treatment options supports that a trial of a second TNFi is worthwhile if treatment with the first TNFi fails, and the available data suggest that switching is at least as useful as in RA. Data on use of TNFi beyond the second drug are, however, very limited. The most recent ASAS/EULAR recommendations for the management of AS state that switching to a second TNFi might be beneficial, especially in patients with loss of response .
Rudwaleit M et al, J Rheumatology 2009;36:801-8.
Rudwaleit M et al, Arthritis Res Ther 2010;12:R117.
Braun J et al, Ann Rheum Dis 2011;70:896-904.
Disclosure of Interest E. Lie Consultant for: Pfizer, AbbVie, Roche, Speakers bureau: Bristol-Myers Squibb, Pfizer, AbbVie, Roche