Subjects were enrolled from 43 centers in the U.S. and Europe . Adults meeting modified New York classification criteria for AS with current active disease and prior failure of 1 or more NSAIDs and 1 or more non-biologic DMARDs (excluding cyclosporine and azathioprine) were randomized to receive adalimumab 40 mg injected subcutaneously every other week or placebo in a double-blind fashion. Prior use of TNF inhibitors was not allowed. Subjects continued on background methotrexate, sulfasalazine, hydroxychloroquine, prednisone ( < 10 mg per day) and NSAIDs, if present. Enrollment of up to 10% of subjects with complete spinal ankylosis was permitted. Subjects were followed for 24 weeks, at which time they were eligible to enter an open-label extension phase. Subjects not achieving at least a 20% response (based on the Assessment in Ankylosing Spondylitis (ASAS20) criteria) at weeks 12, 16, or 20 were rescued into the open-label extension before 24 weeks.
The primary efficacy endpoint of the trial was the proportion achieving an ASAS20 response at 12 weeks. Secondary efficacy endpoints included achievement of pre-specified response in measures of spinal mobility, acute-phase reactants, enthesitis, global assessment, and pain.
208 subjects were randomized to receive adalimumab and 107 to receive placebo. Subjects were predominantly male (75%) and Caucasian race (96%). HLA-B27 was positive in 79% of subjects. Eleven subjects (3.5%) had complete spinal ankylosis. The average disease duration was approximately a decade. Disease activity measures did not significantly differ by treatment allocation. Approximately 97% of subjects completed the 12-week double-blind portion of the study. 51.4% of placebo treated subjects and 26% of adalimumab treated subjects did not fulfill minimal efficacy requirements and entered the open-label rescue phase.
Efficacy outcomes: 58.2% of adalimumab treated subjects, compared to 20.6% of placebo treated subjects, achieved an ASAS20 response by week 12 (p<0.001). Approximately two-thirds of the total response was achieved by 2 weeks in the adalimumab treated subjects, with the response maintained up to week 24. Similar relationships were observed in the other secondary outcomes of the trial (components of the ASAS score, CRP, global assessment, spinal mobility, and enthesitis. 59.5% of placebo treated subjects rescued to active treatment with adalimumab achieved an ASAS20 response at week 16 of open-label treatment as did 39.5% of subjects who had received adalimumab in the double-blind portion of the trial. Three of the six adalimumab treated subjects with complete ankylosis met the primary efficacy endpoint, compared to none of the five subjects in the placebo group.
In analyses stratified by HLA-B27 status, there was no statistically significant difference in the primary efficacy endpoint between HLA-B27 positive and negative subjects.
No statistically significant differences in adverse events (and no serious infections) were observed between treatment allocation. Transaminase concentrations of > 3 times the upper limit of normal were noted in 7 subjects (6 of whom were receiving adalimumab).
These findings add adalimumab to the list of TNF inhibitors effective at modifying the signs and symptoms of AS. It should be noted, however, that no agent (with the exception of NSAIDs), has yet been proven to be a structural modifier in AS. Part of the reason is that not enough well-designed studies with sufficient follow-up have addressed the question. However, in patients with severe, debilitating symptoms, TNF inhibitor use is justified even without the assurance that radiographic progression will be affected.
The inclusion of subjects with complete ankylosis is interesting, although the actual number of subjects enrolled who met this criteria is really too small to make any robust statistical inferences. However, the fact that adalimumab seemed to improve symptoms suggests that aggressive treatment is warranted in even these patients. More investigation is needed to confirm this.
Currently, TNF inhibitors are the most effective therapies for NSAID and other DMARD refractory AS patients. In spite of this, having 60 percent of subjects meeting minimum therapeutic outcomes means that 40 percent did not. Accordingly, there still remains an unmet need for new therapeutic agents for AS.