Discussion
This study is the first clinical trial to incorporate the ASAS axial SpA criteria in classifying nr-axSpA patients and the largest randomised controlled trial of an anti-TNF therapy in this population. Results from this study provide important insights into the characteristics of patients with nr-axSpA and the potential benefits of adalimumab therapy. First, the level of disease activity of nr-axSpA patients enrolled in this study was similar to those of AS patients who participated in randomised controlled trials of anti-TNF therapies. Second, significant clinical improvement was observed in nr-axSpA patients treated with adalimumab compared with placebo after just 12 weeks of therapy. Third, consistent with previous reports, the clinical response to adalimumab treatment in nr-axSpA patients was greater in patients with shorter symptom duration, younger age or presence of elevated CRP at baseline.
The nr-axSpA population enrolled in this study was younger and had a greater proportion of women compared with AS populations in randomised controlled trials of anti-TNF therapies. However, these observations are consistent with what has been reported for other nr-axSpA cohorts, including the patient population that was evaluated to validate the ASAS axial SpA criteria. There was an average delay of 7 years between onset of symptoms to diagnosis in nr-axSpA patients in this study, which highlights the need for better ways to identify these patients. Despite the absence of radiographic sacroiliitis and the above differences in demographics compared with AS patients, patients with nr-axSpA who continued to have symptoms of active disease despite NSAIDs had comparable levels of disease activity to that of patients with AS according to BASDAI, ASDAS and total back pain. However, a smaller proportion of patients with nr-axSpA had elevated CRP at baseline compared with AS patients, and mean MRI SPARCC scores for the SI joints and spine at baseline were lower than previous reports in patients with AS.
The study met its primary endpoint with 36% of patients in the adalimumab group achieving ASAS40 response at week 12 compared with 15% in the placebo group. ASAS40 is a more stringent measure of response than ASAS20 typically used in AS trials. Treatment effect with adalimumab was also significant when other composite measures were used (ie, ASAS20, ASAS 5/6, BASDAI50, ASDAS). More importantly, clinical remission was achieved by more patients in the adalimumab arm than in the placebo arm, whether defined by ASAS PR or ASDAS ID. The clinical efficacy of adalimumab was further supported by significant improvements in objective measures of inflammation (ie, CRP and the SPARCC MRI scores for both SI joints and spine). Although improvements in functionality and quality of life were noted based on the SF36 physical component summary score and HAQ-S, improvement in BASFI and BASMIlin did not meet statistical significance. This could be attributed in part to the relatively low baseline BASFI and BASMIlin scores. These results confirm previous findings from smaller trials of anti-TNF agents in nr-axSpA. In a randomised controlled trial of 46 patients with nr-axSpA, adalimumab therapy resulted in significantly better ASAS40 responses at week 12 compared with placebo. Likewise, in 40 patients with inflammatory back pain for 3 months to 3 years, HLA-B27 positivity and MRI evidence of sacroiliitis, patients receiving infliximab had significantly greater reduction in BASDAI and MRI scores than those on placebo at week 16.
Subgroup analyses of the interaction between certain baseline characteristics and treatment showed that patients whose symptom duration was <5 years, age <40 or baseline CRP was elevated were more likely to achieve ASAS40 at week 12 with adalimumab. Similar observations have been reported in established AS and were noted in a randomised controlled trial of adalimumab in 46 patients with active axial SpA without radiographically-defined sacroiliitis: patients with disease duration ≤3 years, age ≤30 or CRP>6 mg/l at baseline had a greater probability of achieving ASAS40 or BASDAI50 at week 52. These findings further emphasise the need to diagnose patients earlier. No other baseline variables evaluated had an impact on treatment response, including HLA-B27 status and past or present sacroiliitis on MRI according to the ASAS criteria, suggesting that adalimumab is a potential treatment option for nr-axSpA patients regardless of whether they fulfil the imaging or clinical arm of the ASAS axial SpA criteria. However, patients with active inflammation of the SI joints based on a SPARCC score ≥2 at baseline showed a numerically (although non-significant) higher response, and increasing baseline SPARCC SI joint scores were associated with a greater likelihood of clinical response. These findings suggest that the greater the extent of SI joint inflammation, the more likely a patient may benefit from adalimumab treatment. There was also a trend indicating better responses in patients with either inflammation of the SI joints or spine or an elevated CRP at baseline. Thus, objective evidence of active inflammation at baseline, such as presence of a positive MRI or an elevated CRP level, seems to be a good predictor of treatment response to adalimumab.
Adalimumab was well tolerated during the double-blind period of this study. There were no notable imbalances in the occurrence of AEs between treatment groups. Safety data are consistent with what is known about the safety profile of adalimumab in AS and other immune-mediated diseases.
Limitations of this study include the duration of the double-blind period, which does not allow for longer term comparison of the efficacy of adalimumab therapy with placebo in nr-axSpA patients who continue to have active disease despite NSAIDs. This study was not designed to evaluate if adalimumab therapy can prevent progression from nr-axSpA to AS. The trial was also not powered for subgroup analyses, which were further limited by uneven distribution of patients in certain subgroups (eg, HLA-B27 status). In addition, the outcome measures used in this study were validated for AS and have not been specifically developed and validated for a nr-axSpA population. As patients with nr-axSpA and those with AS are part of the same disease spectrum of axial SpA and have similar disease manifestations, the use of previously developed outcome measures for AS in this study of nr-axSpA patients was deemed to be appropriate.
In summary, 12 weeks of adalimumab therapy in patients with nr-axSpA resulted in significant clinical improvements compared with placebo, providing additional evidence that adalimumab controls inflammation with a similar safety profile across a range of spondyloarthritides. Efficacy and safety results from this study suggest that adalimumab is an appropriate treatment option for active nr-axSpA patients who fail NSAIDs, especially those with objective evidence of inflammation. Longer term data would provide information on the optimal use of adalimumab in patients with nr-axSpA.