‘Bamboo spine’, a thing of the past?

There have been significant advances in our understanding of pathogenesis, classification and treatment of ankylosing spondylitis (AS). This editorial addresses the most recent and crucial developments with special emphasis on treatment. Probably the greatest advance in the filed of SpA is the classification itself. There is a proposal to change the very concept of SpA. Instead of looking at SpA as a mixed bag of diseases, current schools of thought divide them broadly into two subsets: those with predominantly axial disease (Ankylosing Spondylitis and Axial Spondyloarthritis) and the others with predominantly peripheral manifestations (Reactive arthritis, Psoriatic Arthritis and Inflammatory Bowel Disease associated SpA). With increasing awareness of the need for earlier diagnosis in the light of delayed appearance of plain radiographic changes in the sacro-iliac joints, new objective criteria like HLA-B27 and specific MRI features were introduced to classify axial SpA, thus broadening the scope of this spectrum of illnesses beyond AS1, 2. The new classification also gave birth to the novel entity of non-radiographic axial SpA (nrAxSpA) which encompasses patients not satisfying the modified New-York Criteria3-5. Anti-inflammatory medications inhibiting both the cyclo-oxygenase (COX) pathways are usually called NSAIDs. A couple of recent studies reporting possible disease modifying potential for high or regular dose NSAIDs in AS have generated new interest in these relatively inexpensive agents in spite of their potential gastric and renal toxicity6, 7. However, this benefit seems to be limited to patients with risk of disease progression as predicted by higher acute phase reactants as well as baseline new bone formation7, 8. The benefit of NSAIDs was demonstrated in relatively small subsets of patients from these studies and a larger study could not confirm these findings9. Conventional DMARDs including Sulfasalazine and methotrexate have not met the primary end point in any study in AS. However, systematic reviews have shown a reduction in ESR and stiffness with Sulfasalazine, but not with methotrexate10, 11. Similarly, the recent ESTHER study comparing Etanercept to Sulfasalazine actually showed good responses in the sulfasalazine arm as well, though significantly lower than etanercept5. Although, several randomised trials with smaller number of patients have shown benefit with Methotrexate in AS, the cochrane review on Methotrexate in AS could not be conclusive due to paucity of powerful studies. Methotrexate and sulfasalazine have several other actions including inhibition of pro-inflammatory cytokines, folate antagonism, purine inhibition and induction of apoptosis12. Larger well-conducted studies on these agents are needed and essential as these are the only medications accessible to a large proportion of people in developing countries. We now have five FDA approved TNFi for use in AS patients. Certolizumab, a PEGylated monoclonal antibody, is the most recent addition to this family. Certolizumab had similar efficacy in both AS and nrAxSpA in clinical trials, thus adding this agent to the club of other TNFi like Adalimumab, Infliximab and Etanercept5, 13-15. Data from early SpA trials also show clearly better response rates with TNFi as compared to the results of trials with these agents in AS patients with mean disease durations of 10 years or longer16. Thus, a role for the early initiation of treatment with TNFi in achieving higher efficacy is now well recognized. The other major advance in the field of TNFi therapy is the recent recognition that these biologics are not only symptom controlling, but also disease modifying in AS. Earlier studies have looked at this question and failed to show this effect due to short duration of follow up and lack of adequately matched contemporaneous controls17-20. A major study involving patients from five large North-American centres addressed this issue. Stringent statistical techniques and adjustments for baseline characteristics in this study showed a significant reduction in radiographic progression in patients on TNFi compared to those receiving other standard of care9. Interestingly, patients who started these agents within the first 5 years of disease did much better than those starting them later9. This observation now makes a strong case for the existence of a therapeutic window in AS much like that in rheumatoid arthritis. Subsequently a smaller study from the German cohort GESPIC also showed similar results and strikingly, both these studies needed a follow up period of >4 years to demonstrate the effect of TNFi on disease progression20. The title of this editorial is definitely catchy, but we need to remember that replication of these results from other longitudinal well-controlled cohorts are needed. A Interleukin-17 (IL-17) blocker is the latest drug studied and it was published after a proof-of-concept double blind study in 30 patients with AS21. Efficacy in reducing the signs and symptoms of AS were demonstrated in this study and larger studies on IL-17 blockade are needed before any firm conclusions are made. A phosphodiesterase-4 (PDE4) inhibitor apremilast was the first oral small molecule inhibitor to be studied in AS. In a double blind randomized controlled phase II study, 36 AS patients were enrolled22. Although there were some differences in the clinical outcomes as compared to placebo, these were not significant enough to favour apremilast therapy. Albeit the nonsignificant changes, discontinuation of the drug led to rapid deterioration. Larger studies and longer follow up will be required for decisive conclusions. A monoclonal antibody against CD-20 was also tried in a proof of concept study in AS which unfortunately failed to show any significant benefit. However, 10 patients in this cohort without prior TNFi therapy were analysed separately and was found to have marginal benefits23. The 1-year follow-up results of these responders is encouraging as the majority of them remained in good control with or without retreatment with rituximab24. Using the French Autoimmunity and Rituximab (AIR) registry, 26 patients with SpA were identified and analysed for efficacy of rituximab25. Again, use of Rituximab resulted in minimal benefits, predominantly in TNFi naïve patients. Abatacept (CTLA4-Ig) blocks T-cell co-stimulation by inhibiting the interaction of CD28 and B7 by binding to B7. Abatacept was tried in an open label pilot study on patients with AS26. Patients were either TNFi naïve (n = 15) or TNFi failure cases (n = 15). There was no significant benefit in either group with abatacept and this result was replicated in an open-label study on seven women with axial SpA27. Tocilizumab is a humanised monoclonal antibody against Interleukin-6 receptor (IL-6 R) and is being used very effectively in the treatment of RA, polyarticular Juvenile Idiopathic Arthritis (JIA) and systemic-onset JIA as an intravenous agent. Around 100 TNFi-naïve AS patients completed a 12-week phase-II RCT28. There was no significant difference between Tocilizumab and placebo in this trial and further exploration for dose-response and efficacy in TNFi-failed patients with this agent were discontinued. Sarilumab is a subcutaneously injectable monoclonal antibody against the α-chain of IL6-receptor (IL-6Rα). In the ALIGN study, a fairly large phase-II RCT, multiple dosing regimens of sarilumab were tried on 300 patients with AS29. There was no significant difference in response rates from placebo, although marginal differences were noted with high dose therapy in patients with higher baseline high-sensitive CRP. Considering the large number of TNFi failures as well as primary non responders, there is a great need for more treatment options for AS patients. Secukinumab and Apremilast certainly look promising at this stage. At the recent American College of Rheumatology meeting in San-Diego, the much awaited results of TOPAS, a study of Ustekinumab in AS30 was presented. In this open-label study, 20 patients received 90 mg Ustekinumab at weeks 0, 4 and 16 and response was assessed at week 24. The results were good and comparable to TNFi with an ASAS40 response of 65% and partial remission rate of 30%. In this era of GWAS, functional, genetic and proteomic studies, several pathogenically crucial molecules have been identified in AS, much beyond HLA B27. These include ERAP1 and IL-23R31. IL-22 was recently identified as a possible driving force for new-bone formation as compared to other cytokines in an animal model of arthritis and enthesitis32. It remains to be seen if this could be a potential therapeutic target to achieve disease-modification in AS. Tofacitinib, an oral JAK-kinase inhibitor approved for treatment of rheumatoid arthritis by FDA is not yet approved by EMA, citing the lack of consistent efficacy at lower doses and the unusual side effects that appear to be independent of immunsosuppression33. Results of the tofacitinib-AS study are still pending. In this issue, a meta-analysis of adalimumab in AS by Wang et al. has reported higher efficacy as well as better quality of life without any major infection or serious adverse events34. Prince et al. reported similar results with infliximab in a small Australian cohort35. Overall there are some excellent leads from pathogenic, genetic and functional studies in AS. The future is bright and we can hope for newer and more effective drugs leaving behind the concept of 'bamboo spine' in oblivion.

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