Classification Criteria and Treatment Guidelines
The Assessment of Spondyloarthritis International Society (ASAS) axial spondyloarthritis (axSpA) classification criteria marked a significant step forward in spondyloarthritis (SpA) research, distinguishing axial from peripheral disease and allowing earlier identification through magnetic resonance imaging (MRI).1 Initially published in 2009, these criteria have been incorporated and updated in the 2016 update of the ASAS-European League Against Rheumatism (EULAR) management recommendations for axSpA2 and the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and non-radiographic axSpA (nr-axSpA).3 These criteria have been applied broadly in research and have been validated in a meta-analysis of international studies.4 Development of the ASAS classification criteria was one of the major breakthroughs in the field over the past decade. They resulted in major advances in understanding the course of axSpA, revealing predictors of progression and providing early diagnosis and treatment.5
A guideline-based treatment algorithm using the axSpA classification criteria is shown in the following figure.
Nonsteroidal antiinflammatory drugs (NSAIDs) and tumor necrosis factor (TNF) blockers are well-known effective treatment options in patients with AxSpA. According to the recommendations noted, first-line therapies for patients with symptomatic axSpA are NSAIDs, including selective cyclooxygenase-2 (COX-2) antagonists, together with exercise/physiotherapy and education of the patient.5 Therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as sulfasalazine may have some beneficial effect in patients with peripheral joint involvement but are generally not effective in the majority of patients with axial involvement.
Up to 50% of patients fail to achieve a clinically significant response on NSAIDs.6 The only other effective FDA-approved treatment for patients with a poor response, contraindications, or intolerance to NSAIDs is therapy with biological DMARDs (bDMARDs): either TNF-alpha inhibitors or interleukin (IL)-17 inhibitors.
Five TNF inhibitors—infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol—are approved in the United States (US), European Union (EU), and most other parts of the world for the treatment of patients with ankylosing spondylitis (AS), also known as radiographic SpA. In the EU, four TNF inhibitors—etanercept, adalimumab, golimumab, and certolizumab pegol—also have approval for the treatment of nr-axSpA after failure of the standard treatments.5 Certolizumab pegol is currently being evaluated for nr-axSpA in the US (NCT02552212). Most of the evidence for TNF inhibitors comes from phase 3 randomized placebo-controlled clinical trials in patients with confirmed AS who were treated with anti-TNF versus placebo. Evaluation of treatment responses in these studies was demonstrated by the ASAS response criteria. All bDMARD therapies have displayed efficacy against placebo, but no direct comparison on efficacy can be made between biologics, given the absence of head-to-head studies at this time.7 Additionally, the first biosimilars for infliximab, etanercept, and adalimumab have now been approved in the US and/or EU.8
There are currently two IL-17 inhibitors approved for the treatment of active AS in the US; these agents are currently being evaluated for nr-axSpA.
- Secukinumab is a monoclonal antibody against IL-17A that has been FDA-approved for AS since January 2016. It also has approvals for the treatment of plaque psoriasis and psoriatic arthritis (PsA). Phase 3 studies for nr-axSpA are ongoing.5
- Evidence from the MEASURE 1 and MEASURE 2 phase 3 trials of secukinumab in patients with active AS that evaluated intravenous and subcutaneous secukinumab, respectively, showed significant reductions in the signs and symptoms of AS.9
- In MEASURE 1, the Assessment of Spondyloarthritis International Society 20 (ASAS20) response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons compared with placebo).9
- In MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose compared with placebo). The significant improvements were sustained through 52 weeks.
- The improvements in AS signs and symptoms seen in MEASURE 1 were sustained through two years of therapy.10
- Secukinumab is currently being evaluated for nr-axSpA in the US (NCT02696031).
- Ixekizumab is an IL-17 inhibitor that received FDA approval for AS in August 2019 and is currently being evaluated for nr-axSpA.
- The FDA expanded the approval of ixekizumab, which has prior approvals for plaque psoriasis and PsA, to include AS based on the results of two 16-week, double-blind, placebo-controlled clinical trials: COAST-V and COAST-W.
- COAST-V compared symptomatic improvements in patients with no previous history of treatments with biologic medications who received ixekizumab, adalimumab, or a placebo. Patients were randomly assigned (1:1:1:1) to 80 mg subcutaneous ixekizumab every 2 or 4 weeks, 40 mg adalimumab every 2 weeks (active reference group), or placebo. At week 16, more patients achieved ASAS40 with ixekizumab every 2 weeks (43 [52%] of 83; P<0.0001), ixekizumab every 4 weeks (39 [48%] of 81; P<0.0001), and adalimumab (32 [36%] of 90; P=0.0053) compared with placebo (16 [18%] of 87).11
- COAST-W evaluated treatment with ixekizumab in individuals who had previously taken TNF inhibitors but did not experience noticeable symptomatic improvements or did not tolerate them. At week 16, significantly higher proportions of patients receiving ixekizumab every 2 weeks (n = 30 [30.6%]; P=0.003) or every 4 weeks (n = 29 [25.4%]; P=0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment.12
- In addition, the phase III COAST-X study that evaluated the safety and efficacy of ixekizumab for the treatment of nr-axSpA biologic-naïve patients met the primary endpoint at both week 16 and week 52, demonstrating a significant improvement in the signs and symptoms of nr-axSpA, as measured by the proportion of patients who achieved ASAS40 response compared with the placebo group.13 Patients were required to have an established diagnosis of nr-axSpA and active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Numeric Rating Scale (NRS) score of ≥4 and total back pain of ≥4 at screening and baseline and were required to have objective signs of inflammation by the presence of sacroiliitis on magnetic resonance imaging (MRI) or the presence of elevated C-reactive protein (CRP).
Studies with IL-23 inhibitors such as tildrakizumab (NCT03552276) are planned or are ongoing in patients with AS and axSpA. The Janus kinase inhibitor tofacitinib (NCT03738956) has shown some efficacy in AS.8
- Rudwaleit M, van der Heijde D, Landewé R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68:777-783.
- van der Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76:978-991.
- Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2016;68:282-298.
- Dubreuil M, Deodhar AA. Axial spondyloarthritis classification criteria: the debate continues. Curr Opin Rheumatol. 2017;29:317-322.
- Proft F, Poddubnyy D. Ankylosing spondylitis and axial spondyloarthritis: recent insights and impact of new classification criteria. Ther Adv Musculoskelet Dis. 2018;10:129-139.
- Cheung PP. Anti-IL17A in axial spondyloarthritis—where are we at? Front Med (Lausanne). 2017;4:1.
- Dubash S, McGonagle D, Marzo-Ortega H. New advances in the understanding and treatment of axial spondyloarthritis: from chance to choice. Ther Adv Chronic Dis. 2018;9:77-87.
- Braun J. Axial spondyloarthritis including ankylosing spondylitis. Rheumatology (Oxford). 2018;57(Suppl 6):vi1–vi3.
- Baeten D, Sieper J, Braun J, et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med. 2015; 373: 2534–2548.
- Braun J, Baraliakos X, Deodhar A, et al. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2017;76:1070-1077.
- van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392:2441-2451.
- Deodhar A, Poddubnyy D, Pacheco-Tena C, et al; COAST-W Study Group. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71:599-611.
- House DW (SeekingAlpha press release). Lilly’s Taltz successful in late-stage study in axial skeleton arthritis. https://seekingalpha.com/news/3452281-lillys-taltz-successful-late-stage-study-axial-skeleton-arthritis