Current Reports (2019) 21: 35 https://doi.org/10.1007/s11926-019-0830-0

SPONDYLOARTHRITIS (M KHAN, SECTION EDITOR)

Emerging Immunomodulatory and New Treatment Paradigms for Axial Spondyloarthritis

Philip Mease1

Published online: 6 June 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract Purpose of Review The purpose of this review is to educate the reader about the evolving classification of axial spondyloarthritis (AxSpA) and describe recent treatment data from clinical trials of medications with mechanisms of action other than TNF inhibition. The review will also address emerging treatment strategies for AxSpA. Recent Findings New and more sensitive classification schema for AxSpA find that the prevalence of the disease is more than twice that of the historic definition of (AS), when patients without radiographically observable damage to the sacroiliac joints are included. TNF inhibitors have shown efficacy in the full spectrum of disease. IL-17 inhibitors, e.g., secukinumab and ixekizumab and janus kinase (JAK) inhibitors, have shown good efficacy and relatively good safety in radiographically defined AxSpA and are being tested in non-radiographic (nr) AxSpA. Several immunomodulatory approved for psoriasis, psoriatic arthritis, and have not shown efficacy in AxSpA, highlighting the impor- tance of conducting good-quality, placebo-controlled trials in this condition. Treatment strategies such as “treat to target” and tapering are being studied. Summary There remains a large unmet need to identify and adequately treat the full spectrum of AxSpA. The use of TNF inhibitors has improved our ability to achieve remission or low disease activity in AxSpA. Newer medicines with different mechanisms of action, e.g., IL-17 or JAK inhibition, are also showing similar ability. Continued research, including identification of new targets of treatment, is critical.

Keywords Axial spondyloarthritis . Ankylosing spondylitis . Non-radiographic axial spondyloarthritis . Biologic therapy . TNF inhibitor . IL-17 inhibitor

Introduction therapies beyond TNF inhibitors (TNFi), thanks to the syner- gism of emerging findings in , increasing numbers The development and approval of TNF inhibitor medications in of investigators coming into the field, encouraged by the ability ankylosing spondylitis (AS) which has occurred over the past to more effectively treat the disease and increased availability two decades revolutionized the management of AS, for which of governmental and biopharmaceutical funding, and an overall there had been scant prior effective therapy. For the first time, increase in interest in diagnosing and treating the remission or low disease activity could be achieved, allowing spondyloarthritis (SpA) disease spectrum by rheumatologists many patients to return to reasonably normal activity and qual- and other specialists. This article will touch on recent data on ity of life. During that time, there has also been a significant TNFi but focus on therapies with different mechanisms of ac- increase in research and education about disease pathophysiol- tion than TNFi that have emerged during the last decade, some ogy, diagnosis, assessment, and the development of new of which are now approved for use in clinical practice.

This article is part of the Topical Collection on Spondyloarthritis Classification * Philip Mease [email protected] A starting point in the discussion is to establish disease termi- 1 Rheumatology Research, Swedish Medical Center/Providence-St. nology. Until 2009, the disease known by rheumatologists, Joseph Health, University of Washington School of , 601 regulatory agencies, and payors has been “ankylosing spon- Broadway Suite 600, Seattle, WA 98122, USA dylitis.” This condition was classified by the modified New 35 Page 2 of 7 Curr Rheumatol Rep (2019) 21: 35

York (mNY) criteria in 1984 [1]. A requisite component of is critical to educate not only rheumatologists but also non- these classification criteria is the identification of characteris- rheumatologists such as primary care clinicians, physiatrists, tic changes of sacroiliac radiographs of sufficient severity, orthopedists, and physical therapists about this evolved under- such as peri-articular sclerosis, joint space narrowing or ero- standing of classification so as to improve case finding at an sions, in addition to clinical features of limitation of back earlier stage of disease when effective treatment may yield mobility and chronicity. By these criteria, it has been significant disease modification and result in shorter duration established that approximately 0.5% of the US population, of disabling symptoms and signs. in a ratio of 2:1 male to female gender, can be classified with In this article, the term “SpA” will refer to the overarching AS [2••]. The great majority of these patients will be positive disease in humans as well as translational studies in animals, for the HLA-B27 gene marker, although the strength of this “AxSpA” will refer to the overall set of both radiographically association varies among different ethnic and racial groups. as well as non-radiographically defined disease, “AS” will be As our understanding of the disease has evolved, including considered synonymous with “radiographic axial increased use of advanced imaging of the spine and sacroiliac spondyloarthritis” (r-AxSpA) and “non-radiographic axial joints with magnetic resonance imaging (MRI) technology spondyloarthritis” or nr-AxSpA will refer to all AxSpA pa- and increased diagnostic sensitivity about earlier diagnosis tients without clearcut radiographic sacroiliac changes. The and effective treatment before fixed spinal structural damage majority of the studies referred to will have been comprised has occurred, the classification schema have also evolved. of patients fulfilling mNY AS criteria. Current drug develop- Several criteria have been proposed, including the European ment programs all include studies of both AS/r-AxSpA and Spondylarthropathy Study Group (ESSG) [3] and Amor [4] nr-AxSpA patient populations. The pathway for regulatory criteria, which allowed for a broader disease definition. The approval for both of these patient groups is now well- most recent classification criteria were developed by the established in Europe and other parts of the world. In the Assessment of SpondyloArthritis International Society USA, the FDA has previously only recognized an indication (ASAS) for predominantly axial SPA (AxSpA), published in for AS, given concerns about potential misclassification of 2009 [5, 6•, 7•] and subsequently accompanied by criteria for other forms of SpA, but has now established a path for regu- predominantly peripheral SpA. A patient with AxSpA may latory approval for a nr-AxSpA indication so that newer ther- fulfill this criteria set by fulfilling the “stem,” i.e., having back apies are anticipated to gain approval in this indication in the pain more than 3 months and onset before 45 years of age, and US in the near future, depending on the outcome of studies. then by fulfilling one of two “arms,” the “imaging” arm or the “HLA-B27/clinical arm”. The former is fulfilled if the patient either demonstrates characteristic radiographic sacroiliac Assessment changes as defined by the original mNY criteria or character- istic sacroiliac MRI changes consistent with inflammation TNF Inhibitors—New Developments along with at least one item from a list of typical SpA fea- tures1. The latter aspect is considered “non-radiographic” Recognizing the pivotal role of the cytokine, TNF, in the path- since MRI is not a radiographic technology. The “clinical” ophysiology of autoimmune and other inflammatory diseases, arm is fulfilled if the patient is positive for the HLA-B27 gene inhibitors of this cytokine were studied in rheumatoid arthritis and also at least two items from the list of SpA features. The (RA) and subsequently psoriatic arthritis (PsA), AS, inflam- two arms taken together yield a specificity of 84.4% and sen- matory bowel disease (IBD), psoriasis and other indications. sitivity of 82.9%. By including the MRI and HLA-B27 ele- Five TNF inhibitors (TNFi), etanercept, infliximab, ments, the new criteria allow for earlier case finding before adalimumab, golimumab, and certolizumab pegol, have been structural damage has occurred, required as part of the mNY approved for AS globally. The most recent approval was for criteria. Eventually, many patients will display characteristic the intravenous form of golimumab, complementing the sub- sacroiliac radiographic changes but not all, so the non- cutaneous form of this agent. All but infliximab have also radiographic “stage” of the disease should not be considered been approved for the treatment of nr-AxSpA in Europe and an automatic precursor to a more structurally damaged state. other parts of the world, but not in the USA. A trial of By the newer criteria, studies suggest that at least 1% of the certolizumab in nr-AxSpA, abiding by FDA regulatory guid- US population may be classified as being afflicted with ance requiring 12 months of placebo control, has been com- AxSpA, with nearly half being “non-radiographic” in presen- pleted; a decision on approval by the FDA in this indication is tation, and the gender ratio of AxSpA is 1:1 male to female. It pending. In this trial, ASAS 40 response was achieved by 48% vs. 11% in the certolizumab 200 mg q 2 weeks arm vs. place- bo respectively at week 12 and 56.6% vs 15.8% at week 52. 1 Inflammatory back pain, Arthritis, Enthesitis (heel), Uveitis, Dactylitis, Psoriasis, Crohn‘s disease/ulcerative colitis, Good response to NSAIDs, TNF-i remain the first line therapy of choice, after a sufficient Family history for SpA, Elevated CRP, HLA-B*27. trial of non-steroidal anti-inflammatory drugs (NSAIDs), in Curr Rheumatol Rep (2019) 21: 35 Page 3 of 7 35 both the Assessment of SpondyloArthritis International Two drugs which inhibit IL-17A, secukinumab and Society (ASAS)-European League Against Rheumatism ixekizumab, have shown efficacy in AxSpA. Secukinumab (EULAR) [8•] and American College of Rheumatology/ is approved for the treatment of AS; approval for ixekizumab Spondylitis Association of America/Spondyloarthritis is pending. These drugs are approved for the treatment of Research and Treatment Network (ACR/SAA/SPARTAN) psoriasis and PsA. An IL-17 A and F inhibitor, bimekizumab, treatment recommendations [9•]. Use of TNF-i that has a has shown efficacy in psoriasis and PsA. Results of studies in monoclonal antibody construct (infliximab, adalimumab, AxSpA are pending. All three of these agents are conducting golimumab, certolizumab) are favored in patients who have studies in nr-AxSpA patients. An IL-17 receptor inhibitor, inflammatory bowel disease and/or uveitis as associated con- brodalumab, has been approved for psoriasis and has shown ditions [9•]. efficacy in PsA. A study in AS was planned but not initiated Biosimilars, i.e., drugs that have been shown to be virtually when the drug faced regulatory scrutiny about suicidality. identical to the “originator” TNFi in quality, safety, and effi- cacy, are now widely approved in Europe and other parts of Secukinumab Secukinumab is a fully human IgG1 monoclo- the world and are increasingly so in the US [10]. For the most nal antibody directed against IL-17A. The MEASURE 2 part, these agents are approved on the basis of pharmacologic phase 3 study assessed the drug given subcutaneously with equivalence and one human trial, which is typically in RA. a 5-weekly loading dose followed by monthly injections vs. Approval in other conditions, such as AxSpA, is based on this placebo [19•]. The study population included both biologic evidence. Thus far, numerous biosimilars of infliximab, naïve and TNF-i experienced patients. At the primary end- adalimumab, and etanercept have been introduced, have been point, week 16, the ASAS 20 results were 61%, 41%, and well accepted and shown to be effective and safe, and have 28% for secukinumab 150 mg, 75 mg, and placebo respec- begun to lead to reduce expenditures for this class of drugs. It tively, achieving statistical significance for the 150 mg group is anticipated that greater access to the highly effective TNF-i vs. placebo. Patients naïve to biologics had better response class will result from lower cost. than patients previously exposed to TNFi. Other key mea- sures which achieved statistical significance at this dose in- Interleukin 17 Inhibitors cluded ASAS 40, BASDAI, quality of life as measured by SF-36 and ASQoL, ASAS partial remission, and improve- The cytokine IL-17Awas discovered in 1993 and other family mentofinflammation measured bysacroiliacand spine MRI. members, IL-17A-F subsequently. One of the main sources of The MEASURE 1 study, utilizing an IV loading dose in the IL-17, the TH17 cell, was discovered in 2005 [11]. The TH17 first month, which is not a currently approved administration cell and its cellular products such as IL-17 have been shown to approach, followed by monthly subcutaneous injections, contribute significantly to the pathogenesis of psoriasis, PsA, was not included in the regulatory filing for efficacy but and AxSpA [12••]. In addition to TH17 cells, there are several was for safety. In this study, however, imaging endpoints other cells which produce IL-17, including other types of lym- were obtained and there was not only improvement of MRI phocytes, mast cells, neutrophils, and keratinocytes. IL-17 is evidence of inflammation but also over time the majority of expressed in AS spine bone marrow, predominantly in MPO+ patients did not have progression of radiographic changes in cells and neutrophils, rather than CD3+T cells, suggesting the spine. The mean change in mSASSS through 2 years was greater innate than adaptive immune system activation [13]. 0.30 overall and approximately 80% did not progress. At Various studies demonstrate elevated IL-17 and TH17 and 4 years, a difference in progression between the 150 mg and other cells producing IL-17 in AS blood samples [14, 15]. 75 mg dose was noted in structural progression. Pending HLA-B27 interaction with natural killer cells results in in- studies with secukinumab include evaluation of a 300 mg creased IL-17 production [16]. In an experimental animal dose in AS as well as effectiveness of the drug in a nr- model, using mice prone to develop SpA, Sherlock demon- AxSpA population. The safety profile of secukinumab has strated that IL-23 stimulated resident lymphocytes with a re- been quite good when considering the totality of studies in ceptor phenotype similar to human TH17 cells at entheseal AxSpA, psoriasis, and PsA. There is a slight increase, rela- sites and the aortic root which in turn produced IL-17 and tive to placebo, in serious infection rate, Candida infection, IL-22, demonstrating pro-inflammatory and bone remodeling mild neutropenia, and a few cases of either flare of known or effects [17••]. This work has been reproduced by Reinhardt new onset inflammatory bowel disease (IBD). The reason for [18], who also demonstrated inflammation in the ciliary body the occurrences of IBD is not well understood; caution of the eye. Taken as a whole, these studies suggest the prom- should be exercised in utilizing this class of agents in patients inent role played by IL-17 and IL-17 producing cells in the with known IBD. To date, there has not been a concerning various manifestations of AxSpA, including spinal inflamma- safety signal regarding malignancy, demyelinating neuro- tion, pathologic bone formation, and associated conditions logical disease, cardiovascular disease, opportunistic infec- such as uveitis, aortic disease, and psoriasis. tion other than Candida, or hepatic or renal toxicity. 35 Page 4 of 7 Curr Rheumatol Rep (2019) 21: 35

Ixekizumab Ixekizumab is a humanized IgG4 monoclonal an- Risankizumab Risankizumab is a monocolonal antibody that tibody which inhibits IL-17A. COAST-V was a study in binds to the p19 subunit of IL-23, thus inhibiting the cytokine. which 341 patients fulfilled both mNY criteria for AS and It has demonstrated efficacy in psoriasis and PsA in pre- the radiographic arm of the AxSpA (r-AxSpA) criteria, now approval trials in psoriasis and PsA [27, 28]. However, a phase considered synonymous by ASAS, and were naïve to biologic 2 study in AS did not show differentiation from placebo, so medications,testedforixekizumab80mgq2weeks, further development of that drug in AS was not continued ixekizumab q 4 weeks, adalimumab 40 mg q 2 weeks, and [29]. placebo [20•]. ASAS40 response was achieved by 52%, 48%, 36%, and 18% respectively. Other key endpoints, including Tildrakizumab A phase 2 trial of tildrakizumab, which also function, QoL, sacroiliac joint and spine MRI evidence of inhibits IL-23 by binding to its p19 subunit, is currently being inflammation also showed significant improvement in the conducted. ixekizumab arms. COAST-W was a study in which 316 pa- Although we are still awaiting the results of the tients, similarly classified as COAST-V and were previously tildrakizumab study, the failure of two study programs in exposed to 1 or 2 TNF-i tested ixekizumab 80 mg q 2 weeks, AxSpA with drugs whose principle mechanism of action is ixekizumab q 4 weeks, and placebo [21•]. ASAS40 response through the inhibition of IL-23 raises doubt that this will be was achieved by 30.6%, 25.4%, and 12.5% respectively. a successful avenue of treatment in AxSpA. Although it is Other key endpoints, including function, QoL, and spine possible that some of the apparent lack of effect lies with MRI evidence of inflammation also showed significant im- issues such as dosing, study populations, and high placebo provement in the ixekizumab arms. Similar safety and tolera- effect, mechanistic reasons must be considered as well [30•]. bility issues have been observed with ixekizumab as with A consideration to explain why IL-17 inhibition works and secukinumab, other than slightly higher rates of injection site IL-23 does not is the possibility that populations of immune reactions with ixekizumab. cells in the spine produce IL-17 independent of IL-23. Another possibility, based on animal studies, is that some Interleukin 23 Inhibitors Translational and animal model inflammatory pathways in the peripheral joints and entheses studies in conditions such as psoriasis, PsA, and AxSpA may differ from those in the spine, leading to different patho- demonstrate a pro-inflammatory role of IL-23. Increased logic manifestations in these body sites [30•]. Thus far, these expression of IL-23 due to perturbations in the gut results emphasize the importance of conducting well-de- microbiome, infection, tissue micro-trauma, and HLA- signed, placebo-controlled studies in humans to test drugs, B27 misfolding, among other inciting factors [22••]. since even drugs whose mechanisms seem certain to work in Upon IL-23 stimulation of TH17 cells or resident lympho- a disease may not. cytes, cellular activation leads to increased production of such pro-inflammatory cytokines as IL-17, IL-22, and Other Biologic Drug Classes Not Deemed to Be TNF. There is known association of the IL-23 receptor Effective in AxSpA gene and AS. Thus, it stands to reason that inhibition of IL-23 would yield beneficial effects in the treatment of Several drugs which have demonstrated effectiveness in RA AxSpA, analogous to the benefits demonstrated in psori- have not demonstrated efficacy, or adequate efficacy, in asis and PsA [12••, 23, 24]. AxSpA, including an IL-1 inhibitor, anakinra, an IL-6 receptor inhibitor, tocilizumab, a T cell modulator, abatacept, and a B Ustekinumab Ustekinumab is a humanized monoclonal an- cell ablator, rituximab. These results reinforce the point that tibody directed against the shared p40 subunit of IL-23 not all immunomodulatory agents that are effective in reduc- and IL-12. It is approved for the treatment of psoriasis, ing inflammation in synovial tissues of joints will be effective PsA, and ulcerative colitis in a dose of 45 or 90 mg every in the of AxSpA, which involves different immu- 3 months. The 90 mg dose was tested in an open label nologic pathways and osteitis and enthesitis in involved ana- study of 20 patients with AS [25]. Sixty-five percent tomic areas, especially the spine. achieved and ASAS40 response and MRI evidence of inflammation improved. These results were robust enough that rather a large Phase 3 program of three trials (biologic Targeted Synthetic Disease Modifying Drugs naïve and TNF experienced r-AxSpA and biologic naïve nr-AxSpA) were initiated. The 24 week results of the first Several oral medications which are designed to target specific trial showed no difference between placebo and two dose pro-inflammatory intracellular pathways have proven efficacy arms of ustekinumab, nor did other measures, including in RA, PsA, and/or psoriasis, including the phosphodiesterase MRI evidence of inflammation, show differentiation from 4 (PDE-4) inhibitors, apremilast, and the Janus kinase (JAK) placebo [26]. The program was halted. inhibitor, tofacitinib. One other JAK inhibitor has been Curr Rheumatol Rep (2019) 21: 35 Page 5 of 7 35 approved for RA, baricitinib, and several are in development Treat to Target The concept of treating to target, originally for RA and PsA, including filgotinib and upadacitinib. developed in diseases such as diabetes, in which treatment to a state of such good glucose control that the hemoglobin A1C Apremilast Apremilast, a PDE-4 inhibitor which can reduce can be normalized and numerous downwind consequences of TNF and other pro-inflammatory cytokines, has been ap- uncontrolled disease may be avoided, has been adopted in proved for the treatment of PsA and psoriasis. In a small several rheumatologic diseases, beginning with RA but now proof-of-concept study [31], numeric improvement of also AxSpA. The evidence base for this concept has been most BASDAI in the treatment arm vs. placebo, led to a larger clearly shown in RA, i.e., demonstrating that quantitating dis- phase 3 trial. Unfortunately, the latter failed to show discrim- ease activity and aggressively adjusting therapy intensity to ination between actively treated and placebo patients achieve a threshold of remission or LDA yields superior out- (POSTURE study, clinicaltrials.gov NCT01583374). comes in disease activity, function, QoL, work productivity, and inhibition of progressive structural damage of joints [34]. Tofacitinib Tofacitinib is the first of a generation of JAK inhib- An expert panel has met on several occasions to draft the itors emerging for the treatment of autoimmune inflammatory framework for treating to target in PsA and AxSpA [35, and other inflammatory conditions. Depending on the design of 36••]. A treat to target trial has been conducted in PsA and the molecule, they inhibit pairs of JAK1, 2, or 3 and TYK2 shown superior outcomes in disease activity using a target of molecules which control heterodimeric receptors for a number minimal disease activity (MDA) and therapeutic tight control of different cytokines which may induce immune cells to be- exercised at monthly visits till MDA was achieved [37]. A come activated. Tofacitinib preferentially inhibits JAK1 and 3, similar study is being performed in AxSpA (TICOSPA, reducing signaling from several key pro-inflammatory cyto- NCT03043846) to provide evidence for whether this treat- kines. Tofacitinib is approved for the treatment of RA and ment paradigm is appropriate for management of AxSpA. PsA. Although shown to be effective in psoriasis, the drug did not receive approval by the FDA in that condition. Tofacitinib Treatment to Remission with Subsequent Treatment Taper or wastestedinaphase2studyin208ASpatients[32•]. ASAS 20 Discontinuation Numerous trials have been conducted to de- response at week 12 occurred in 63%, 67%, and 40% in the termine if an AxSpA patient in sustained remission or LDA on tofacitinib 5 and 10 mg arms and placebo, respectively. treatment can have treatment tapered or discontinued to see if Reduction of inflammation as measured by MRI was also dem- remission or LDA can be sustained [38]. This is a particularly onstrated. A phase 3 study in AS is currently underway. important issue in resource-challenged settings where the abil- ity to afford costly therapies is difficult. In general, tapering Filgotinib Filgotinib, which preferentially inhibits JAK1, was trials, most commonly of TNFi, have been reasonably suc- tested in a phase 2 trial in 263 AS patients [33••]. At 12 weeks, cessful, allowing for use of a lower dose or increased dosing ASAS 20 response was achieved in 76% of patients treated interval for these agents. However, most drug discontinuation with 200 mg of filgotinib vs. 40% treated with placebo and trials have not shown ability to permanently discontinue med- ASAS 40 response was 38% and 19% respectively. ication, as disease flare typically occurs within 6–24 weeks, Significant reduction of inflammation by MRI assessment of depending on the trial and medication being studied. spine and sacroiliac joints occurred with filgotinib, as did im- provement of function and QoL. One serious infection, pneu- Conclusion The classification of AxSpA is changing yielding monia, occurred in the filgotinib group. a higher prevalence in the population as our ability to recog- The availability of effective oral immunomodulatory drugs nize patients at an earlier stage as well as patients, especially to treat AxSpA will likely broaden the reach of therapies to a females, who may not have classic evidence of radiologic larger group of patients, some of whom are reticent to use damage, has improved with advances in imaging, biomarker parenteral drugs. It should also be noted that whereas in rare use, and improved clinical screening. Our understanding instances, parenteral biologic treatment efficacy may be about pathophysiology has also deepened, leading to discov- blunted by the phenomenon of immunogenicity, development ery of new targets of treatment and the development of drugs of anti-drug antibodies which can neutralize therapeutic effect which modulate these immunologic pathways. TNF inhibitors of the biologic, this is not an issue with oral medications. have become more widely used to effectively treat AxSpA, and are strongly recommended in treatment guidelines. Now, Treatment Paradigms in addition, the IL-17A inhibitor secukinumab has been ap- proved, showing comparable efficacy as the TNF-i, and we Several emerging treatment paradigms have arisen as a result anticipate that another IL-17A inhibitor, ixekizumab, will of the availability of bDMARDs and tsDMARDs which are soon be approved. The addition of these medicines to our potent enough to achieve a state of remission or low disease treatment armamentarium is important to broaden our initial activity (LDA) in AxSpA. choice of treatment and to be available if prior therapies either 35 Page 6 of 7 Curr Rheumatol Rep (2019) 21: 35 are not effective or lose efficacy over time. There are a number 3. Dougados M, van der Linden S, Juhlin R, et al. The European of other promising medicines in development, including the Spondylarthropathy Study Group preliminary criteria for the classi- fication of spondylarthropathy. Arthritis Rheum. 1991;34:1218–27. IL-17A/F inhibitor, bimekizumab, and several JAK inhibitors. 4. Amor B, Dougados M, Mijiyawa M. Criteria for the classification of Furthermore, we anticipate these medicines will show effec- . Rev Rheum Mal Osteoaric. 1990;57:85–9. tiveness in the group of patients currently classified as nr- 5. Rudwaleit M, Landewe R, van der Heijde D, et al. The develop- AxSpA, broadening the therapeutic options for this large ment of Assessment of Spondylo Arthritis International Society classification criteria for axial spondyloarthritis (part I): classifica- group of patients. Some drugs which have shown efficacy in tion of paper patients by expert opinion including uncertainty ap- RA or psoriasis have not worked in AxSpA, highlighting the praisal. Ann Rheum Dis. 2009;68(6):770–6. point that although there may be some pathophysiologic sim- 6.• Rudwaleit M, van der Heijde D, Landewe R, et al. The develop- ilarities between these diseases, that AxSpA is its own unique ment of Assessment of Spondylo Arthritis International Society classification criteria for axial spondyloarthritis (part II): validation disease requiring placebo-controlled trials to establish drug and final selection. Ann Rheum Dis. 2009;68(6):777–83 These efficacy. As clinicians become more educated about the im- two papers describe the axial spondyloarthritis classification portance of quantifying disease activity and aiming for a target criteria—the study design and conduct of the study upon which of remission or low disease activity, i.e., “treat to target”,we the criteria is based and the final criteria. 7.• Rudwaleit M, van der Heijde D, Landewe R, et al. The Assessment anticipate better outcomes for patients as this treatment para- of Spondylo Arthritis International Society classification criteria for digm is pursued. Other treatment strategies being investigated peripheral spondyloarthritis and for spondyloarthritis in general. including treatment taper or discontinuation in patients who Ann Rheum Dis. 2011;70(1):25–31 These two papers describe — have attained sustained remission; trials to date support the the axial spondyloarthritis classification criteria the study de- sign and conduct of the study upon which the criteria is based ability to taper medicine dose or dose frequency. In discontin- and the final criteria. uation trials, return of disease after a period of time reveals that 8.• van der Heijde D, Ramiro S, Landewe R, et al. 2016 update of the we have not achieved ability to “cure” AxSpA. That goal ASAS-EULAR management recommendations for axial – awaits future therapy approaches. spondyloarthritis. Ann Rheum Dis. 2017;76(6):978 91 This paper summarizes the most recent ASAS-EULAR treatment recom- mendations for AxSpA. Compliance with Ethical Standards 9.• Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/ Conflict of Interest Dr. Mease reports grants and personal fees from Spondyloarthritis Research and Treatment Network 2015 recom- AbbVie, grants and personal fees from Amgen, grants and personal fees mendations for the treatment of ankylosing spondylitis and from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, nonradiographic Axial spondyloarthritis. Arthritis Rheum. grants and personal fees from Celgene, personal fees from Galapagos, 2016;68(2):282–98 This paper summarizes the ACR-SAA- personal fees from Genentech, personal fees from Gilead, grants and SPARTAN treatment recommendations for AxSpA. personal fees from Janssen, grants and personal fees from Lilly, grants 10. Dorner T, Strand V, Cornes P, et al. The changing landscape of and personal fees from Novartis, grants and personal fees from Pfizer, biosimilars in rheumatology. Ann Rheum Dis. 2016;75(6):974–82. grants and personal fees from Sun, grants and personal fees from UCB, 11. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper during the conduct of the study. T cells. N Engl J Med. 2009;361(9):888–98. 12.•• Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 Human and Animal Rights and Informed Consent This article does not cell pathway in the treatment of psoriatic arthritis and psoriasis. – contain any studies with human or animal subjects performed by any of Curr Opin Rheumatol. 2015;27(2):127 33 This paper reviews the authors. the IL-17/IL-23/TH17 cell pathway which is of critical impor- tance in the pathophysiology of AxSpA, psoriasis, and psoriatic arthritis. 13. Appel H, Maier R, Wu P, et al. Analysis of IL-17(+) cells in facet References joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17- mediated adaptive immune response. Arthritis Res Ther. Papers of particular interest, published recently, have been 2011;13(3):R95. highlighted as: 14. Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of • peripheral blood Th17 cells in ankylosing spondylitis and rheuma- Of importance – •• toid arthritis. Arthritis Rheum. 2009;60(6):1647 56. Of major importance 15. Zhang L, Li YG, Li YH, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with anky- 1. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic losing spondylitis and rheumatoid arthritis. PLoS One. 2012;7(4): criteria for ankylosing spondylitis. A proposal for modification of e31000. the New York criteria. Arthritis Rheum. 1984;27(4):361–8. 16. Bowness P, Ridley A, Shaw J, et al. 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