The major breakthrough in the treatment of ankylosing spondylitis (AS) came in 2003 with the approval of the first two TNF inhibitors (TNFi) [1]. Since then, three additional TNFi have been approved for the treatment of AS, but biologics with different mechanisms of action (e.g., anakinra, abatacept, tocilizumab) were found to be not efficacious in these patients [2]. In 2009, the Assessment of SpondyloArthritis International Society (ASAS) redefined the spectrum of axial inflammatory diseases by developing classification criteria for axial spondyloarthritis (axSpA), an umbrella term that includes AS and non-radiographic axSpA (nr-axSpA) [3]. Only a few trials since the reclassification have included subjects from the entire spectrum of axSpA or those with nr-axSpA [4–6].
Despite these advances, pharmaceutical interventions for axSpA are quite limited compared with other chronic inflammatory diseases such as rheumatoid arthritis (RA). Some major unresolved questions and possible challenges for future studies in the treatment of axSpA are shown in Table 1.
We use anti-inflammatory therapies, but are they symptom- or structure-modifying?
Although there are hardly any studies on the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in nr-axSpA, these agents are recommended and routinely used as the first-line treatment for pain and stiffness in active, symptomatic axSpA [7]. The question of whether NSAIDs prevent osteoproliferation is still a matter of debate. The German Spondyloarthritis Inception Cohort (GESPIC) and a randomized NSAID trial showed that NSAIDs, when given in high dosages (vs. low dosage) or continuously (vs. on demand), led to a reduction in radiographic progression over 2 years in subjects with AS. This effect was most pronounced in those who presented with increased C-reactive protein (CRP) levels [8–10]. However, in the Prospective Study of Ankylosing Spondylitis (PSOAS) cohort, NSAIDs failed to show any inhibitory effect on radiographic progression in a multivariate analysis model [11]. This discrepancy in results is possibly due to a stronger and more robust TNFi effect blunting the NSAID effect on osteoproliferation in the PSOAS cohort (see below). High NSAID intake has also not been shown to have any significant effect on radiographic progression in nr-axSpA patients in the GESPIC cohort [8].
The efficacy of TNFi for clinical symptoms in patients who are not responding to NSAIDs is well established, although the effects of long-term TNFi on structure modification were shown only very recently. In 2013, two independent studies demonstrated a benefit from TNFi on radiographic progression when treatment was extended beyond 4 years. In a comparison of a TNFi trial with long-term follow-up vs. a historical cohort [12], and in a careful follow-up of a well-characterized subgroup in the PSOAS cohort [11], subjects on TNFi showed decreased rates of spinal radiographic progression compared to those treated with NSAIDs, but only after 4 years.
Osteoproliferation in axSpA occurs slowly; hence, “structure modification” studies need to be longer than 2 years’ duration. Studies described above serve as a template for future investigations on osteoproliferation prevention. Long-term placebo-controlled prospective studies on any agent are unlikely to be done due to the economic (large number of subjects to be followed for several years) and ethical (placebo-administered controls) considerations. We also do not know whether treatment with either NSAIDs or TNFi, if prescribed at an early disease stage, is able to prevent progression of nr-axSpA to AS, or if the combination of NSAIDs and TNFi leads to even better radiographic outcomes.
Data on conventional disease-modifying anti-rheumatic drugs (DMARDs) in the management of AS are limited, and there are only a couple of studies in subjects with nr-axSpA. Sulfasalazine is the only DMARD to show some efficacy for the peripheral manifestations of AS [13]. However, it does not appear to have an effect on early spinal manifestations of SpA. A placebo-controlled trial in patients with inflammatory back pain due to undifferentiated SpA and early AS showed that sulfasalazine was no better than placebo for the treatment of the signs and symptoms of undifferentiated SpA [14]. Methotrexate is the most commonly used DMARD in RA, but it has not been found effective in a few small AS trials at doses ranging from 7.5 to 20 mg/week [15, 16] (doses used in RA) and there are no large, placebo-controlled trials of this agent either in AS or axSpA. Regardless, methotrexate is widely used for axSpA in many parts of the world [17], which suggests patients may draw some benefits from it. Pamidronate, a bisphosphonate with both anti-osteoclastic and anti-inflammatory properties [18], has demonstrated clinical efficacy in AS [19], but not in nr-axSpA or in TNFi-refractory AS. In a small, open-label, short-term trial of another bisphosphonate, neridronate was found to be equally effective as infliximab in reducing disease symptoms in AS [20].
In the absence of well-designed studies, DMARDs remain undervalued in the management of axSpA and are likely to remain so as there is little economic incentive for such studies to be conducted.
New agents with different mechanisms of action are currently in clinical evaluation in AS. Apremilast is a small-molecule inhibitor of phosphodiesterase 4, which modulates pro-inflammatory and anti-inflammatory mediator production. Secukinumab is a fully human anti–interleukin (IL)-17A monoclonal antibody. Increasing evidence suggests that IL-17A is involved in AS pathogenesis [21] and may be a mediator of joint destruction in animal models of arthritis [22]. In a recent mouse model of SpA, IL-23 and entheseal-resident T cells were found to promote enthesitis and bone remodeling through IL-17 and IL-22 [23]. Both apremilast and secukinumab are being tested in phase III clinical trials for AS (but not nr-axSpA). Ustekinumab, a fully human monoclonal antibody that inhibits the IL-12/23 pathway, very recently showed reduction of clinical and imaging signs and symptoms in a small open-label proof-of-concept study of subjects with active AS [24]. Because of the commercial potential of these new agents, we are likely to learn more about their efficacy than the efficacy of DMARDs and NSAIDs in the treatment of axSpA.
Biosimilars—is interchangeability justified in axSpA?
With health care costs skyrocketing, there is a huge unmet need for less-expensive biologic therapies. Biosimilars, expected to have similar quality, safety, and efficacy, but lower cost to reference biologics, may provide a window of opportunity to alleviate economic pressures.
Data from the first studies with biosimilars have been published very recently for both AS and RA, and both studies met their primary endpoints, demonstrating similar clinical responses as the innovator biologic infliximab [25, 26]. Neither long-term safety data nor convincing radiographic data in either disease have been provided so far. Nevertheless, based on the early data, the Korean Ministry of Food and Drug Safety and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) not only recommended this particular biosimilar for the treatment of both AS and RA but also extrapolated these results for approval in other diseases like ulcerative colitis, Crohn’s disease, and psoriasis [27]. Whether approval will be extended to nr-axSpA and whether the efficacy and safety data of biosimilars will be comparable to those of innovator biologics in the long term will have to be shown in the future.
What is the optimum dose of therapies we currently use and can they be withdrawn after patients reach remission?
Non-pharmacological treatment options for AS center around patient education and physical therapy (PT) [2], based on expert opinion and decades of collective experience. While the nature of these interventions prevents double-blind, placebo-controlled studies, the available clinical trials of physical therapy in AS are not standardized and mostly not well designed. There are very few comparative studies on the efficacy of well-defined physiotherapy interventions and those that exist lack adequate information on exercise frequency (or the “dose” of physical therapy) [28, 29].
Is additional physiotherapy even required in an axSpA patient whose disease is well-controlled on pharmacotherapy? In one study in AS subjects, physical rehabilitation added to existing TNFi therapy improved all clinically relevant outcomes [30]. In clinical practice, our experience shows that adherence to exercise dwindles in most patients after they start TNFi. If exercises add substantial value over and above the new pharmacotherapy, we need more evidence to convince our patients.
As noted earlier, there is little evidence for the efficacy of DMARDs in AS. An unexplored possibility is that DMARD doses higher than those conventionally used in RA might work in axSpA. The use of higher dose DMARDs in combination with TNFi in TNFi-inadequate responders is another area that will be economically prohibitive to investigate, considering the large number of subjects required and the possible toxicity of the compounds used in such a scenario.
While the efficacy of TNFi for the treatment of active AS is well established, the optimal dose and frequency of administration of TNFi in AS is not known. In the past, TNFi trials in AS generally evaluated a single dose, mostly the same dose used in RA trials. Most non-responders to a conventional infliximab regimen did respond to dose escalation in one study [31], similar to the clinical experience of practicing rheumatologists. Recent studies of TNFi have evaluated the differences in efficacy of different doses (golimumab and etanercept) or dosing intervals (certolizumab) in patients with axSpA, but the findings were negative [5, 32, 33]. Dose de-escalation of TNFi in patients who are in remission would have important economic implications. A recent small study of etanercept in AS showed that remission appeared to be maintained in most patients after halving of the dose [34]. Large TNFi dose titration studies (up and down) based on clinical symptoms would mimic a real-life scenario, but such data are most likely to be generated from cohort studies rather than in the setting of a controlled trial.
It has been shown that disease activity returns within months if long-term TNFi therapy is discontinued in patients with established AS [35]. However, in patients with early, active axSpA, the INFAST study showed the encouraging result that partial remission could be maintained in almost half of the patients at 6 months after stopping the treatment (infliximab/placebo+naproxen); improvements in several less-stringent measures of disease activity were generally maintained with very few patients experiencing disease flares [36]. Whether this low level of disease activity could be maintained beyond 6 months has not been studied. Nevertheless, these results suggest that drug-free remission in axSpA might become an achievable goal with early and aggressive treatment.
Which patients are appropriate for the different therapies?
Not all patients improve and many experience significant side effects after using NSAIDs, such as exacerbation of inflammatory bowel disease or increased risk of myocardial infarction [37, 38]. Consequently, a risk–benefit analysis of the long-term use of NSAIDs in axSpA is essential, but has not been studied so far in a controlled manner in clinical registries.
Predictive factors such as genetic markers, serum biomarkers, or advanced imaging are not yet sophisticated enough to identify “pre-AS” patients within the nr-axSpA population who will develop structural changes as defined by the modified New York criteria for AS (Fig. 1) [3]. As we do not know definitively if any of the available therapies will be able to prevent the progression of nr-axSpA to AS, this is only of theoretical interest currently. Predictors of response to TNFi therapy in AS have been identified; a model combining age, HLA-B27 genotype, CRP level, and functional status and presence of enthesitis at baseline appears to predict the outcomes of TNFi therapy [39]. However, pharmacogenomic data regarding genetic factors (other than HLA-B27) that predict the most efficacious and least toxic therapy for individual patients (true “personalized medicine”) remain elusive. As the economic value of treatment becomes increasingly important to payers, progress in the field of personalized medicine with stress on pharmaco-economics is likely to make inroads in this area.
Do the approved therapies prevent long-term complications associated with axSpA?
The effects of TNFi on important long-term complications associated with axSpA (e.g., amyloidosis, pulmonary apical fibrosis, cauda equina syndrome, aortic valve disease), long-term work productivity, disability, and mortality remain to be investigated. The effect of TNFi on malignancy risk in patients with RA is controversial and not adequately studied in patients with AS [40]. In a recent long-term safety analysis, adalimumab was not associated with significantly higher risk of total malignancy, lymphoma, melanoma, or non-melanoma skin cancer in the subset of 1,684 AS patients compared with the age- and sex-matched general population [41]. Patient registry data can better define this risk in AS patients in comparison to the general population and determine whether TNFi use influences these risks. AS patients in everyday clinical practice usually have more comorbidities than those in clinical trials. Registry data will therefore also capture the risks associated with treatment in real-world settings.
What is the role of MRI in monitoring disease progression?
Inflammatory activity in the sacroiliac joints or the spine, as shown by MRI, precedes structural changes and can be related to osteoproliferation in axSpA [42]. In AS, the degree of spinal inflammation can predict the efficacy of TNFi [43]. TNFi, but not NSAID [44], treatment significantly decreases inflammation in nr-axSpA [45] and AS [46]. In addition, it is becoming increasingly clear that not only inflammation but also its combination with fatty lesions are significantly related to future syndesmophyte progression [47]. The role of MRI is therefore considered especially important in this regard because it is the only imaging modality that can depict both abnormalities, either alone or in combination [47]. The use of MRI beyond the diagnosis and prediction of disease course or treatment response, such as to monitor patients treated with TNFi, remains unexplored. There is also no guidance on how to proceed when a disparity occurs between treatment response (i.e., improved signs and symptoms) and MRI findings (i.e., ongoing inflammatory activity). Long-term follow-up studies with serial MRI examinations are necessary to answer these questions, but the economic cost may prevent such studies from being performed.
Conclusion
Current treatment strategies for axSpA are based on studies predominantly conducted in AS, and few data exist for nr-axSpA and advanced AS. NSAIDs and TNFi are effective in reducing the signs and symptoms of axSpA, but evidence is lacking regarding the effect of anti-inflammatory treatment on the progression of nr-axSpA to AS. The data on inhibition of radiographic progression in patients with established AS is emerging for NSAIDs as well as for TNFi. There is insufficient data on a possible additional effect of physiotherapy or the use of conventional DMARDs at any disease stage. Several investigational agents are in late-stage evaluation and, if shown to be safe and effective, will face many of the same questions raised about existing therapies.
References
Braun J, Pham T, Sieper J et al (2003) International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis 62:817–824
Kiltz U, Heldmann F, Baraliakos X, Brown J (2012) Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives? Curr Opin Rheumatol 24:252–260
Rudwaleit M, van der Heijde D, Landewé R et al (2009) The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 68:777–783
Sieper J, van der Heijde D, Dougados M et al (2013) Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 72:815–822
Landewé R, Braun J, Deodhar A et al (2014) Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled phase 3 study. Ann Rheum Dis 73:39–47
Dougados M, van der Heijde D, Sieper J, et al (2014) The symptomatic efficacy and effect on objective signs of inflammation of etanercept in early nonradiographic axial spondyloarthritis. Arthritis Rheum. doi:10.1002/art.38721
Braun J, van den Berg R, Baraliakos X et al (2011) 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 70:896–904
Poddubnyy D, Rudwaleit M, Haibel H et al (2012) Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis 71:1616–1622
Kroon F, Landewé R, Dougados M, van der Heijde D (2012) Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis 71:1623–1629
Wanders A, Heijde DV, Landewé R et al (2005) Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum 52:1756–1765
Haroon N, Inman RD, Learch TJ et al (2013) The impact of tumor necrosis factor α inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum 65:2645–2654
Baraliakos X, Haibel H, Listing J, Sieper J, Braun J (2014) Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis 73:710–715
Clegg DO, Reda DJ, Abdellatif M (1999) Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum 42:2325–2329
Braun J, Zochling J, Baraliakos X et al (2006) Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial. Ann Rheum Dis 65:1147–1153
Chen J, Liu C, Lin J (2006) Methotrexate for ankylosing spondylitis. Cochrane Database Syst Rev 4:CD004524
Haibel H, Brandt HC, Song IH et al (2007) No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann Rheum Dis 66:419–421
Soriano ER, Clegg DO, Lisse JR (2012) Critical appraisal of the guidelines for the management of ankylosing spondylitis: disease-modifying antirheumatic drugs. Am J Med Sci 343:357–359
Toussirot E, Wendling D (2007) Antiinflammatory treatment with bisphosphonates in ankylosing spondylitis. Curr Opin Rheumatol 19:340–345
Maksymowych WP, Jhangri GS, Fitzgerald AA et al (2002) A six-month randomized, controlled, double-blind, dose-response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 46:766–773
Viapiana O, Gatti D, Idolazzi L et al (2014) Bisphosphonates vs infliximab in ankylosing spondylitis treatment. Rheumatology (Oxford) 53:90–94
Noordenbos T, Yeremenko N, Gofita I et al (2012) Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 64:99–109
Daoussis D, Andonopoulos AP, Liossis SN (2010) Wnt pathway and IL-17: novel regulators of joint remodeling in rheumatic diseases. Looking beyond the RANK-RANKL-OPG axis. Semin Arthritis Rheum 39:369–383
Sherlock JP, Joyce-Shaikh B, Turner SP et al (2012) IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nat Med 18:1069–1076
Poddubnyy D, Hermann KG, Callhoff J, Listing J, Sieper J (2014) Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis 73:817–823
Yoo DH, Hrycaj P, Miranda P et al (2013) A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 72:1613–1620
Park W, Hrycaj P, Jeka S et al (2013) A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 72:1605–1612
Lee H (2014) Is extrapolation of the safety and efficacy data in one indication to another appropriate for biosimilars? AAPS J 16:22–26
Valle-Onate R, Ward MM, Kerr GS (2012) Physical therapy and surgery. Am J Med Sci 343:353–356
Dagfinrud H, Halvorsen S, Vøllestad NK, Niedermann K, Kvien TK, Hagen KB (2011) Exercise programs in trials for patients with ankylosing spondylitis: do they really have the potential for effectiveness? Arthritis Care Res 63:597–603
Masiero S, Bonaldo L, Pigatto M, Lo Nigro A, Ramonda R, Punzi L (2011) Rehabilitation treatment in patients with ankylosing spondylitis stabilized with tumor necrosis factor inhibitor therapy: a randomized controlled trial. J Rheumatol 38:1335–1342
Inman RD, Maksymowych WP, CANDLE Study Group (2010) A double-blind, placebo-controlled trial of low dose infliximab in ankylosing spondylitis. J Rheumatol 37:1203–1210
Braun J, Baraliakos X, Hermann KG et al (2014) The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. Ann Rheum Dis 73:1107–1113
Navarro-Sarabia F, Fernández-Sueiro JL, Torre-Alonso JC et al (2011) High-dose etanercept in ankylosing spondylitis: results of a 12-week randomized, double blind, controlled multicentre study (LOADET study). Rheumatology (Oxford) 50:1828–1837
Cantini F, Niccoli L, Cassarà E, Kaloudi O, Nannini C (2013) Duration of remission after halving of the etanercept dose in patients with ankylosing spondylitis: a randomized, prospective, long-term, follow-up study. Biologics 7:1–6
Baraliakos X, Listing J, Brandt J et al (2005) Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab. Arthritis Res Ther 7:R439–R444
Sieper J, Lenaerts J, Wollenhaupt J, All INFAST Investigators, et al (2014) Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: results from a 6-month, randomised, open-label follow-up study, INFAST Part 2. Ann Rheum Dis 73:108–113
Rudwaleit M, Baeten D (2006) Ankylosing spondylitis and bowel disease. Best Pract Res Clin Rheumatol 20:451–471
Antman EM, Bennett JS, Daugherty A, American Heart Association et al (2007) Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 115:1634–1642
Vastesaeger N, van der Heijde D, Inman RD et al (2011) Predicting the outcome of ankylosing spondylitis therapy. Ann Rheum Dis 70:973–981
Keystone EC (2011) Does anti-tumor necrosis factor-α therapy affect risk of serious infection and cancer in patients with rheumatoid arthritis?: a review of longterm data. J Rheumatol 38:1552–1562
Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP (2013) Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis 72:517–524
Bennett AN, McGonagle D, O'Connor P et al (2008) Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years. Arthritis Rheum 58:3413–3418
Rudwaleit M, Schwarzlose S, Hilgert ES, Listing J, Braun J, Sieper J (2008) MRI in predicting a major clinical response to anti-tumour necrosis factor treatment in ankylosing spondylitis. Ann Rheum Dis 67:1276–1281
Jarrett SJ, Sivera F, Cawkwell LS et al (2009) MRI and clinical findings in patients with ankylosing spondylitis eligible for anti-tumour necrosis factor therapy after a short course of etoricoxib. Ann Rheum Dis 68:1466–1469
Haibel H, Rudwaleit M, Listing J et al (2008) Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 58:1981–1991
Baraliakos X, Davis J, Tsuji W, Braun J (2005) Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept. Arthritis Rheum 52:1216–1223
Baraliakos X, Heldmann F, Callhoff J et al (2013) Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography. Ann Rheum Dis. 2013 Jul 14. doi:10.1136/annrheumdis-2013-203425
Acknowledgments
The authors would like to thank Barry Weichman for assistance in drafting the manuscript and Andrew Horgan of BioScience Communications, Inc, New York, NY, for editorial assistance, activities that were supported by Novartis Pharmaceuticals. This work was supported by an unrestricted writing grant from Novartis Pharmaceuticals. No compensation was paid to the authors.
Conflict of interest
Dr. Baraliakos has received grant and research support and consultancy fees from Abbott Laboratories, Amgen, Centocor, Chugai, Merck, Novartis, Pfizer, Schering-Plough, UCB, and Wyeth. Dr. Deodhar has received grant and research support from AbbVie, Amgen, Johnson & Johnson, Novartis, and UCB, and received consultancy fees and/or speaking honoraria from AbbVie, Merck Sharp & Dohme, Novartis, Pfizer, and UCB.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baraliakos, X., Deodhar, A. Unanswered questions in the management of axial spondyloarthritis: an opinion piece. Clin Rheumatol 33, 1359–1365 (2014). https://doi.org/10.1007/s10067-014-2740-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-014-2740-x