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Ankylosing Spondylitis

Axial Spondyloarthritis and Ankylosing Spondylitis

Muhammad Asim Kahn, MD, FRCP, MACP; Nurullah Akkoç, MD 
Reviewed on July 15, 2024
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Introduction

This module deals with axial spondyloarthritis (axSpA) that encompasses ankylosing spondylitis (AS) and spondylitic disease without radiographic evidence of sacroiliitis that is currently termed non-radiographic axSpA (nr-axSpA). Together they form the predominantly axial subgroup of spondyloarthritis (SpA), whereas psoriatic arthritis (PsA), enteropathic arthritis (associated with Crohn’s disease [CD] and ulcerative colitis [UC]), reactive arthritis and undifferentiated SpA form the predominantly peripheral subgroup of SpA (Figure 1-1). These diseases show a strong association with HLA-B27, but the strength of this association varies among these various forms and among some of the racial/ethnic groups worldwide.

For many years, AS/axSpA was considered to be a predominantly male disease but a relatively recent study from Switzerland, shows that the male to female ratio has declined from 2.57:1 in 1980 to 1.03:1 by the end of 2016. Although the age of onset of AS is…

Introduction

This module deals with axial spondyloarthritis (axSpA) that encompasses ankylosing spondylitis (AS) and spondylitic disease without radiographic evidence of sacroiliitis that is currently termed non-radiographic axSpA (nr-axSpA). Together they form the predominantly axial subgroup of spondyloarthritis (SpA), whereas psoriatic arthritis (PsA), enteropathic arthritis (associated with Crohn’s disease [CD] and ulcerative colitis [UC]), reactive arthritis and undifferentiated SpA form the predominantly peripheral subgroup of SpA (Figure 1-1). These diseases show a strong association with HLA-B27, but the strength of this association varies among these various forms and among some of the racial/ethnic groups worldwide.

For many years, AS/axSpA was considered to be a predominantly male disease but a relatively recent study from Switzerland, shows that the male to female ratio has declined from 2.57:1 in 1980 to 1.03:1 by the end of 2016. Although the age of onset of AS is similar, women have a significantly longer delay in diagnosis and a significantly lower tumor necrosis factor inhibitor (TNFi) efficacy and drug survival. Men show a little stronger association with HLA-B27 and a higher radiographic progression, but the disease burden is similar between males and females.

AS is the prototypic form of SpA with potentially most severe outcome and is characterized by predominantly axial skeletal symptoms and radiographic evidence of sacroiliitis, as defined by the modified New York (mNY). For practical purposes it has been also called radiographic axSpA (r-axSpA), as discussed in Presentation and Diagnosis. The typical sites of inflammation are the entheses and “synovio-entheseal complex” where ligaments and tendons insert into bone and form sites of high biomechanical stress. This is also accompanied by reactive osteitis, periostitis and osteoproliferation. The wide spectrum of musculoskeletal features is shown in Figure 1-2, and axSpA also may be accompanied by many extraskeletal manifestations, the commonest of them being acute anterior uveitis, and co-morbid conditions (Figure 7-1). Figure 1-3 shows the wide clinical spectrum of axSpA.

The key pathological element is enthesitis, but sacroiliitis is the main diagnostic feature of AS/axSpA. Diagnostic criteria for spondylitic disease that encompasses AS were proposed in 1987 but they have not as yet been validated (Table 11-2). In the absence of any validated diagnostic criteria, clinicians sometimes inappropriately use the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axSpA for diagnosis, and this is unfortunately perpetuated in part by the statement in the abstract of the original paper describing the final selection of these criteria that they “may help rheumatologists in clinical practice in diagnosing axSpA in those with chronic back pain.” The diagnostic approach in clinical practice is aimed at the estimation of the probability of a suspected disease based on the patient’s clinical history, physical examination, investigations and the exclusion of alternative explanations that are not included in the ASAS classification criteria.

There is still 3 to 10 years (mean 6 years) delay between onset of axSpA and its final diagnosis, and as discussed in Presentation and Diagnosis, it is hoped that advances in our understanding of its biology via novel imaging, genetic and biomarker studies will probably enable the resolution of many current issues and facilitate early diagnosis that is sorely needed now that there has been substantial progress made in its treatment. However, when compared with rheumatoid arthritis (RA), the treatment options for AS/axSpA are relatively limited, although the choices are expected to increase. A set of recommendations for the treatment of AS and nr-axSpA, developed as a joint effort by the American College of Rheumatology (ACR), the Spondylitis Association of America (SAA) and the Spondyloarthritis Research and Treatment Network (SPARTAN), has recently been updated.

The strong genetic association of AS with HLA-B27 has been known for 48 years, and by now more than 100 additional disease predisposing genetic loci have been discovered, and some of them are shared between AS, UC and CD. Intestinal inflammation, observed in >60% of patients with AS, intestinal microbial dysbiosis and Th17 immunity are all linked to the pathophysiology of this disease, and the gut inflammation is characterized by an overexpression of IL-23 and possibly other cytokines that regulate lamina propria NKp44(+) natural killer (NK) cells that appear to play a tissue-protective role.

A truly remarkable study was published by Sherlock and associates in 2012 (discussed in Etiology), the results of which were well summarized in a figure by Lories and McInnes (Figure 4-10) that demonstrated that an excess of IL-23 is sufficient in generating specific prototypic SpA manifestations because mice injected with IL-23 genetic mini-circles (to overexpress IL-23) develop enthesitis and subsequently arthritis (including sacroiliitis), osteoproliferation, psoriasis and inflammation of the aortic root. Expression of inflammatory genes (e.g., TNF-α, IL-6, chemokines and matrix metalloproteinases) was observed in the inflamed paws, but tumor necrosis factor (TNF) blockers did not inhibit development of this IL-23–mediated disease. Inflammation occurred independently of the classic CD4+ Th17 cells. Rather, IL23R+RORyt+ CD4-CD8- innate lymphoid-like T cells were found to be residing in both the entheses and the aortic root. Remarkably, treatment of these mice with anti-IL-17 or anti-IL-22 ameliorated enthesitis and arthritis, but it was most effective when given in combination. IL-23 and Th17 signature cytokines (IL-17 and IL-22) thus provide another link between mucosal and joint immunity. IL-23 and IL-17 expression has been reported to be upregulated in the gut, peripheral blood and synovium of SpA patients. IL-23 mediates inflammatory process through IL-17 and TNF, while IL-22 predisposes to new bone formation. Recently, a novel pathogenetic model has been proposed which postulated that changes in the local metabolic environment (pH, salt) may play a key role in the development of AS by induction of a Th17 pro-inflammatory phenotype through activation of glycosphingolipid sensors (encoded by the GPR genes – in particularly GPR65) and serum and glucocorticoid-regulated kinase-1 (SGK1) (Figure 4-11).

Anti-IL-12/23 P40 monoclonal antibody, ustekinumab, has been approved for the treatment for psoriasis and PsA. and IL-17 inhibitors (IL-17is) secukinumab and ixekizumab have now been approved by both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of psoriasis, PsA, and AS. This module covers the FDA approved certolizumab pegol, secukinumab, and ixekizumab to treat nr-axSpA, based on the studies conducted using designs addressing the key concerns raised by the FDA in the past, after reviewing the initial application files of adalimumab and certolizumab submitted for approval for the indication of nr-axSpA.

Janus kinase inhibitors (JAKis) have been used for the treatment of RA as the latest drug class of disease-modifying category. This class of drugs are now emerging as new potential therapeutics for AS, after the successful results obtained in phase 2 and phase 3 trials of tofacitinib (pan-JAK inhibitor), upadacitinib (selective JAK1 inhibitor) and filgotinib (selective JAK1 inhibitor) in AS. Their efficacy appears to be comparable to each other as well as to the available biologics drugs, which unfortunately loose efficacy or fail in a considerable number of patients with AS. Upadacitinib has just been approved in the European Union (EU) countries for the treatment of adults patients with active AS (who have responded inadequately to conventional therapy) and active PsA (who had inadequate response or are intolerant to one or more disease-modifying antirheumatic drug (DMARDs)). It is hoped that JAKis can address some of the unmet need in the treatment of such patients, if the recent safety concerns raised by the FDA regarding the increased cardiovascular and cancer adverse events associated with tofacitinib relative to TNF inhibitors observed in RA patients can be resolved. Drug maker of filgotinib has paused the two ongoing phase 3 trials for AS upon the request of additional safety data by the FDA regarding the testicular toxicity of the drug in RA trials.

Enlarge  Figure 1-1: Components of Spondyloarthritis. AAU, acute anterior uvelitis, AI+HB, aortic incompetence plus heart block. The various forms of SpA are divided into predominantly axial and predominantly peripheral forms. Source: Ozgocmen S, Khan MA. Curr Rheumatol Rep. 2012; 14(5):409-414.
Figure 1-1: Components of Spondyloarthritis. AAU, acute anterior uvelitis, AI+HB, aortic incompetence plus heart block. The various forms of SpA are divided into predominantly axial and predominantly peripheral forms. Source: Ozgocmen S, Khan MA. Curr Rheumatol Rep. 2012; 14(5):409-414.
Enlarge  Figure 1-2: Synovio-Entheseal Complex Involvement and Resultant Clinical and Pathological Features of SpA. Source: Khan MA. In: Axial Spondyloarthritis. Mease P, Khan MA eds, Elsevier. 2020.
Figure 1-2: Synovio-Entheseal Complex Involvement and Resultant Clinical and Pathological Features of SpA. Source: Khan MA. In: Axial Spondyloarthritis. Mease P, Khan MA eds, Elsevier. 2020.
Enlarge  Figure 1-3: The Concept of axSpA. This figure schematically shows a unifying concept of axSpA that has a wide clinical spectrum. Inflammatory back pain is the leading symptom that may be present throughout the disease course without any occurrence of structural damage. As further explained in the text, the decreasing sizes of the three chevrons from the left to the right of this figure are meant to emphasize that only a portion of patients with nr‐axSpA will progress to r‐axSpA/AS, whereas others may remain as nr‐axSpA, perhaps forever or have a self‐limiting disease course. This figure also shows that not all patients with radiographic sacroiliitis progress to form syndesmophytes with resulting spinal ankylosis. Source: Khan MA, van der Linden S. ACR Open Rheumatol. 2019;1(5):336-339.
Figure 1-3: The Concept of axSpA. This figure schematically shows a unifying concept of axSpA that has a wide clinical spectrum. Inflammatory back pain is the leading symptom that may be present throughout the disease course without any occurrence of structural damage. As further explained in the text, the decreasing sizes of the three chevrons from the left to the right of this figure are meant to emphasize that only a portion of patients with nr‐axSpA will progress to r‐axSpA/AS, whereas others may remain as nr‐axSpA, perhaps forever or have a self‐limiting disease course. This figure also shows that not all patients with radiographic sacroiliitis progress to form syndesmophytes with resulting spinal ankylosis. Source: Khan MA, van der Linden S. ACR Open Rheumatol. 2019;1(5):336-339.
Enlarge  Figure 7-1: Extra-articular Manifestations/Comorbidities. Source: Khan MA. In: Hochberg M, et al, eds. Rheumatology. 3rd ed. Edinburgh, Scotland: Mosby; 2003:1161-1170; Lautermann D, Braun J. Clin Exp Rheum. 2002;6(suppl 28):S11-S15; Smale S, et al. Arthritis Rheum. 2001;44(12):2728-2736; Rodrigues CE, et al. Rev Bras Rheumatol. 2012;52(3):379-383; Solak O, et al. Rheumatology (Oxford). 2009;48(4):433-435; El Maghraoui A. Eur J Intern Med. 2011;22(6):554-560; Jacquet A, et al. Nephrol Dial Transplant. 2009;24(11):3540-3542; Ben Taarit C, et al. Rev Med Interne. 2005;26(12):966-969.
Figure 7-1: Extra-articular Manifestations/Comorbidities. Source: Khan MA. In: Hochberg M, et al, eds. Rheumatology. 3rd ed. Edinburgh, Scotland: Mosby; 2003:1161-1170; Lautermann D, Braun J. Clin Exp Rheum. 2002;6(suppl 28):S11-S15; Smale S, et al. Arthritis Rheum. 2001;44(12):2728-2736; Rodrigues CE, et al. Rev Bras Rheumatol. 2012;52(3):379-383; Solak O, et al. Rheumatology (Oxford). 2009;48(4):433-435; El Maghraoui A. Eur J Intern Med. 2011;22(6):554-560; Jacquet A, et al. Nephrol Dial Transplant. 2009;24(11):3540-3542; Ben Taarit C, et al. Rev Med Interne. 2005;26(12):966-969.
Enlarge 
Enlarge  Figure 4-10: Enthesitis and Sequence of Events in AS. The typical sites of inflammation are at the entheses (regions of high biomechanical stress where ligaments and tendons insert into bone) and at the adjacent subchondral bone marrow (osteitis). There is also reactive osteoproliferation that can ultimately progress to ankylosis at the involved sites. It shows speculation about links between the metabolic environment and T-cell plasticity. Existing or potential drug targets are indicated with a syringe symbol next to them. Source: Voruganti A, et al. Immunology. 2020;161(2):94-102.
Figure 4-10: Enthesitis and Sequence of Events in AS. The typical sites of inflammation are at the entheses (regions of high biomechanical stress where ligaments and tendons insert into bone) and at the adjacent subchondral bone marrow (osteitis). There is also reactive osteoproliferation that can ultimately progress to ankylosis at the involved sites. It shows speculation about links between the metabolic environment and T-cell plasticity. Existing or potential drug targets are indicated with a syringe symbol next to them. Source: Voruganti A, et al. Immunology. 2020;161(2):94-102.
Enlarge  Figure 4-11: The Enthesitis and Sequence of Events in AS. The typical sites of inflammation are at the entheses (regions of high biomechanical stress where ligaments and tendons insert into bone) and at the adjacent subchondral bone marrow (osteitis). There is also reactive osteoproliferation that can ultimately progress to ankylosis at the involved sites.
Figure 4-11: The Enthesitis and Sequence of Events in AS. The typical sites of inflammation are at the entheses (regions of high biomechanical stress where ligaments and tendons insert into bone) and at the adjacent subchondral bone marrow (osteitis). There is also reactive osteoproliferation that can ultimately progress to ankylosis at the involved sites.
 

References

  • Kahn MA, Akkoç N. Ankylosing Spondylitis— Axial Spondyloarthritis, 3rd ed. Professional Communications Inc. 2023
  • Baumberger H, Khan M. SAT0417 Gradual progressive change to equal prevalence of ankylosing spondylitis among males and females in switzerland: data from the swiss ankylosing spondylitis society (SVMB). Ann Rheum Dis. 2017;76(suppl 2):929-929.
  • Berlinberg AJ, Regner EH, Stahly A, et al. Multi ‘Omics analysis of intestinal tissue in ankylosing spondylitis identifies alterations in the tryptophan metabolism pathway. Frontiers Immunol. 2021;12.
  • Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol. 2016;12(2):81-91.
  • Cats A, Van der Linden SJ, Goei The HS, Khan MA. Proposals for diagnostic criteria of ankylosing spondylitis and allied disorders. Clin Exp Rheumatol. 1987;5(2):167-171.
  • Ciccia F, Guggino G, Rizzo A et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann Rheum Dis. 2015;74(9):1739-1747.
  • Cimzia [package insert]. US Food and Drug Administration Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125160s237lbl.pdf. Published March, 2019. Accessed May 24, 2021.
  • Cosentyx [package insert]. US Food and Drug Administration Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125504s035lbl.pdf. Published June, 2020. Accessed May 24, 2021.
  • Cosentyx [summary of product characteristics]. European Medicines Agency Web site. https://www.ema.europa.eu/en/documents/product-information/cosentyx-epar-product-information_en.pdf. Published March 25, 2021. Accessed May 24, 2021.
  • Deodhar A, Blanco R, Dokoupilova E et al. Improvement of signs and symptoms of nonradiographic axial spondyloarthritis in patients treated with secukinumab: primary results of a randomized, placebo-controlled phase III study. Arthritis Rheumatol. 2021;73(1):110-120.
  • Deodhar A, Gensler LS, Kay J et al. A fifty-two-week, randomized, placebo-controlled trial of certolizumab pegol in nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2019;71(7):1101-1111.
  • Deodhar A, Sliwinska-Stanczyk P, Xu H, et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2021.doi: 10.1136/annrheumdis-2020-219601.
  • Deodhar A, van der Heijde D, Gensler LS, et al. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64.
  • Ellinghaus D, Jostins L, Spain SL et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48(5):510-518.
  • FDA Drug Safety Communication. Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate (Xeljanz, Xeljanz XR). US Food and Drug Administration. www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. Accessed March 23, 2021.
  • Khan MA, van der Linden S. Axial spondyloarthritis: a better name for an old disease: a step toward uniform reporting. ACR Open Rheumatol. 2019;1(5):336-339.
  • Khan MA, van der Linden SM, Kushner I, Valkenburg HA, Cats A. Spondylitic disease without radiologic evidence of sacroiliitis in relatives of HLA-B27 positive ankylosing spondylitis patients. Arthritis Rheum. 1985;28(1):40-43.
  • Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012;18(7):1018-1019.
  • McGonagle D, Aydin SZ, Tan AL. The synovio-entheseal complex and its role in tendon and capsular associated inflammation. J Rheumatol. 2012;89(suppl):11-14.
  • Mease P, Khan MA, eds. Axial Spondyloarthritis, 1st ed. St. Louis, MO: Elsevier; 2020:1-294
  • Rinvoq [summary of product characteristics]. European Medicines Agency Website. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf. Published February 3, 2021. Accessed May 24, 2021.
  • Robinson PC, van der Linden S, Khan MA, Taylor WJ. Axial spondyloarthritis: concept, construct, classification and implication for therapy. Nat Rev Rheumatol. 2021;17(2):109-118.
  • Rudwaleit M, van der Heijde D, Landewe 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(6):777-783.
  • Rusman T, van Bentum RE, van der Horst-Bruinsma IE. Sex and gender differences in axial spondyloarthritis: myths and truths. Rheumatology (Oxford). 2020;59(suppl 4):iv38-iv46.
  • Sherlock JP, Joyce-Shaikh B, Turner SP et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069-1076.
  • Sherlock JP, Taylor PC, Buckley CD, Cua DJ. Spondyloarthropathy: interleukin 23 and disease modification. Lancet. 2015;385(9982):2017-2018.
  • Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390 (10089):73-84.
  • Stelara [package insert]. US Food and Drug Administration Web site.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125261s154,761044s006lbl.pdf. Published December, 2020. Accessed May 24, 2021.
  • Stelara [summary of product characteristics]. European Medicines Agency Web site. https://www.ema.europa.eu/en/documents/product-information/stelara-epar-product-information_en.pdf. Published May 4, 2021. Accessed May 24, 2021.
  • Taltz [package insert]. US Food and Drug Administration Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125521s014lbl.pdf. Published March, 2021. Accessed May 24, 2021.
  • Taltz [summary of product characteristics]. European Medicines Agency Web site. https://www.ema.europa.eu/en/documents/product-information/taltz-epar-product-information_en.pdf. Published February 26, 2021. Accessed May 24, 2021.
  • Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374(26):2563-2574.
  • US Food and Drug Administration. Hong C, Neogi T. Summary minutes of the Arthritis Advisory Committee Meeting, July 23, 2013.
  • van der Heijde D, Baraliakos X, Gensler LS et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial. Lancet. 2018;392(10162):2378-2387.
  • van der Heijde D, Song I-H, Pangan AL et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019;394(10214):2108-2117.
  • Voruganti A, Bowness P. New developments in our understanding of ankylosing spondylitis pathogenesis. Immunology. 2020;161(2):94-102.
  • Ward MM, Deodhar A, Gensler LS et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599-1613.
  • Wordsworth BP, Cohen CJ, Vecellio M. Quantifying the genetic risk for the development of axial spondyloarthropathy: could this become a diagnostic tool? Curr Opin Rheumatol. 2018;30(4):319-323.
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