Axial Spondyloarthritis and Ankylosing Spondylitis
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…
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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 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.
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.
