Extra-articular manifestations (EAMs) are common, important features of axial spondyloarthritis (axial SpA) – the most prevalent being acute anterior uveitis (AAU), inflammatory bowel disease (IBD) and psoriasis. The pooled prevalence of AAU, psoriasis and IBD in axial SpA has previously been estimated at 16–23%, 10–11% and 4–6%, respectively1. Across the axial SpA spectrum (from non-radiographic axial SpA to radiographic axial SpA – radiographic axial SpA otherwise known as ankylosing spondylitis), the prevalence of EAMs is broadly similar. With the exception of AAU, which is slightly more prevalent in ankylosing spondylitis. EAMs contribute to the disease burden and add further complexity to the management of axial SpA2. However, they offer an excellent opportunity to pick up axial SpA early in secondary care specialities such as ophthalmology, gastroenterology and dermatology. Below, we summarise some of the key research publications discussing EAMs in axial SpA.
- de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18(1):196.
- Gao X, Wendling D, Botteman MF, Carter JA, Rao S, Cifaldi M. Clinical and economic burden of extra-articular manifestations in ankylosing spondylitis patients treated with anti-tumor necrosis factor agents. Journal of medical economics. 2012;15(6):1054-63.
Data from the Screening for Axial Spondyloarthritis in Psoriasis, Iritis, and Colitis (SASPIC) Study
Maksymowych WP, Carmona R, Yeung J, Chan J, Martin L, Aydin S, et al. THU0393 PERFORMANCE OF THE ASAS CLASSIFICATION CRITERIA PRESENTING WITH UNDIAGNOSED BACK PAIN? DATA FROM THE SCREENING IN AXIAL SPONDYLOARTHRITIS IN PSORIASIS, IRITIS, AND COLITIS (SASPIC) COHORT. Annals of the Rheumatic Diseases. 2019;78(Suppl 2):482-. https://ard.bmj.com/content/78/Suppl_2/482.1
Maksymowych WP, Carmona R, Yeung J, Chan J, Martin L, Aydin S, et al. SAT0339 WHAT IS THE IMPACT OF IMAGING ON DIAGNOSTIC ASCERTAINMENT OF PATIENTS PRESENTING WITH UNDIAGNOSED BACK PAIN AND WHAT IS THE IMPACT OF CENTRAL EVALUATION? DATA FROM THE SCREENING IN AXIAL SPONDYLOARTHRITIS IN PSORIASIS, IRITIS, AND COLITIS (SASPIC) COHORT. Annals of the Rheumatic Diseases. 2019;78(Suppl 2):1248-9. https://ard.bmj.com/content/78/Suppl_2/1248
Maksymowych WP, Carmona R, Chan J, Yeung J, Aydin S, Martin L, et al. SAT0383 ENHANCED PERFORMANCE OF THE ASAS CLASSIFICATION CRITERIA BY DELETION OF NON-DISCRIMINATORY CLINICAL ITEMS: DATA FROM THE SCREENING IN AXIAL SPONDYLOARTHRITIS IN PSORIASIS, IRITIS, AND COLITIS COHORT. Annals of the Rheumatic Diseases. 2020;79(Suppl 1):1140-. https://ard.bmj.com/content/79/Suppl_1/1140.1
In the multicentre Screening for Axial SpA in Psoriasis, Iritis (AAU), and Colitis cohort, 48% of people with psoriasis, AAU or colitis, ≤45 years of age with ≥3 months undiagnosed back pain were diagnosed with axial SpA if using a three-stage evaluation approach (clinical evaluation, laboratory results [HLA-B27, CRP] and radiography, MRI); 69% were diagnosed with axial SpA after the clinical evaluation alone. These figures suggest that many opportunities to identify, diagnose and treat axial SpA are being missed.
The following clinical SpA features were non-discriminatory between axial SpA/not axial SpA: NSAID response, family history of SpA, heel enthesitis, peripheral arthritis, dactylitis. This effect was particularly noteworthy in patients with lower degree of symptomatology (back pain severity <5/10), short symptom duration (<5 years) and in females. In a prospective cohort with a high pre-test probability of axial SpA certain clinical SpA features were not helpful in discriminating a diagnosis of SpA.
Data from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis
Derakhshan MH, Dean L, Jones GT, Siebert S, Gaffney K. Predictors of extra-articular manifestations in axial spondyloarthritis and their influence on TNF-inhibitor prescribing patterns: results from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis. RMD Open. 2020;6(2). https://rmdopen.bmj.com/content/rmdopen/6/2/e001206.full.pdf
Clinical and patient-reported outcomes of 2420 patients with axial SpA from 83 centres were collected by the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS). This study demonstrates that one in three patients with axial SpA have at least one EAM of axial SpA; however, 84% have a single EAM, suggesting that there are unrelated pathogenic mechanisms. AAU was significantly associated with HLA-B27; however, patients with psoriasis and IBD had lower rates of HLA-B27 positivity than the overall cohort. The presence of EAMs does not increase the likelihood of patients being started on a TNF-inhibitor; however, EAMs do influence TNF-inhibitor choice. Patients with previous AAU and IBD are more likely to be prescribed adalimumab and less likely to receive etanercept, consistent with the superior efficacy of monoclonal TNF-inhibitors for these indications. Future longitudinal analysis will determine whether EAMs influence TNF-inhibitor survival and whether or not individual TNF-inhibitors protect patients from incident or flares of existing EAMs.
The impact of EAMs on disease activity, functional status, and treatment patterns in patients with axial spondyloarthritis
Redeker I, Siegmund B, Ghoreschi K, Pleyer U, Callhoff J, Hoffmann F, et al. The impact of extra-musculoskeletal manifestations on disease activity, functional status, and treatment patterns in patients with axial spondyloarthritis: results from a nationwide population-based study. Ther Adv Musculoskelet Dis. 2020;12:1759720×20972610.
A total of 1729 patients with axial SpA were included in the analyses (mean age: 56 years; 46% female), of whom 6%, 10% and 9% had current IBD, psoriasis, and AAU, respectively; and 9%, 15% and 27% had ever had IBD, psoriasis, and AAU, respectively. Ever having presence of IBD and history of psoriasis were significantly associated with higher level of disease activity. Ever presence of psoriasis was also associated with higher level of functional impairment, whereas current AAU was significantly associated with lower disease activity. Patients with current IBD or psoriasis received biological and conventional synthetic disease-modifying anti-rheumatic drugs more frequently, as well as systemic steroids. AAU was associated with a higher use of conventional synthetic disease-modifying anti-rheumatic drugs only.
Sykes MP, Hamilton L, Jones C, Gaffney K. Prevalence of axial spondyloarthritis in patients with acute anterior uveitis: a cross-sectional study utilising MRI. RMD Open. 2018;4(1):e000553. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845401/
AAU is known to be the most common EAM of axial SpA. In this study, the minimum prevalence of axial SpA in AAU was 20.2%; nearly one-quarter of these patients previously undiagnosed despite years of back pain – representing a substantial hidden burden of disease. HLA-B27 diagnosis is often the trigger for referral of patients with AAU to rheumatology. However, nearly one-half of patients identified as missed diagnoses were HLA-B27 negative. Similarly, nearly two-thirds of new diagnoses would have been missed if using inflammatory back pain rather than chronic back pain as a referral strategy – supporting the presence of inflammatory back pain as an axial SpA feature rather than mandatory criterion for referral, in line with Assessment of Spondyloarthritis International Society (ASAS)-endorsed recommendations for early referral. Due to the high prevalence of axial SpA among individuals presenting with AAU, the authors thereby recommend that all individuals with AAU and chronic back pain with onset before the age of 45 should be referred to rheumatology regardless of HLA-B27 status, gender or number of episodes of AAU.
Haroon M, O’Rourke M, Ramasamy P, Murphy CC, FitzGerald O. A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool). Annals of the rheumatic diseases. 2015;74(11):1990-5. https://ard.bmj.com/content/74/11/1990
In the present paper, the authors developed The Dublin Uveitis Evaluation Tool (DUET) algorithm – which prompts referral to rheumatology if a patient has AAU, is HLA-B27 positive, or has co-existing psoriasis or peripheral arthritis. The algorithm was found to have high sensitivity and specificity (96% and 97% respectively) – potentially implicating HLA-B27 as the ‘anchor criterion’ for the ASAS classification criteria clinical arm. However, importantly, in the prior study discussed by Sykes et al., nearly one-half of patients identified as missed diagnoses were HLA-B27 negative. These patients would therefore have remained lost if utilising the DUET algorithm. A cohort of 101 patients with AAU and know prior diagnosis of SpA was used to develop the algorithm; whereby 41.6% were found to have undiagnosed SpA.
Jadon DR, Sengupta R, Nightingale A, Lindsay M, Korendowych E, Robinson G, et al. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis. Annals of the rheumatic diseases. 2017;76(4):701-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530328/
The recent ADIPSA (Axial Disease In PSoriatic Arthritis [PsA]) study found that 49/201 (23.9% ) of PsA patients fulfilled Modified New York criteria for ankylosing spondylitis (radiographic axial SpA). Although due to lack of MRI, fulfilment of the full ASAS criteria could not be assessed, 85/118 (72%) of Psoriatic SpA cases and 9/127 (7%) of peripheral PsA cases fulfilled ASAS clinical or radiographic imaging criteria.
Rondags A, Arends S, Wink FR, Horváth B, Spoorenberg A. High prevalence of hidradenitis suppurativa symptoms in axial spondyloarthritis patients: A possible new extra-articular manifestation. Seminars in Arthritis and Rheumatism. 2019;48(4):611-7. https://www.sciencedirect.com/science/article/pii/S0049017218300155
Interestingly, hidradenitis suppurativa (HS) has recently also been implicated as a potential additional EAM of axial SpA. SpA and HS share several clinical and pathophysiological features, such as the association with IBD, and with elevated cytokine levels IL-17 and TNF-α. Recently, SpA was reported to be more prevalent (2.3–28.2%) in patients with HS than in the general population. The present study found that in a cohort of axial SpA patients, HS is more prevalent than in the general population (9.1% versus 0.053–4.1%). HS is associated with female gender, lower QoL, and especially higher axial SpA disease activity.
Karreman MC, Luime JJ, Hazes JMW, Weel AEAM. The Prevalence and Incidence of Axial and Peripheral Spondyloarthritis in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Journal of Crohn’s and Colitis. 2016;11(5):631-42. https://academic.oup.com/ecco-jcc/article/11/5/631/2418078
The objective of this systematic review and meta-analysis was to give a systematic overview of the prevalence and incidence of SpA in patients with IBD. A total of 71 studies were included, reporting on the prevalence of sacroiliitis, ankylosing spondylitis, arthritis, enthesitis, and dactylitis. Pooled prevalences were calculated. SpA was found to occur in up to 13% of patients with IBD. Ankylosing spondylitis was the least common (3%) followed by sacroiliitis (10%) and peripheral arthritis (13%). Few estimates were available for enthesitis (prevalence range from 1% to 54%) and dactylitis (prevalence range from 0% to 6%).
Evans J, Sapsford M, McDonald S, Poole K, Raine T, Jadon DR. Prevalence of axial spondyloarthritis in patients with inflammatory bowel disease using cross-sectional imaging: a systematic literature review. Ther Adv Musculoskelet Dis. 2021;13:1759720×21996973. https://journals.sagepub.com/doi/full/10.1177/1759720X21996973
Another recent systematic review investigated the prevalence of axial SpA, including previously undiagnosed cases, in IBD patients from studies involving cross-sectional imaging. They then also identified the IBD features potentially associated with axial SpA. A total of 20 observational studies were identified. The prevalence of sacroiliitis, the most commonly reported axial SpA feature, ranged from 2.2% to 68.0% with a pooled prevalence of 21.0% (95% confidence interval 17–26%). Associated IBD-axial SpA features include increasing IBD duration, increasing age, male sex, IBD location, inflammatory back pain and peripheral arthritis. No significant difference in the prevalence of sacroiliitis between Crohn’s disease and ulcerative colitis was identified. This work has informed a prospective observational study of magnetic resonance enterography as a screening tool for axial SpA, initiated in March 2019 (ClinicalTrials.gov NCT03817983) https://clinicaltrials.gov/ct2/show/NCT03817983.