Muhammad Asim Khan

Diffuse idiopathic skeletal hyperostosis (DISH) and axial spondyloarthritis (axSpA) are diseases with inflammatory involvement of the axial skeleton that can result in new bone formation that may lead to total ankylosis of the spine and functional impairment of different extent in individual patients. In these diseases, the new bone formation may lead to total ankylosis of the spine and impaired mobility with functional impairment. This review will highlight the similarities and differences of these two conditions. In axSpA, the genetic background with the association with human leukocyte antigen-B27 (HLA-B27) is known for 50 years, while in DISH, a genetic contribution is not yet proven. The phenotype of new bone formation and its anatomic features are different between these diseases. In axSpA symmetric, thin and marginal syndesmophytes representing an ossification of enthesitic inflammation at the area of the attachment of the annulus fibrosus that may extend to the adjacent deeper layers anterior longitudinal ligament and are typical, while in DISH the so-called “chunky bridging osteophytes” grow as an additional layer on the anterior longitudinal ligament. Besides distinct anamnestic and clinical features, magnetic resonance imaging is helpful differentiating the two diseases since inflammatory changes with the typical pattern of axSpA are reliably visualized. Similar in both diseases is the high prevalence of vertebral fractures, which are mainly caused by the local osteoporosis and decreased flexibility of the affected bones, and therefore may occur even after minor traumata. The presence of extraarticular manifestations like uveitis, inflammatory bowel disease or psoriasis are only linked to axSpA. In contrast, DISH is associated with obesity, diabetes mellitus, and other metabolic diseases. Although DISH and axSpA are distinct conditions, the cooccurrence of these two diseases exists in some patients. Various therapeutic options are becoming available for axSpA, but no therapy has been approved for DISH yet.

Purpose of Review To commemorate the 50th anniversary of the groundbreaking discovery of a remarkably strong association between HLA-B*27 and ankylosing spondylitis (AS). Recent Findings In addition to HLA-B*27, more than 116 other recognized genetic risk variants have been identified, while epigenetic factors largely remain unexplored in this context. Among patients with AS who carry the HLA-B*27 gene, clonally expanded CD8 + T cells can be found in their bloodstream and within inflamed tissues. Moreover, the α and β chain motifs of these T-cell receptors demonstrate a distinct affinity for certain self- and microbial-derived peptides, leading to an autoimmune response that ultimately results in the onset of the disease. These distinctive peptide-binding and presentation characteristics are a hallmark of the disease-associated HLA-B*27:05 subtype but are absent in HLA-B*27:09, a subtype not associated with the disease, differing by only a single amino acid. This discovery represents a significant advancement in unraveling the 50-year-old puzzle of how HLA-B*27 contributes to the development of AS. Summary These findings will significantly accelerate the process of identifying peptides, both self- and microbial-derived, that instigate autoimmunity. This, in return, will pave the way for the development of more accurate and effective targeted treatments. Moreover, the discovery of improved biomarkers, in conjunction with the emerging technology of electric field molecular fingerprinting, has the potential to greatly bolster early diagnosis capabilities. A very recently published groundbreak paper underscores the remarkable effectiveness of targeting and eliminating disease-causing T cells in a HLA-B*27 patients with AS. This pivotal advancement not only signifies a paradigm shift but also bolsters the potential for preventing the disease in individuals carrying high-risk genetic variants.

Introduction Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. Methods In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). Results AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. Discussion AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

Objective We aimed to characterize differences of clinical features, extra-musculoskeletal manifestations and treatment utilizations based on the patients’ HLA-B*27 status in a global axSpA cohort and identify predictors of HLA-B*27 negativity in these patients. Methodology In post-hoc analysis of the ASAS-PerSpA study, patients fulfilling the 2009 ASAS classification criteria for axSpA and typed for HLA-B*27 were included. The patient characteristics cwere compared between the HLA-B*27(+) and HLA-B*27(-) subgroups. Multivariablete logistic regression was conducted to identify predictors of HLA-B*27 negativity. Results Of 2910 patients with axSpA from 24 countries, 2269 were tested for HLA-B*27 [1753 HLA-B*27(+) and 516 HLA-B*27(-)]. The proportion of males was higher in the HLA-B*27 (+) compared to the HLA-B*27 (-) subgroup (72.1 vs 54.3%). Patient population with HLA-B*27 (+) more often had positive family history for axSpA (29.8 vs 15.3%), and younger age at diagnosis, 31.6 years (SD 10.9) vs 37.7 years (SD 12.1). HLA-B*27 (-) patients had significantly higher peripheral arthritis (47.5 vs 42.1%, pConclusion HLA-B*27 (-) axSpA patients had a longer delay in diagnosis, more frequently had peripheral arthritis, enthesitis, IBD, psoriasis, and were more often treated with csDMARDs compared to HLA-B*27 (+) subgroup.

Objective: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that causes inflammation in the axial skeleton, resulting in structural damage and disability. We aimed to understand the effect of axSpA on work activity, day‐to‐day function, mental health, relationships, and quality of life and to examine barriers to early diagnosis.Methods: A 30‐minute quantitative US version of the International Map of Axial Spondyloarthritis survey was administered online to US patients aged 18 years and older with a diagnosis of axSpA who were under the care of a health care provider from July 22 to November 10, 2021. This analysis describes demographics, clinical characteristics, journey to axSpA diagnosis, and disease burden.Results: We surveyed 228 US patients with axSpA. Patients had a mean diagnostic delay of 8.8 years, with a greater delay in women versus men (11.2 vs. 5.2 years), and 64.5% reported being misdiagnosed before receiving an axSpA diagnosis. Most patients (78.9%) had active disease (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), reported psychological distress (57.0%; General Health Questionnaire 12 score ≥3), and experienced a high degree of impairment (81.6%; Assessment of Spondyloarthritis International Society Health Index score ≥6). Overall, 47% of patients had a medium or high limitation in activities of daily living, and 46% were not employed at survey completion.Conclusion: The majority of US patients with axSpA had active disease, reported psychological distress, and reported impaired function. US patients experienced a substantial delay in time to diagnosis of axSpA that was twice as long in women versus men.

Objective The lifetime recurrence rate (RR) of axial spondyloarthritis (axSpA) among first-degree relatives (FDR) and the effect of proband’s gender, HLA-B27 and radiographic status is unclear. Our 35-year-follow-up family study has enabled these issues to be addressed. Methods In 1985, 363 ankylosing spondylitis (AS) probands (members of the Swiss AS Patient Society) and 806 FDR recruited into the study, completed questionnaires regarding axSpA manifestations, underwent a physical examination and most also underwent pelvic radiography and HLA-B27 typing. At follow-up in 2018–2019, of the former participants whose current addresses could be retrieved, 162 had died and 485 (125 patients with AS plus 360 FDR) completed a postal questionnaire. Results At follow-up, 48 of 177 HLA-B27(+) FDR had developed axSpA, an RR of 27.1% (95% CI 20.6% to 33.7%). 27/148 (18.2%) children of AS probands (modified New York (mNY) criteria) were affected versus 2/50 (4.0%) children of non-radiographic axSpA probands (p=0.0138, OR=5.36; 95% CI 1.23 to 23.40). Children of female probands were more often affected (12/22; 54.5%) than of male probands (15/78; 19.2%) (p=0.0003; OR=4.89; 95% CI 1.96 to 12.23). This increased risk applies equally to sons and daughters. Conclusion The lifetime RR of axSpA for HLA-B27(+) FDR is substantial (27.1%), and disease severity (as defined by radiographic sacroiliitis by the mNY criteria) is an additional risk factor. Affected mothers pass on the disease significantly more often to their offspring than do affected fathers. These findings may lead to better assessment of lifetime risk for axSpA in the offspring. Moreover, investigation of this gender effect may uncover additional putative disease susceptibility factors.

Objective Axial spondyloarthritis (axSpA) comprises both radiographic and non-radiographic disease. However, the paucity of specific objective measures for the disease and current classification criteria showing suboptimal specificity contribute to disease heterogeneity observed in clinical practice and research. We used a historical cohort of patients with axSpA to assess sources of heterogeneity. Methods The study involved 363 axSpA probands recruited from membership of the Swiss Ankylosing Spondylitis Patient Society. Participants underwent examination by a rheumatologist, completed questionnaires and provided blood samples for HLA typing. Patients underwent radiography of sacroiliac joints and were categorised according to the New York (NY) criteria (ankylosing spondylitis (AS) or non-radiographic axSpA (nr-axSpA)) and HLA-B27 status. Genetic characterisation by single nucleotide polymorphism microarray was performed and AS polygenic risk scores (PRS) were calculated. Results Considerable heterogeneity was observed. The male to female ratio for AS (NY+) was 3:1, but 1:1 for nr-axSpA. For HLA-27(+) AS, the ratio was 2.5:1, but nearly 1:1 for HLA-B27(−) disease. Women with nr-axSpA had strikingly lower mean PRS and lower HLA-B27 prevalence than men with nr-axSpA or NY(+) male and female patients with AS. PRS was able to distinguish male but not female patients with nr-axSpA from related healthy first-degree relatives. Radiographic sacroiliitis was strongly associated with HLA-B27, especially in men. Conclusion Women clinically diagnosed with axSpA but without radiographic sacroiliitis as a group have a disease that is distinct from AS by the modified New York criteria overall and from nr-axSpA in men. Given the high degree of heterogeneity, stratified or adjusted analysis of effectiveness studies is indicated, taking genetics, sex and radiographic damage (sacroiliitis) into account.

Objective Factors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands’ HLA-B27 and radiographic sacroiliitis status on disease occurrence among their FDR. We also assessed the predictive value of features of the clinical history, including chronic inflammatory back pain (CIBP) and acute anterior uveitis (AAU), among the FDR and how they can be used to improve classification and diagnosis of axSpA. Methods In 1985, we studied 363 AS probands and 806 FDR who underwent rheumatologic examination, completed questionnaires, provided blood samples for HLA-typing and underwent radiography of sacroiliac joints. At follow-up in 2018–2019, 125 patients and 360 FDR were available for study, and completed a postal questionnaire about axSpA features. FDRs were asked to report whether after 1985 they had been diagnosed by Swiss rheumatologists as having axSpA. Results Among HLA-B27(+) FDR, axSpA occurred in 25.4%–26.3%, independent of the radiographic sacroiliitis status of the proband. AAU occurred in 13/34 (38.2%) FDR with axSpA vs 29/251 (11.6%) FDR without axSpA (p=0.00004, OR=4.74 95% CI 2.15 to 10.47). The presence of CIBP at baseline did not predict later occurrence of axSpA but combining CIBP and pain/discomfort at the thoracic spine and at anterior (ventral) chest wall ever, assessed at follow-up in 2018–2019, provided 83.1% sensitivity and 87.2% specificity for current axSpA. Conclusion Occurrence of AAU among FDR of axSpA probands should prompt screening for axSpA. Moreover, co-occurrence of CIBP and pain/discomfort in the thoracic spine and at anterior chest wall as a three-question tool may further enhance clinical suspicion of axSpA among these FDR.