OBJECTIVE:To examine whether baseline comorbidity burden and extra-musculoskeletal manifestations (EMMs)-psoriasis, uveitis, IBD-are associated with spinal radiographic progression in AS. METHODS:We analysed participants fulfilling modified New York criteria with one or more lateral cervical or lumbar radiograph. Radiographic progression was quantified using the modified Stoke AS Severity Score (mSASSS), excluding score 1 at each vertebral corner (range 0-48). Comorbidity count (22 self-reported conditions: none, one, two, three or more) and ever-presence of each EMM at baseline were exposures. mSASSS change over time with exposure-time interactions was modelled using generalized estimating equations; coefficients were rescaled to represent mean difference in progression (units/10 years). Models adjusted for baseline mSASSS, sex, symptom duration, CRP, HLA-B27, smoking, TNF inhibitor use, and number of EMMs or comorbidity count. Secondary analyses examined potential sex- and segment-specific effects. RESULTS:Among 1150 individuals (mean age 44 years; 75% male; 84% HLA-B27 positive), 3441 patient-years were analysed (median follow-up 2 years; median two radiographs). Compared with those with no comorbidities, progression was greater amongst patients with two (2.7 units/10 years; 95% CI 1.9-3.5) and three or more (2.3; 1.5-3.1) comorbidities. Uveitis (2.2 units/10 years; 1.3-3.0) and psoriasis (2.4 units/10 years; 1.4-3.5), but not IBD, were associated with greater progression. Sex-specific analyses suggested greater spinal progression in females than males with psoriasis. Cervical-predominant changes were seen with uveitis and psoriasis. CONCLUSION:Comorbidity burden, uveitis and psoriasis are independently associated with greater spinal radiographic progression in AS. These readily identifiable features may inform risk stratification and targeted management strategies.

It is 50 years since the original spondyloarthritis concept was proposed by Moll and Wright, and in November 2025, rheumatologists (and other health and research professionals in rheumatology and dermatology) gathered in Leeds, the birthplace of spondyloarthritis, to celebrate the milestone. Here, we report on the proceedings of the meeting, which looked back over the last 50 years, noted the current state of the art, and had a look at what might develop in the next 50 years.

OBJECTIVES:To determine disease-specific associations of serum vascular cell adhesion molecule-1 (VCAM-1) and associated mortality in SSc. METHODS:Participants were identified from the Australian Scleroderma Cohort Study. Data were linked with the National Death Index for cause-specific mortality. VCAM-1 was measured using a magnetic Luminex assay. Participant characteristics and information on organ specific manifestations were extracted until February 2024. Participants were stratified into VCAM-1 quartiles. RESULTS:Of 388 participants, 87.1% were female and 76.8% had limited cutaneous disease. Median age at diagnosis was 45.7 years (interquartile range 36.4-56.7). Participants with upper quartile VCAM-1 (quartile 4; Q4) had increased mortality compared with others [hazard ratio (HR) 2.17, 95% CI 1.54-3.04; P < 0.001]. Despite the significant increased mortality in Q4, there were no statistically significant differences in sex, age, disease duration, disease subtype, autoantibody profile or forced vital capacity across the VCAM-1 quartiles. Q4 were more likely to have pulmonary arterial hypertension (PAH; P = 0.028), SSc-attributable myocardial disease (P = 0.009) and digital ulcers (P = 0.003). In cause-specific mortality analysis, Q4 were more likely to have PAH (HR 3.08, 95% CI 1.68-5.65; P < 0.001), SSc-attributable myocardial disease (HR 2.85, 95% CI 1.51-5.38; P = 0.001) and all-cause cardiovascular disease (HR 2.50, 95% CI 1.60-3.89; P < 0.001) listed as a cause or contributor to death. Q4 VCAM-1 level was not associated with interstitial lung disease presence, severity or cause-specific mortality. CONCLUSION:The increased mortality in participants with SSc and Q4 VCAM-1 levels is attributable to increased frequency of vascular disease manifestations. Q4 participants do not have a disproportionate frequency of other established risk factors for increased mortality, suggesting an independent role for VCAM-1 in disease pathophysiology.

BACKGROUND:Most research on genetic screening and precision oncology is based on individuals of European ancestry. We applied the National Health Service (NHS) England's cancer variant prioritisation workflow to evaluate the performance of these approaches in ethinically and ancestrally diverse populations. The second aim of the study was to assess the representativeness of the 100 000 Genomes Project cancer cohort of the population of England. METHODS:In this cross-sectional analysis, whole-genome sequencing data from patients with cancer recruited into the 100 000 Genomes Project between February 2015 to December 2018 were analysed. Clinical information, including tumour stage and grade, was gathered from the NHS England National Cancer Registration and Analysis Service. Patients with cancer types with fewer than five individuals, haematological cancers, childhood cancers, unknown primary carcinomas, patients with indeterminate sex, and patients missing somatic mutations in genes were excluded. To assess ethnicity representation in the 100 000 Genomes Project, we calculated the recruitment ratios for self-reported ethnicities for patients with cancer recruited to the 100 000 Genomes Project and patients with cancer in England. We also analysed differences in classification rates for potentially pathogenic variants to assess ancestry-related differences in germline and somatic mutations of different ancestry groups. FINDINGS:14 775 patients with cancer were recruited between February, 2015, and December, 2018, into the 100 000 Genomes Project. There was no evidence of under-representation of diverse ethnic groups in the 100 000 Genomes Project when compared with the national statistics. The recruitment rate ratio for breast cancer was 2·2 (95% CI 1·6-3·0) for Black versus White women in the 100 000 Genomes Project compared with 0·81 (0·79-0·83) for Black versus White women in the national data (fold-change in rate ratios 2·7; 95% CI 2·0-3·7, p<0·0001), suggesting higher representation of Black women in the 100 000 Genomes Project than expected given the ethnicity-specific incidence rates in England. Compared with national rates, the 100 000 Genomes Project also had higher recruitment rates of Black versus White men with prostate cancer (fold-change in rate ratios 3·7; 1·8-7·5, p=0·0004), Black versus White men with bladder cancer (fold change in rate ratios 6·1; 2·0-18·8, p=0·0016), and Asian versus White women with breast cancer (fold change in rate ratios 1·4; 1·2-1·7, p=0·0008). Ancestry had a significant association with the likelihood of carrying a variant classified as a potentially pathogenic (likelihood ratio test p=0·0011). Potentially pathogenic variants were identified in 23 (4·6%) of 500 South Asian (adjusted model odds ratio [OR] 1·88, 95% CI 1·21-2·93, p=0·0052) and 24 (5·3%) of 453 African ancestry patients (OR 2·24, 1·44-3·48, p=0·0003) compared with 263 (2·2%) of 11 955 in European-ancestry patients. However, we found that fewer tumour mutations in actionable genes were identified for patients of non-European ancestry compared with patients of European ancestry when adjusting for sex and cancer type (likelihood ratio test p<0·0001). INTERPRETATION:The was an excess of germline variants classified as potentially pathogenic variants in patients with non-European ancestry, which might impede the diagnostic process. Improved variant prioritisation workflows and more research in diverse groups are needed to ensure equitable implementation of genomics in cancer care. FUNDING:The UK Department of Health and Social Care and the EU's Horizon 2020 Research and Innovation Programme.

We report the largest genome-wide association study meta-analysis in ankylosing spondylitis (AS) to date (25,645 cases, 71,224 controls), identifying 27 novel loci and 86 independent genetic associations. Variations in FUT2 (non-secretor status) and ABO (blood group A) increase AS risk, with Mendelian randomisation (MR) linking non-secretor status to increased AS risk from reduced gut carriage of Ruminococcus torques. Associations with three telomerase maintenance genes (TERT, TERC, RTEL1), and MR analysis, suggest increased telomere length causally increases AS susceptibility. Fine-mapping prioritised likely causal variants at multiple loci. Transcriptome- and proteome-wide association studies implicated 644 genes, highlighting immune-related pathways. Lower genetically-determined IL-6 and IL-12, and similar IL-23, levels were found in AS cases, offering a genetic explanation for the failure of IL-6, IL-12, and IL-23 inhibition in AS treatment. Finally, multi-omic analyses showed chromosome 2p15 association acts via reduced B3GNT2 expression. These findings deepen understanding of AS pathogenesis, highlighting new pathways and therapeutic opportunities.

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with limited therapeutic options. Genetic association studies for IPF have identified several associations and probable effector genes that could not only help understanding IPF pathogenesis but also develop effective treatments. Assessing genetic overlap between IPF and severe COVID-19, an acute respiratory disease that can trigger pulmonary fibrosis, may reveal shared aetiology and mechanisms, thereby supporting the development of common treatments. METHODS:We carried out genome-wide association studies (GWAS), post-GWAS, and rare variant analyses using whole genome sequencing data from the 100,000 Genomes Project IPF cohort (n = 586). We performed a meta-analysis combining 100 kGP with published IPF GWASs (total 11,746 cases and 1,416,493 controls). We tested inhibition in vitro for a probable effector gene of an identified association. We also investigated genetic colocalisation between IPF and severe COVID-19 and leveraged their genetic correlation through multi-trait meta-analysis for discovery. FINDINGS:IPF meta-analysis identified an additional association at 1q21.2 (rs16837903, OR [95% CI] = 0.88 [0.85, 0.92], P = 9.5 × 10-9), which was replicated in independent data. MCL1, one of the probable effector genes of the 1q21.2 signal has a known antiapoptotic role, but MCL1 inhibition in vitro did not selectively deplete senescent alveolar epithelial cells. Rare variant burden analysis identified ANGPTL7, a secreted glycoprotein involved in the regulation of angiogenesis, as an IPF candidate gene (OR [95% CI] = 28.8 [8.51, 97.4], P = 6.7 × 10-8). We discovered additional shared genetic loci between IPF and severe COVID-19 at 1q21.2, 6p24.3, and 16p13.3, with probable effector genes MCL1, DSP, and RHBDF1, implicating regulation of apoptosis, cell adhesion, and epidermal growth factor signalling, respectively. The genetic correlation between IPF and severe COVID-19 was rg [95% CI] = 0.39 [0.25, 0.53]. Using multi-trait meta-analysis, we identified and replicated an additional candidate IPF signal at 2p16.1 with probable effector gene BCL11A, a regulator of haematopoiesis and lymphocyte development. INTERPRETATION:These findings prioritise probable effector genes mediating IPF risk and identify potential therapeutic targets that require validation, with genes colocalising with severe COVID-19 suggesting potential for developing common treatments. FUNDING:None.

Advances in T cell receptor (TCR) profiling techniques have substantially improved our ability to investigate T cell responses to antigens that are presented on HLA class I and class II molecules and associations between autoimmune T cells and rheumatic diseases. Early-stage studies in axial spondyloarthritis (axSpA) identified disease-associated T cell clonotypes, benefiting from the relative genetic homogeneity of the disease. However, both the genetic and the T cell immunological landscape are more complex in other rheumatic diseases. The diversity or redundancy in the TCR repertoire, epitope spreading over disease duration, genetic heterogeneity of HLA genes or other loci, and the diversity of epitopes contributing to disease pathogenesis and persistent inflammation are all likely to contribute to this complexity. TCR profiling holds promise for identifying key antigenic drivers and phenotypic T cell states that sustain autoimmunity in rheumatic diseases. Here, we review key findings from TCR repertoire studies in axSpA and other chronic inflammatory rheumatic diseases including psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome. We explore how TCR profiling technologies, if applied to better controlled studies focused on early disease stages and genetically homogeneous subsets, can facilitate disease monitoring and the development of therapeutics targeting autoimmune T cells, their cognate antigens, or their underlying biology. Garrido-Mesa and Brown review findings from TCR profiling studies in rheumatic diseases and discuss how improved study design might help elicit information about autoreactive T cell clones and their contribution to disease pathogenesis.

Objectives To report updated uveitis incidence in bimekizumab (BKZ)-treated patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) in Phase 2b/3 studies over a treatment duration of 3 years in Phase 3 studies. Methods Data are reported for 2 pools, each comprising 1 Phase 2b and 2 Phase 3 studies and their open-label extensions, in patients with axSpA and PsA, respectively (data cut-off in axSpA: September 2024; PsA: August 2024). Uveitis events were identified using the preferred terms “autoimmune uveitis”, “iridocyclitis”, “iritis”, and “uveitis”, classified using the MedDRA v19.0; “acute anterior uveitis” was not a specific preferred term available in MedDRA v19.0. Uveitis rates and exposure-adjusted incidence rates (EAIR) per 100 patient-years (PY) for patients who received ≥1 BKZ 160 mg every 4 weeks (Q4W) dose are reported separately for axSpA and PsA, respectively. Results Patients with axSpA (N=848) and PsA (N=1,409) had a mean (standard deviation [SD]) age of 40.3 (11.9) and 49.3 (12.4) years, respectively. Mean (SD) time since diagnosis was 6.1 (7.8) years in patients with axSpA and 7.0 (8.0) in patients with PsA. Of patients with axSpA, 130 (15.3%) had a history of uveitis (PsA: 21 [1.5%]). Most patients with axSpA were HLA-B27 positive (717/848 [84.6%]). In patients with axSpA across the pooled Phase 2b/3 data, BKZ exposure was 2,748.9 PY. In total, uveitis occurred in 33/848 (3.9%; EAIR [95% CI]: 1.2/100 PY [0.8, 1.7]) patients overall and in 20/130 (15.4%; 5.0/100 PY [3.0, 7.7]) patients with history of uveitis. In patients without a history of uveitis, 13/718 (1.8%; 0.6/100 PY [0.3, 1.0]) patients had uveitis events (Figure 1). Most events were mild/moderate, 1 was severe; 2 (0.2%) patients discontinued treatment due to uveitis. Incidence of uveitis in patients with PsA was low across the pooled Phase 2b/3 data (total BKZ exposure: 4,264.7 PY); uveitis occurred in 4/1,409 (0.3%; 0.1/100 PY [0.0, 0.2]) patients overall; 2 had a history of uveitis. No uveitis events led to treatment discontinuation. Figure 1. Incidence of uveitis in patients with axSpA stratified by history of uveitis Conclusion Over 3 years of BKZ treatment, the incidence of uveitis in patients with spondyloarthritis receiving BKZ long-term was low.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in "The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations" which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL17A. Here, we report long-term incidence of acute anterior uveitis (uveitis’) following BKZ treatment in patients (pts) with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA). Safety data are reported for 2 pools, each comprising 3 phase 2b/3 studies and their open-label extensions, in pts with active axSpA (non-radiographic and radiographic axSpA) and active PsA, respectively. Uveitis events were identified using the preferred terms “autoimmune uveitis,” “iridocyclitis,” “iritis,” and “uveitis,” coded according to MedDRA v19.0; note that “acute anterior uveitis” was not a specific preferred term available in MedDRA v19.0. Uveitis rates and exposure-adjusted incidence rates (EAIR) per 100 pt-years (PY) for pts who received ≥1 BKZ 160 mg dose are reported (data cutoff: July 2023). Pts with axSpA (N=848) had a mean age (standard deviation [SD]) of 40.3 (11.9) years, and pts with PsA (N=1,409) had a mean age (SD) of 49.3 (12.4) years, with a mean time since diagnosis (SD) of 6.1 (7.8) and 7.0 (8.0) years, respectively. Of pts with axSpA, 130 (15.3%) had a history of uveitis; 21 (1.5%) pts with PsA had a history of uveitis. The majority of pts with axSpA were human leukocyte antigen (HLA)-B27 positive (717/848 [84.6%]). In pts with axSpA across the pooled phase 2b/3 axSpA trial data, BKZ exposure was 2,514 PY. Uveitis occurred in 31/848 (3.7%; EAIR [95% confidence interval; CI]: 1.3/100 PY [0.9, 1.8]) pts overall and in 18/130 (13.8%; 4.8/100 PY [2.8, 7.6]) pts with history of uveitis. In pts without a history of uveitis, 13/718 (1.8%; 0.6/100 PY [0.3, 1.1]) pts had uveitis events (Figure). All events were mild/moderate, 1 led to treatment discontinuation. Incidence of uveitis in pts with PsA was low across the pooled phase 2b/3 PsA trial data (total BKZ exposure: 3,656 PY); uveitis occurred in 3 (0.2%; 0.1/100 PY [0.0, 0.2]) pts overall; 1 had a history of uveitis. No uveitis events led to treatment discontinuation. Figure. Incidence of uveitis (EAIR/100 PY [95% CI]) in patients with axSpA stratified by history of uveitis Across 2,514 PY in pts with axSpA and 3,656 PY in pts with PsA, the long-term incidence of uveitis in pts treated with BKZ remained low. Previously submitted to: ACR 2024.

The worldwide epidemiology of axial spondyloarthritis (axSpA), psoriatic arthritis (PsA) and peripheral spondyloarthritis, as well as of HLA-B27 and other MHC and non-MHC genes in these diseases, is reviewed herein. The frequency of axSpA is highest in circumpolar groups (such as Sami people and certain Indigenous American groups) and lowest in those of Japanese and African ancestry. The same pattern holds for PsA, although the overall prevalence of PsA seems much lower in East Asia, where it is less frequent than axSpA. The prevalence of PsA in people with psoriasis is increased where rheumatological assessment was carried out and seems to be increasing over time. HLA-B27 remains the most important genetic factor in axSpA susceptibility, although its frequency is lower in African American, South American and Middle Eastern populations than in others. The presence of HLA-B27 and other HLA alleles seems to be important in discerning clinical subsets of SpA and PsA, particularly those characterized by acute anterior uveitis or by axSpA with psoriasis, although these HLA-B27 and other MHC and non-MHC associations are derived from genome-wide association studies and other chip-based studies in large populations. These studies have been carried out mainly in populations of European and East Asian ancestry, and similar data from Latin America, sub-Saharan Africa and South Asia are lacking. This under-representation is an unmet need in applying genetic factors to understand the pathogenesis, diagnosis and classification of SpA and PsA. This article provides a comprehensive overview of the epidemiology of spondyloarthritis — including axial spondyloarthritis, psoriatic arthritis and peripheral spondyloarthritis — worldwide, as well as the epidemiology of genetic factors implicated in these diseases.

Chondrocalcinosis (CCAL), also known as calcium pyrophosphate dihydrate deposition disease (CPPDD), is a frequent multifactorial condition in the elderly, but there are two rare autosomal dominant Mendelian forms, CCAL1 (OMIM %600668) and CCAL2. Only three families with molecularly proven CCAL1 have been reported. Here, we describe an additional family from Germany (12 individuals, nine living) with CPPDD manifesting in the third decade of life, presenting with severe spinal problems and variable levels of disability, only two of them with hip problems. The mildly impaired growth in this family (median height at age 20: 10th percentile) may represent an as yet undescribed sign of CCAL1, or alternatively familial short stature. In all documented families and in this family, the disorder resulted from the recurrent heterozygous stop-loss variant NM_002546.4:c.1205A>T; p.(Ter402Leuext*19) in TNFRSB11B on chromosome 8q24, which predicts an extended osteoprotegerin protein with 19 additional amino acid residues. The pathomechanism of CCAL1 is not known. Biallelic TNFRSF11B loss-of-function variants cause autosomal recessive juvenile Paget's disease of bone (PDB5); shared features between CCAL1 and PDB5 include demineralization, osteoporosis, increased fractures, and a progressive height loss with age, but PDB5 and CCAL1 have very different phenotypes and heterozygous carriers of PDB5-associated variants are asymptomatic. Summing up, NM_002546.4:c.1205A>T represents a rare type of stop-lost variant, likely a gain-of-function variant, and to date no other variant is known to cause CCAL1. Our findings expand the phenotypic spectrum of CCAL1 and underscore that CCAL1 is a distinct rare Mendelian disorder for which the underlying molecular basis is now known.

Objectives Factors associated with peripheral arthritis and enthesitis, especially Achilles tendonitis and plantar fasciitis, were examined in a longitudinal cohort of 1075 patients with ankylosing spondylitis (AS) (also known as radiographic axial spondyloarthritis). Methods Patients were derived from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort. Disease activity and functional indices, as well as physical examination and medications used, were measured at every study visit. Univariable and multivariable analyses of the association of peripheral arthritis and enthesitis with clinical, sociodemographic factors were performed. Human leucocyte antigen (HLA)-B alleles were analysed by single-stranded conformational polymorphism analysis. Results Those with peripheral arthritis on examination were more likely to have psoriasis (p=0.001, OR=1.68; CI, 1.11, 2.54), greater functional impairment (p<0.001 OR=1.72; CI, 1.31, 2.27), higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (p<0.001), greater tumour necrosis factor (TNF) inhibitor (p<0.001, OR=1.50; CI, 1.14, 1.97) and use methotrexate/sulfasalazine (p<0.001, OR=2.25, CI [1.57, 3.23]). Patients with enthesitis were less likely to be male (p<0.001, OR=0.57; CI, 0.43, 0.75) and have peripheral arthritis (p<0.001, OR=2.35; CI, 1.47, 3.75), greater functional impairment (p<0.001, OR=1.91; CI, 1.43, 2.55) and higher ESR/CRP levels (p<0.001). Patients with plantar fasciitis and/or Achilles’ tendonitis on examination were less likely to male (p<0.001 OR=0.57; CI, 0.43, 0.75), to have significant functional impairment (p<0.001), to be using TNF inhibitors (p<0.001, OR=1.48; CI 1.13, 1.93) and to be using either sulfasalazine or methotrexate (p<0.001, OR=1.86, CI, 1.30, 2.67). HLA-B*15 (p=0.03, OR=1.84; CI, 1.05, 3.21) and HLA-B*37 (p=0.04, OR=3.00; CI, 1.03, 8.74) were marginally increased in frequency in those with peripheral arthritis on examination compared with those without. Conclusion There was a higher prevalence of peripheral musculoskeletal manifestations in women with AS, with significant impact on physical function and greater use of methotrexate or sulfasalazine and TNF inhibitors and enrichment for certain non-HLA-B27 HLA-B alleles.