Randomised controlled trials (RCTs) use restrictive eligibility criteria, raising concerns about external validity for heterogeneous routine-care populations. We aimed to characterise real-world patients with rheumatoid arthritis who would be ineligible for phase III RCTs, to evaluate their outcomes on biological/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in routine care and to assess how eligibility status influences comparative effectiveness estimates. We analysed 5462 patients who initiated b/tsDMARDs between 2003 and 2023. RCT ineligibility was defined using common phase III trial exclusions (eg, renal/hepatic impairment). Outcomes were treatment persistence and Clinical Disease Activity Index remission at 26 weeks. Comparative effectiveness across drug classes was estimated using propensity score weighting, stratified by RCT eligibility. Overall, 39.7% (2167/5462) met at least one RCT exclusion criterion and ineligible patients had higher baseline disease activity and worse functional status. However, after propensity score adjustment for clinical characteristics, remission rates did not differ between groups (24.0% vs 23.2%; OR 0.90; 95% CI 0.78 to 1.04). The proportion ineligible differed by b/tsDMARDs, highest with interleukin 6 inhibitors (47.4%) and CTLA4-Ig (45.1%) and lowest with Janus kinase (JAK) inhibitors (31.0%). In the RCT-eligible cohort, remission with JAK inhibitors exceeded that with tumour necrosis factor inhibitors (OR 1.39; 95% CI 1.09 to 1.76), consistent with head-to-head RCTs. In the RCT-ineligible cohort, this advantage was attenuated and no longer statistically significant (OR 1.24; 95% CI 0.81 to 1.91). Approximately 40% of routine-care patients would be RCT ineligible. Although these patients achieved comparable adjusted outcomes, between-drug differences were smaller than in trial-eligible populations. Real-world comparative analysis should therefore consider composition and calendar time when interpreting treatment effects.

BackgroundAntitopoisomerase I (ATA), anticentromere (ACA) and anti-RNA polymerase III (RNAP3) antibodies are included in the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis (SSc). A subset of patients with SSc satisfy criteria but may lack these specific autoantibodies, being classified as ‘triple-negative’.MethodsWe conducted a retrospective evaluation of triple-negative patients with SSc prevalence and clinical features among the multicentric Systemic sclerosis Progression INvestiGation registry.ResultsOut of 1480 patients with SSc, 295 (19.9%) were triple-negative, while 1185 (81.1%) had SSc-specific antibodies: ACA (54.3%), ATA (43.6%) and RNAP3 (2.1%). The triple-negative group showed a higher prevalence of myopathy (16.7% vs 10.1%, p=0.003), suggested by higher creatine phosphokinase (CPK) levels (126.2 vs 92.5 U/mL, p=0.002), more frequent CPK increase over 2–3 times (2.4% vs 0.2%, p=0.028). Triple-negative patients also exhibited fewer vascular complications, including digital ulcers (17.3% vs 22.8%, p=0.04) and calcinosis (8.2% vs 12.8%, p=0.027), and a higher prevalence of interstitial lung disease (p<0.001). Consistently, lower diffusing capacity for carbon monoxide (66.4% vs 70.98%, p=0.004) and forced vital capacity (97.01% vs 102.92%, p<0.001) were found in the triple-negative group. Triple-negative patients more frequently received corticosteroids (79.3% vs 67.9%, p=0.003), cyclophosphamide (43.4% vs 26%, p<0.001) and azathioprine (38.5% vs 22.3%, p=0.002), while less frequently received prostanoids (71.6% vs 85.9%, p<0.001), calcium channel blockers (80.1% vs 87.7%, p=0.005) and phosphodiesterase-5 inhibitors (4% vs 20%, p<0.001).ConclusionsA higher prevalence of myopathy and interstitial lung disease and a reduced vascular burden were found in the triple-negative patients, suggesting that the non-specific and non-routinely tested autoantibodies may identify an SSc endotype resembling sclero-myositis.

BackgroundCardiovascular disease and osteoarthritis (OA) share risk factors, but the link between comprehensive cardiovascular health and OA incidence is unclear. We investigated the association of Life’s Essential 8 (LE8), a multidimensional health metric, with OA risk and explored proteomic mechanisms.MethodsIn 102 794 UK Biobank participants without OA at baseline, LE8 scores (0–100) were derived from eight components. Incident OA was ascertained from medical records. Cox models estimated HRs. Plasma proteomics in a subset identified proteins linked to LE8 and OA, used to construct a protein risk score.ResultsOver 13.1 median years, 15 984 OA cases occurred. The highest versus lowest LE8 quartile had a 32% lower OA risk (HR 0.68, 95% CI 0.64 to 0.71), consistent across knee (HR 0.56), hip (HR 0.72) and hand OA (HR 0.57). Each SD increase in LE8 reduced risk by 14% (HR 0.86, 95% CI 0.84 to 0.87). Protective associations were stronger in individuals with younger phenotypic age (HR 0.86, 95% CI 0.84 to 0.88). Proteomics identified nine associated proteins (eg, fibroblast growth factor 21, insulin-like growth factor-binding protein 1); a protein risk score showed graded positive associations with OA.ConclusionsHigher cardiovascular health is associated with substantially lower OA risk, modified by biological ageing. Proteomic pathways involving metabolism, inflammation and tissue remodelling may underlie this relationship, supporting cardiovascular health optimisation for OA prevention.

ObjectivesTo assess the patient characteristics and treatment patterns, effectiveness, safety and patient-reported outcomes (PROs) of sarilumab in routine clinical practice, used as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) in Japan.MethodsProspective Sarilumab (Prefilled Syringe/Pen) Observational Study–Japan (PROFILE-J) was a 52-week, prospective, non-interventional, observational study conducted across Japan. Adult patients with RA initiating sarilumab were enrolled. Effectiveness endpoints included Clinical Disease Activity Index (CDAI) scores, disease activity and PROs. Safety endpoints included treatment-emergent adverse events (TEAEs) and other clinically relevant safety outcomes.ResultsAmong 1998 patients (monotherapy, n=567; combination, n=1431), the mean age was 66.6 years, with 63.2% aged ≥65 years and 67.9% naïve to biologic DMARDs. Sarilumab retention at week 52 was 67.5%. Effectiveness analysis population included 1715 patients (monotherapy, n=461; combination, n=1254). Baseline mean CDAI scores (21.2) decreased to low disease activity range (9.7) at week 12; mean changes from baseline were −13.6 and −13.1 at week 24 and –14.2 and −14.9 at week 52 for monotherapy and combination therapy respectively. Other measures, including PROs, showed similar improvements in both groups. In the safety population, TEAEs occurred in 44.6% of patients, with a slightly lower rate observed in monotherapy (40.2%) than in combination therapy (46.3%).ConclusionsThis study described real-world treatment patterns of sarilumab, highlighting frequent initiation in biologic DMARD-naïve patients, particularly among older adults. Sarilumab demonstrated sustained effectiveness and a consistent safety profile with no new safety signals, supporting its use as monotherapy or combination therapy.Trial registration numberjRCT1071190016.

ObjectivesTo provide a comprehensive description of a standardised, landmark-based ultrasound (US) technique for evaluating the lateral costotransverse (LCTL), supraspinous (SSL) and iliolumbar (ILL) ligaments of the thoracolumbar spine and to assess its reliability, feasibility and its potential applicability in spondyloarthritis (SpA).MethodsLCTL, SSL and ILL were examined using US in specimens, followed by dissection to confirm structure location and validate US findings using a standardised anatomic-based and sonoanatomic-based landmark approach. The US technique was subsequently applied in 20 healthy controls (HC), in whom feasibility and inter-rater and intra-rater reliability among four operators with different expertise were assessed. Ligament visualisation was scored as: 0, not visualised; 1, incompletely visualised; 2, perfectly visualised. The technique was tested in three patients with SpA to evaluate its applicability.ResultsAnatomical study confirmed location and landmarks for all three ligaments. 120 ligaments were assessed in two rounds in HC. Visualisation scores ranged from 1 to 2 in 100% LCTL, 99.1% SSL and 85.9% ILL, with score 2 obtained in 69.6% of 960 assessments. Mean examination time decreased from 12′17″ to 10′56″ between rounds, with no significant differences between operators. Intra-rater and inter-rater agreement ranged from moderate to high. In patients with SpA, US detected both inflammatory and structural lesions in the three ligament entheses.ConclusionThe proposed standardised US approach allows reliable assessment of LCTL, SSL and ILL. This technique provides a robust and reproducible method for evaluating the ligaments of the thoracolumbar spine and opens a new approach to the US assessment of patients with spinal inflammatory diseases, including SpA.

Antiphospholipid syndrome (APS) is an autoimmune disease characterised by obstetric morbidity and recurrent venous and/or arterial thrombosis. It is frequently associated with systemic lupus erythematosus, and thrombocytopenia is a common manifestation. This study aimed to compare patients with APS, with and without thrombocytopenia, and to describe management and outcomes of severe thrombocytopenia. We performed a retrospective single-centre study that included 432 patients with APS. Patients were divided into three groups according to the platelet count nadir: severe thrombocytopenia (< 50 G/L), moderate thrombocytopenia (between 50 and 130 G/L) and no thrombocytopenia (≥ 130 G/L). 142 patients developed thrombocytopenia during follow-up (32.9%): 57 (13%) had severe thrombocytopenia (< 50 G/L) and 85 (19.4%) had moderate thrombocytopenia (50-130 G/L). Patients with thrombocytopenia more frequently experienced thrombotic manifestations, including lower limb deep vein thrombosis (49% vs 37%, p=0.014), coronary thrombosis (15% vs 6.6%, p=0.006) and catastrophic antiphospholipid syndrome (CAPS) (27% vs 2.1%, p<0.001). Thrombocytopenia was more frequently associated with pre-eclampsia (16.8% vs 3.7%, p<0.001) and other APS manifestations, including skin (ulcer 4.9% vs 1.4%, p=0.046, cutaneous necrosis 7% vs 0.7%, p<0.001), cardiovascular (MINOCA 7% vs 0.7%, p<0.001, valvular disease 19.7% vs 9.3%, p=0.002), renal (18.3% vs 3.1%, p<0.001) and pulmonary (5.6% vs 1%, p=0.007) manifestations. Aetiologies of severe thrombocytopenia were mainly immune thrombocytopenia (ITP) and CAPS. In patients with severe thrombocytopenia, treatment followed the approach used for primary ITP, and anticoagulation was generally maintained even in the presence of bleeding episodes. Overall survival was poorer in patients with severe thrombocytopenia (p<0.0001). Our results suggest that thrombocytopenia is associated with a more severe APS phenotype and increased mortality.

ObjectiveA panel of antibodies against three antigens, University Hasselt (UH)-rheumatoid arthritis (RA).305, 318 and 329, has been associated with lack of response to first-line therapy in the Care in early RA trial. This study aimed to determine the association of this antibody panel with first-line therapy response in an independent cohort.MethodsAnti-UH-RA.305/318/329 antibody reactivity was determined using ELISA in 165 baseline samples of the CAP48 cohort, an observational cohort of patients with early and naïve RA treated mainly with methotrexate monotherapy. Multivariable analyses assessed associations between baseline antibody reactivity and failure to reach remission or low disease activity (LDA) at 3, 6, 9 and 24 months according to the Disease Activity Score 28-joint C-reactive protein (DAS28CRP) and clinical/simplified disease activity index (SDAI).ResultsIn the total RA cohort, baseline anti-UH-RA.305/318/329 antibody reactivity was significantly higher in patients not achieving LDA versus those achieving LDA at 9 months (31.6% vs 11.3% for DAS28CRP/SDAI; OR 3.64, 95% CI 1.34 to 9.91, p=0.045). In patients with seronegative RA, a significant association between antibody reactivity and not achieving LDA based on DAS28CRP (42.1% vs 12.5%; OR 5.09, 95% CI 1.2 to 27.0, p=0.05) was already observed at 6 months. After 24 months, baseline antibody positivity remained significantly associated with not achieving LDA based on SDAI (OR 29.9, 95% CI 2.5 to 109.2, p=0.01) in patients with seronegative status.DiscussionIn the CAP48 cohort, the anti-UH-RA antibody panel was associated with a lack of response to first-line therapy for certain clinical measures, observed at 9 months in the total RA cohort and at 6 and 24 months in patients with seronegative status. The antibody panel should be further validated for its use in early personalised RA treatment.

To assess structural changes at peripheral entheses and the association with spinal bone formation in patients with long-standing radiographic axial spondyloarthritis (r-axSpA) overall and stratified by sex. Peripheral entheses were examined cross-sectionally using ultrasound (US) in patients fulfilling the modified New York criteria for ankylosing spondylitis (AS) and assessed for Outcome Measures in Rheumatology consensus-based structural lesions (enthesophytes, calcifications and erosions) summed to a damage US score (0-42). Spinal radiographs were graded with the modified Stoke AS Spinal Score (mSASSS). Associations between US damage score and mSASSS were assessed with negative binomial regression analyses overall, by sex and by age quartiles. US was performed in 173 patients, 54% males, with a mean (SD) age of 55 (13) years and symptom duration of 29 (13) years. The prevalence of any structural US lesion was 92%. The US damage score was higher in males than females (mean (SD) 4.7 (3.0) versus 3.3 (2.4), p<0.001) and increased significantly with age, as did mSASSS. Univariate associations between US damage score and mSASSS were found overall and in males, but diminished with older age. The association remained significant for males when the multivariable model was adjusted for symptom duration (rate ratio (95% CI) for log-transformed mSASSS+1: 1.32 (1.04 to 1.67)). Overall, mSASSS was not associated with the US damage score when the multivariable model was adjusted for age or symptom duration. Structural lesions at the peripheral entheses are common in long-standing r-axSpA and accumulate with age, which may obscure the possible association with spinal bone formation.

18F-Fibroblast activation protein inhibitor ([18F]FAPI) positron emission tomography (PET)/CT is an emerging tool for detecting IgG4-related disease (IgG4-RD). However, standardised quantitative analysis and image scoring present ongoing challenges in patients with IgG4-RD. To establish organ-specific reference thresholds for IgG4-RD involvement on [18F]FAPI PET/CT images, and to develop a novel, clinically applicable scoring system to monitor disease activity in patients with IgG4-RD. This retrospective study recruited 85 patients with IgG4-RD and 10 healthy individuals, all of whom underwent [18F]FAPI PET/CT. Organ-specific uptake thresholds were defined as [18F]FAPI uptake greater than the maximal standardised uptake value +3 SD in the corresponding anatomical regions of healthy individuals. Moreover, we developed a novel method, [18F]FAPI PET/CT Activity Score of IgG4-RD (FPAS-IgG4), for scoring disease activity using a logistic regression model with receiver operating characteristics curve analysis. Among 85 patients with IgG4-RD, 64 lesions suspected of IgG4-RD involvement were biopsied and 58 (90.6%) of these lesions were positive for IgG4. [18F]FAPI PET/CT achieved a sensitivity, specificity and accuracy of 86.2%, 83.3% and 85.9%, respectively, for detecting IgG4-RD based on organ-specific uptake thresholds. The active disease group had a higher FPAS-IgG4 than the inactive disease group (5.2±3.0 vs 1.7±1.3, p<0.0001). FPAS-IgG4 >2 showed a sensitivity of 93.2% and a specificity of 73.1% in distinguishing between active and inactive disease. Multivariable logistic regression analysis demonstrated that FPAS-IgG4 was strongly associated with active IgG4-RD (p=0.001). [18F]FAPI PET/CT could be a valuable tool for monitoring the activity of IgG4-RD, aiding in disease stratification.