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Bone reconstruction requires the use of autografts from patients’ iliac crest (IC); for large-volume defects bone void fillers and autologous mesenchymal stem cells (MSCs) are often added. The Reamer/Irrigator/Aspirator (RIA) device provides the means of harvesting large amounts of autograft and additionally yields a waste bag containing MSCs, which is currently discarded. The aim of this study was to enumerate and characterise native MSCs from RIA waste bag and compare them to ‘gold-standard’ donor-matched MSCs from IC bone marrow (BM). IC-BM from age matched trauma patients was used as control. In RIA waste bags the median MSC yield established using a colony-forming fibroblast assay was 314333 (range 5 x 104-1.4 x 106), equivalent to approximately one litre of IC-BM aspirate. CD271+ cells were present at high levels in RIA waste bags, had MSC surface phenotype (CD90+CD73+CD105+CD34>sup>-CD61-CD19-CD31-CD33-) and expressed genes associated with multipotentiality, osteogenesis, adipogenesis and angiogenic support. RIA- CD271+ MSCs were transcriptionally similar to donor-matched IC-CD271+ MSCs (76 % transcripts); with the majority of bone-related and Wnt pathway molecules being expressed at comparable levels. Lower-level expression of MCAM/CD146 and 5/13 hypoxia-related molecules was found in RIA-CD271+ MSCs, potentially reflecting their native residence in a more hypoxic environment of the endosteum and bone cortex. These data suggest that long bones contain very large numbers of MSCs, transcriptionally-similar to IC-BM MSCs; they can be procured by reaming using the RIA device and used, following concentration, as autologous and potentially allogeneic bone repair therapy.

Biomechanical factors including occupational joint physical stressing and joint injury have been linked to spondyloarthritis. We explored such factors in ankylosing spondylitis (AS). A retrospective, online survey was developed alongside the UK National Ankylosing Spondylitis Society (NASS). Questions on early entheseal symptoms, potential precipitating trauma, sporting activity, and physiotherapy were asked. A total of 1026 patients responded with 44% recalling an instance of injury or trauma as a potential trigger for their AS. After symptom onset, 55% modified sporting activities and 28% reported that the initial AS recommended exercises exacerbated symptoms. Patients report physical trauma, exercise and physiotherapy as potential triggers for AS symptoms. These findings further support the experimental evidence for the role of biomechanical factors in disease.

Objectives. Diffuse swelling of the distal interphalangeal (DIP) joint beyond the joint margin is a common feature of arthritis in psoriatic arthritis (PsA). The purpose of this study was to explore the microanatomical basis for the inflammation and nail disease in PsA using a combined high-resolution magnetic resonance imaging (MRI) and histological studies.Methods. High-resolution MRIs of the DIP joint were obtained in 30 subjects [10 PsA, 10 osteoarthritis (OA) and 10 normal volunteers]. The relationship between the DIP joint capsule and associated tendon enthesis and the nail bed and root were evaluated. Histological studies to define the relationship between the normal cadaveric DIP joint capsule and the nail root were performed on the middle and ring fingers of 10 dissecting room cadavers.Results. On MRI, the dorsal capsular enthesis was the epicentre of an inflammatory reaction. This extended to involve the soft tissues adjacent to the nail in 8 of 10 cases in PsA, but only 4 of 10 cases in OA where the inflammation is less intense and in none of the normal fingers. The DIP joint capsule was intimately linked with the nail complex on histology, with the dorsal, volar and lateral aspects of the nail bed being ensheathed in fibres extending from the entheses.Conclusion. The study suggests that the extended nature of the enthesis organ associated with the DIP joint may explain the diffuse nature of the inflammatory response around the nail in PsA. Therefore the nail is as much an integral part of the enthesis organ as it is of the skin, which has implications for a better understanding of the disease. [ABSTRACT FROM AUTHOR]

To describe the basis for entheseal‐associated bone disease in the spondylarthritides, by analyzing microanatomic and histopathologic relationships between soft tissue, bone cortex, and adjacent trabeculae.Serial sections from 52 entheses were examined; these entheses encompassed small and large insertions in the upper limb (n = 21), lower limb (n = 27), and spine (n = 4) from 60 cadavers. Enthesis microdamage (fissuring) as well as vascular and reparative changes were evaluated. Contact radiographs were used to ascertain the relationship between entheses and the trabecular network.At virtually all fibrocartilaginous entheses, the deep cortical boundary was extremely thin (typically 50–600 μm) or indistinguishable, and 96% of entheses had small holes in the cortical shell (typically 100–400 μm wide). Such regions were frequent sites of bone formation and renewal (96%) and microdamage (31%); these changes were more common in the lower limb. The presence of blood vessels near holes in the cortical shell was common; in 85% of attachments, blood vessels were present on the soft tissue side of the enthesis. Highly orientated trabeculae were more obvious in the lower limb than the upper limb (59% versus 29%).The trabecular network supporting the cortical shell is an integral part of the enthesis, transferring load to an extensive skeletal region. In many cases, tendons/ligaments are anchored directly to such networks. This functional integration is associated with microdamage and repair at the hard tissue–soft tissue interface. These findings have implications for understanding bone involvement in SpA and for the SpA concept in general, especially the hypothesis that enthesis–bone architecture may be important in disease initiation. [ABSTRACT FROM AUTHOR]

The Achilles tendon insertion is associated with a complex of adjacent fibrocartilages, a bursa, and a fat‐pad, and is functionally much more than a focal insertion. This has important implications for a better understanding of the spondylarthropathies (SpA). However, the degree to which other insertions form comparable “enthesis organs” has not been established. The aim of this study was to demonstrate the applicability of the enthesis organ concept to other insertion sites. Both joint‐related (articular) and extraarticular entheses were removed from 28 sites in the limbs of formalin‐fixed cadavers (age at death 70–101 years) that had been donated for anatomic study. The samples were prepared for paraffin histologic analysis and sectioned longitudinally. The presence and extent of enthesis organs was evaluated at each site in serial sections stained with Masson's trichrome and toluidine blue. Articular enthesis organs were found at 14 entheses, including the attachments of the digital extensor tendons and collateral ligaments, the cruciate ligaments, tibialis anterior, the lateral collateral ligament of the knee, and the popliteal tendon. Extraarticular enthesis organs were seen at 2 sites, the biceps brachii and patellar tendon insertions. In all enthesis organs, sesamoid and/or periosteal fibrocartilage was present in close association with synovium. The concept of an enthesis organ is of general significance in understanding attachment sites and may explain the diverse pathologic changes, including synovitis, bursitis, and extracapsular changes, seen adjacent to tendon/ligament entheses in SpA. These findings may provide insight into the reason the target tissues in SpA are apparently so diverse. [ABSTRACT FROM AUTHOR]

Objectives. This study assessed the utility of rituximab for the therapy of RA in a non-academic environment in a group of cases where anti-TNF was either not available or relatively contraindicated. Methods. Thirty-nine patients with active RA who had failed at least one DMARD received two rituximab infusions 2 weeks apart. Seventeen patients received two 1000 mg doses, and 22 received the 500 mg regimen. The 28-joint disease activity index (DAS28) and European League against Rheumatism (EULAR) response criteria were recorded at baseline, 3, 6, 9 and 12 months. RF and ANA were recorded at baseline and at 6 and 12 months. Results. There was a significant improvement in the DAS28 at all time points, and EULAR response was observed in 29 of 33 patients (87.9%) at 3 months, 25 of 33 patients (75.8%) at 6 months, 22 of 29 patients (75.9%) at 9 months and 23 of 30 patients (76.7) at 12 months. Improvement was also noted in CRP, and both RF and ANA were generally reduced after treatment. Patients who were on the higher regimen of two 1000 mg doses appeared to respond slightly better compared with the lower dose regimen. Conclusions. Rituximab is well tolerated in everyday clinical practice and may represent a good short-term treatment option where anti-TNF therapy is either unavailable or relatively contraindicated. [ABSTRACT FROM AUTHOR]

Objectives. The utility of autologous chondrocytes for cartilage repair strategies in older subjects with osteoarthritis (OA) may be limited by both age-related and disease-associated decline in chondrogenesis. The aim of this work was to assess OA Hoffas fat pad as an alternative source of autologous chondroprogenitor cells and to compare it with OA chondrocytes derived from different areas of cartilage. Methods. Cartilage and fat pad tissue digests were obtained from 26 subjects with knee OA and compared with normal bone marrow (BM) mesenchymal stem cells (MSCs) with respect to their in vitro colony-forming potential, growth kinetics, multipotentiality and clonogenicity. Flow cytometry was used to investigate their MSC marker phenotype. Results. Expanded cultures derived from eroded areas of cartilage were slightly more chondrogenic than those derived from macroscopically normal cartilage or chondro-osteophytes; however, all cartilage-derived cultures failed to maintain their chondrogenic potency following extended expansion. In contrast, OA fat pads contained highly clonogenic and multipotential cells with stable chondrogenic potency in vitro, even after 16 population doublings. Standard colony-forming assays failed to reflect the observed functional differences between the studied tissues whereas flow cytometry revealed higher levels of a putative MSC marker low-affinity growth factor receptor (LNGFR) on culture expanded fat pad-derived, but not cartilage-derived, MSCs. Conclusions. In contrast to OA cartilage from three different sites, OA Hoffas fat pad contains clonogenic cells that meet the criteria for MSCs and produce multipotential cultures that maintain their chondrogenesis long term. These findings have broad implications for future strategies aimed at cartilage repair in OA. [ABSTRACT FROM AUTHOR]

Takayasu arteritis, a granulomatosis vasculitis with a pathogenesis that is poorly defined but known to be associated with HLA-B*52, shares many features with other MHC-I-opathies. In addition to the shared clinical features of inflammatory bowel diseases, cutaneous inflammation, and HLA-B*52, is shared association of an IL12B single- nucleotide polymorphism encoding the common IL-12 and IL-23 p40 subunit, which might affect not only type 17 cytokine responses, but also IFNγ and TNF production-the cardinal type 1 cytokines in granuloma formation. Considering the translational context of responses to TNF inhibition in Takayasu arteritis, in this Personal View we propose Takayasu arteritis as a type 1 MHC-I-opathy. Additionally, type 1 and type 17 T-cell immune responses show immune plasticity, which connects the overlapping features of Takayasu arteritis and spondyloarthritis spectrum disorders, providing a basis for shared anti-TNF responses, and points to p40 and IFNγ cytokine antagonism and potential selective CD8 T-cell repertoire ablation., Competing Interests: Declaration of interests DM has received grant funding and honoraria from AbbVie, Janssen, Eli Lilly, Novartis, and UCB. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background & Objectives : To explore the potential association between positive ANA serology and all-cause mortality in a large cohort of patients, including those with and without rheumatological conditions and other immune-related diseases. Material and Methods : A retrospective cohort study analyzed all-cause mortality among 205,862 patients from Clalit Health Services (CHS), Israel's largest health maintenance organization (HMO). We compared patients aged 18 and older with positive ANA serology (n = 102,931) to an equal number of ANA-negative controls (n = 102,931). Multivariable Cox regression models were used to assess hazard ratios (HR) for mortality, adjusting for demographic and clinical factors. Results : ANA positivity was strongly associated with increased mortality (adjusted HR [aHR] 4.62; 95% CI 4.5-4.7, p < 0.001). Significant predictors of mortality included male gender (39.2% vs. 24.4%, p < 0.001), older age at testing (72.4 ± 13.0 vs. 50.1 ± 17.3 years, p < 0.001), and Jewish ethnicity (89.6% vs. 83.2%, p < 0.001). Certain ANA patterns, such as mitochondrial (and dense fine speckled (DFS-AC2)), were highly predictive of mortality, with aHRs of 36.14 (95% CI 29.78-43.85) and 29.77 (95% CI 26.58-33.34), respectively. ANA-positive patients with comorbid rheumatological immune-related disorders (RIRDs) demonstrated a higher survival rate compared to those without such a condition (aHR 0.9, 95% CI 0.86-0.95, p < 0.001). This finding remained significant after adjusting for several parameters, including age. Conclusions : ANA positivity is associated with increased all-cause mortality, particularly in individuals without rheumatologic disorders, after adjusting for confounders such as age. This may indicate occult malignancies, cardiovascular pathology, or chronic inflammatory states, necessitating more vigilant surveillance.

Variable axial skeleton inflammation and axial skeleton tissue remodelling with aberrant ligamentous soft-tissue ossification occurs across the axial spondyloarthritis (ax-SpA) axial psoriatic arthritis (ax-PsA) and the diffuse idiopathic skeletal hyperostosis (DISH) spectrum. In this article, we show how imaging has resulted in an enthesis-centric model for different disease pathology compartmentalisation or a 'root and trunk' model for pathological process development. Whilst ankylosing spondylitis is predominantly characterised by early entheseal bony anchorage-related osteitis (root inflammation) and DISH is characterised by ligamentous soft-tissue ossification, ax-PsA is more heterogenous. Whilst ax-PsA may share an identical osteitis pattern to ax-SpA, a substantial proportion of ax-PsA cases have a soft tissue or tree trunk pathology that manifests as back pain with lack of osteitis but prominent ligamentous trunk ossification at later stages. We illustrate this using different imaging modalities to create a base for imaging research to elucidate this pattern of pathology., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Psoriatic arthritis (PsA) is a chronic rheumatic disease that usually appears in patients with skin psoriasis, making it a model for detection of joint disease in the pre-clinical phases in a setting where therapy for cutaneous disease may ameliorate or prevent arthritis development. Such PsA prevention appears credible due to the increasingly recognized closely shared immunopathology between the skin and joints, especially the entheses. Recently, several initiatives have explored the concept of pre-clinical PsA, and nomenclatures have been developed with the recent EULAR nomenclature proposing a simplified three stages from psoriasis to clinical PsA development, namely at risk of PsA, subclinical PsA and early PsA. A better comprehension of early PsA and the identification of individuals predisposed to its development could enable interventions to 'prevent' the appearance of PsA. Several recent retrospective observational studies have demonstrated disease interception feasibility, i.e. treatment of people with psoriasis may prevent the appearance of PsA, in particular using biologic disease-modifying drugs. However, further data are urgently required due to unexpected findings in some studies where TNF inhibition for psoriasis does not reduce the rate of PsA development. In this review we address the current challenges in early PsA, including comparisons of pre-PsA nomenclature sets, its risk factors and the potential for disease interception., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aim: Diagnostic imaging is an integral part of identifying spondyloarthropathies (SpA), yet the interpretation of these images can be challenging. This review evaluated the use of deep learning models to enhance the diagnostic accuracy of SpA imaging., Methods: Following PRISMA guidelines, we systematically searched major databases up to February 2024, focusing on studies that applied deep learning to SpA imaging. Performance metrics, model types, and diagnostic tasks were extracted and analyzed. Study quality was assessed using QUADAS-2., Results: We analyzed 21 studies employing deep learning in SpA imaging diagnosis across MRI, CT, and X-ray modalities. These models, particularly advanced CNNs and U-Nets, demonstrated high accuracy in diagnosing SpA, differentiating arthritis forms, and assessing disease progression. Performance metrics frequently surpassed traditional methods, with some models achieving AUCs up to 0.98 and matching expert radiologist performance., Conclusion: This systematic review underscores the effectiveness of deep learning in SpA imaging diagnostics across MRI, CT, and X-ray modalities. The studies reviewed demonstrated high diagnostic accuracy. However, the presence of small sample sizes in some studies highlights the need for more extensive datasets and further prospective and external validation to enhance the generalizability of these AI models., Key Points: Question How can deep learning models improve diagnostic accuracy in imaging for spondyloarthropathies (SpA), addressing challenges in early detection and differentiation from other forms of arthritis? Findings Deep learning models, especially CNNs and U-Nets, showed high accuracy in SpA imaging across MRI, CT, and X-ray, often matching or surpassing expert radiologists. Clinical relevance Deep learning models can enhance diagnostic precision in SpA imaging, potentially reducing diagnostic delays and improving treatment decisions, but further validation on larger datasets is required for clinical integration., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is Eyal Klan. Conflict of interest: The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry: No complex statistical methods were necessary for this paper. Informed consent: Written informed consent was not required. Ethical approval: Institutional Review Board approval was not required. Study subjects or cohorts overlap: No study subjects or cohorts have been previously reported. Methodology: Multicenter study, (© 2024. The Author(s).)

Background: Despite the well-established association between chronic inflammatory conditions and pulmonary embolism(PE), previous investigations of the relationship between Dermatomyositis(DM) and Polymyositis(PM) with PE were scarce and have been subject to significant limitations, including small sample sizes and failure to account for potential confounders., Objectives: To investigate the correlation between DM/PM and PE, as well as assessing the impact of serologic status, myonecrosis, and inflammation markers on this relationship., Methods: In this large, nationwide population-based study, we used the Clalit Health Services medical database and extracted all DM/PM patients who were first diagnosed between 1 January 2002 to 31 December 2018 and compared them with age and gender matched controls in a ratio of 1:5. Serological and laboratory values were obtained for each patient. Rates of PE were compared between groups using multivariate models., Results: The study included 1557 DM patients with 7633 controls, and 528 PM patients with 2560 controls. Compared with matched controls, the rates of PE were significantly higher in the DM/PM group, PM patients(2.8 % vs 0.5 % in controls, OR = 5.73, p < 0.001), DM patients(1.2 % vs 0.3 % in controls, OR = 3.42, p < 0.001). APLA seropositivity was significantly more prevalent in DM/PM patients compared with their matched controls, PM patients(10.8 % vs 2.7 % in controls, p < 0.001), DM patients(7.9 % vs 1.6 % in controls, p < 0.001). APLA seropositivity had a synergistic effect for PE in the DM/PM(OR = 23.18, p < 0.001)., Conclusions: DM and PM are associated with higher rates of PE. Furthermore, patients with DM/PM demonstrate a significantly higher prevalence APLA which act as a potentiator of thrombosis in these patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Imaging has transformed the understanding of inflammatory and degenerative arthritis in both peripheral and axial disease. In axial inflammation, fat suppression magnetic resonance imaging (MRI) has unravelled the role of sub-fibrocartilaginous osteitis in axial spondyloarthritis and the role of peri-entheseal vertebral body osteitis and subsequent spinal new bone formation. Established or late-stage axial psoriatic arthritis (PsA) cases often exhibit impressive para-marginal or chunky syndesmophytosis on conventional X-ray that pathologically represents entheseal soft tissue ossification. However, the spinal entheseal soft tissue and contiguous ligamentous tissues are poorly visualized on MRI in subjects with early inflammatory back pain including those with axial PsA. In this article, we highlight the need for imaging modalities to discern the crucial soft tissue "ligamentous" component of axial PsA towards diagnosis, prognosis and therapy validation. We issue a clarion call to focus advanced imaging methodology on spinal ligamentous soft tissue that represents the last hidden backwater of PsA immunopathology that needs visualization to fully decipher axial PsA pathogenesis. This in combination with the existing ability to visualize ligamentous bony anchorage site osteitis is needed to define a gold standard test for axial PsA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Midfoot pain is common but poorly understood, with radiographs often indicating no anomalies. This study aimed to describe bone, joint and soft tissue changes and to explore associations between MRI-detected abnormalities and clinical symptoms (pain and disability) in a group of adults with midfoot pain, but who were radiographically negative for osteoarthritis., Methods: Community-based participants with midfoot pain underwent an MRI scan of one foot and scored semi-quantitatively using the Foot OsteoArthritis MRI Score (FOAMRIS). Foot pain and disability were recorded using visual analog scales (VAS) and the Modified-Manchester Foot Pain Disability Index (MMFPDI). Associations were assessed for continuous data using Spearman's Rho, and for categorical data, a Wilcoxon signed rank test. Linear regression was used to explore the association between participant-reported measures and MRI abnormalities, adjusted for age, sex and BMI., Results: Sixty-one participants (70% female, mean age 48.5 years, median BMI 28.6 kg/m 2 ) were included. Median VAS pain was 31/100 mm (IQR 21-47) and median disability was 30/48 (IQR 26-36). There was a moderate association between midfoot pain severity and the number of joints exhibiting joint space narrowing; adjusted results suggested 31% (95% confidence interval 3%-68%) worse VAS pain with each additional affected joint. Greater numbers of joints with cysts were associated with worse VAS pain [14% (0%-31%)] and disability [1.1 units (0-2.2)]. Effusion/synovitis was associated with MMFPDI pain. No other MRI abnormalities were associated with sex, body mass and foot pain/disability measures. Bone marrow lesions, joint space narrowing, cysts and osteophytes occurred more frequently with age. MRI abnormalities were common, particularly in the talo-navicular joint, first and second cuneo-metatarsal joints. Those with dorsal foot pain had more multi-joint involvement, bone marrow lesions, joint space narrowing and cysts and for those with pain on midfoot movement, bone marrow lesions and cysts were reported., Conclusions: In people with midfoot pain, MRI-detected features of osteoarthritis and soft-tissue abnormalities were found, clustered in the medial and intermediate cuneiform joints. These features were more common with age but not associated with pain or disability measures. Younger people with dorsal midfoot pain exhibited early signs of bone and joint features of osteoarthritis and we recommend further imaging studies to determine the clinical and diagnostic significance., (© 2025 The Author(s). Journal of Foot and Ankle Research published by John Wiley & Sons Australia, Ltd on behalf of Australian Podiatry Association and The Royal College of Podiatry.)

Background: Sarcoidosis is a multisystem granulomatous disorder with a variable clinical course and complications. The relationship between sarcoidosis and malignancies remains unclear, including specific malignancy associations with sarcoidosis and whether the association is short-term, long-term, or a result of misdiagnoses or coincidence. This study investigated the association between sarcoidosis and malignancy by analyzing the varying intervals between the diagnoses of these two conditions to clarify their inter-relationship. Methods: This retrospective cohort study included almost 24,000 sarcoidosis patients and matched controls at a 1:5 ratio in patients diagnosed between 2000 and 2015 in Israel. Patients had a median age of 57 years. Malignancy rates were compared across several timeframes: overall, within one year before or after sarcoidosis diagnosis and more than one year. Logistic regression models were employed to estimate odds ratios for the association between sarcoidosis and malignancy, adjusting for sociodemographic and clinical variables. Results: Sarcoidosis patients had a significantly higher prevalence of malignancies (19.5%) compared to controls (13.6%) ( p < 0.001). The association remained significant for both hematologic malignancies (OR: 2.94, 95% CI: 2.41-3.57) and solid malignancies (OR: 1.41, 95% CI: 1.27-1.55). The strongest association was observed with lymphoma, particularly within the first year of sarcoidosis diagnosis (OR: 14.88, 95% CI: 8.83-25.1). Elevated odds for malignancies persisted both within one year and beyond, including sarcoma and soft tissue cancers and genitourinary malignancies. Conclusions: Our study confirms a significant association between sarcoidosis and both hematologic and solid malignancies in both the short and long term across various timeframes. These findings emphasize the need for increased clinical vigilance in sarcoidosis patients and highlight the importance of further research into the shared genetic and environmental mechanisms that may underlie this relationship.

Objectives: To characterize the effect of upadacitinib 15 mg once daily (UPA15) on enthesitis in patients with PsA from the SELECT-PsA Phase 3 trials., Methods: Patients with an inadequate response/intolerance to one or more non-biologic DMARD (SELECT-PsA 1) or one or more biologic DMARD (SELECT-PsA 2) received UPA15, adalimumab 40 mg every other week or placebo (weeks 0-24) switched to UPA15 (week 24 onward). The Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada (SPARCC) index were used to assess improvement in enthesitis, enthesitis resolution, maintenance of enthesitis resolution and protection from enthesitis development through week 56., Results: Data from 639 patients receiving UPA15 and 635 patients receiving placebo (including 317 patients who switched from placebo to UPA15) were analysed. UPA15 led to higher rates of enthesitis resolution vs placebo at week 24 (LEI: 59.8% vs 38.0%; SPARCC index: 50.6% vs 31.5%, respectively) and greater improvements in the LEI (-1.7 vs -1.0) and SPARCC index (-3.4 vs -1.9); improvements were maintained through week 56. Improvements were observed after 12 weeks of UPA15 treatment. Over 90% of patients without enthesitis (LEI = 0) at baseline receiving UPA15 were enthesitis-free at week 56, and UPA15 prevented recurrence of enthesitis at week 56 in >80% of patients with enthesitis at baseline who achieved resolution (LEI = 0) at week 24., Conclusions: UPA15 is associated with a comprehensive improvement in enthesitis, with improvements observed after 12 weeks of treatment. Additionally, treatment with UPA15 was associated with maintaining an enthesitis-free state after resolution and protection against new-onset enthesitis., Trial Registration: ClinicalTrials.gov identifiers: NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The immunological basis for cardiac deaths remote from potential triggering viral infection, including SARS-CoV-2 infection, remains enigmatic. Cardiac surface inflammation, including the pericardium, epicardium and superficial myocardium with associated coronary artery vasculitis in infant Kawasaki Disease (KD) and multisystem inflammatory syndrome in children (MIS-C) is well recognised. In this perspective, we review the evidence pointing towards prominent post-viral infection related epicardial inflammation in older subjects, resulting in atherosclerotic plaque destabilisation with seemingly unrelated myocardial infarction that may be temporally distant from the actual infectious triggers. Cardiac surface inflammation in the relatively immune cell rich tissues in the territory though where the coronary arteries traverse is common in the adult post-COVD pneumonic phase and is also well described after vaccination including pre-COVID era vaccinations. Immunologically, the pericardium/epicardium tissue was known to be critical for coronary artery territory atherosclerotic disease prior to the COVID-19 era and may be linked to the involvement of the coronary artery vasa vasorum that physiologically oxygenates the coronary artery walls. We highlight how viral infection or vaccination-associated diffuse epicardial tissue inflammation adjacent to the coronary artery vasa vasorum territory represents a critical unifying concept for seemingly unrelated fatal coronary artery atherosclerotic disease, that could occur soon after or remote from infection or vaccination in adults. Mechanistically, such epicardial inflammation impacting coronary artery vasa vasorum immunity acts as gateways towards the slow destabilisation of pre-existing atherosclerotic plaques, with resultant myocardial infarction and other cardiac pathology. This model offers immunologists and academic cardiologists an immunopathological roadmap between innocuous viral infections or vaccinations and seemingly temporally remote "unrelated" atherosclerotic disease with excess cardiac deaths., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To assess the frequency of simultaneous distal interphalangeal (DIP) joint disease and adjacent nail psoriasis (finger unit) among patients with psoriatic arthritis (PsA) and compare the efficacy of the IL-17A antagonist ixekizumab (IXE) and the TNF-α inhibitor adalimumab (ADA)., Methods: This post hoc analysis evaluated the simultaneous occurrence of DIP joint involvement (tenderness and/or swelling) and adjacent nail psoriasis among patients with PsA from the SPIRIT-H2H (NCT03151551) trial comparing IXE to ADA. Among patients with simultaneous DIP joint involvement and adjacent nail psoriasis in ≥1 digit at baseline, treatment effects were assessed through week 52 for each affected finger unit; 'finger unit' defines the connected DIP joint and adjacent nail of an individual digit., Results: A total of 354 patients had simultaneous DIP joint involvement and adjacent nail psoriasis in ≥1 finger unit at baseline. Among them, 1309 (IXE: 639; ADA: 670) finger units had baseline DIP joint tenderness and/or swelling and adjacent nail psoriasis. Proportions of affected finger units achieving complete resolution were significantly higher with IXE vs ADA as early as week 12 (38.8% vs 28.4%, P < 0.0001) and at all post-baseline assessments through week 52 (64.9% vs 57.5%, P = 0.0055)., Conclusion: In this study cohort, patients with DIP joint involvement almost always had adjacent nail psoriasis. Greater resolution of DIP joint tenderness, swelling and adjacent nail psoriasis was achieved at all time points over 52 weeks through targeting IL-17A with IXE than TNF-α with ADA, which is noteworthy given prior comparable musculoskeletal outcomes for both drug classes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

To develop a core outcome set for Achilles tendinopathy (COS-AT) for use in clinical trials we performed a five-step process including (1) a systematic review of available outcome measurement instruments, (2) an online survey on truth and feasibility of the available measurement instruments, (3) an assessment of the methodological quality of the selected outcome measurement instruments, (4) an online survey on the outcome measurement instruments as COS and (5) a consensus in-person meeting. Both surveys were completed by healthcare professionals and patients. The Outcome Measures in Rheumatology guidelines with a 70% threshold for consensus were followed. We identified 233 different outcome measurement instruments from 307 included studies; 177 were mapped within the International Scientific Tendinopathy Symposium Consensus core domains. 31 participants (12 patients) completed the first online survey (response rate 94%). 22/177 (12%) outcome measurement instruments were deemed truthful and feasible and their measurement properties were evaluated. 29 participants (12 patients) completed the second online survey (response rate 88%) and three outcome measurement instruments were endorsed: the Victorian Institute of Sports Assessment-Achilles questionnaire, the single-leg heel rise test and evaluating pain after activity using a Visual Analogue Scale (VAS, 0-10). 12 participants (1 patient) attended the final consensus meeting, and 1 additional outcome measurement instrument was endorsed: evaluating pain during activity/loading using a VAS (0-10). It is recommended that the identified COS-AT will be used in future clinical trials evaluating the effectiveness of an intervention. This will facilitate comparing outcomes of intervention strategies, data pooling and further progression of knowledge about AT. As COS-AT is implemented, further evidence on measurement properties of included measures and new outcome measurement instruments should lead to its review and refinement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The enthesitis hypothesis posits that enthesitis is a primary lesion and that inflammation at the enthesis initiates the musculoskeletal symptoms of psoriatic arthritis (PsA) and spondyloarthropathies (SpA). The hypothesis suggested that inflamed entheseal tissue near the synovium could trigger cytokine-mediated synovitis, that enthesis bone anchorage could explain osteitis, and that the location of entheses at the soft tissue interface could explain dactylitis. Advances in imaging techniques that allow better visualization of enthesitis lesions and the development of animal models have allowed evolution of the concept of enthesitis as a central mechanistic driver of musculoskeletal symptoms in PsA and SpA. A debate between Drs. Dennis McGonagle and Bruce Kirkham at the Group for Research on Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting discussed the data supporting and refuting this hypothesis in PsA and SpA, respectively. The major points of this debate are summarized in this article., (Copyright © 2024 by The Journal of Rheumatology.)

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20 th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Abacar, Macleod, Direskeneli and McGonagle.)

Psoriatic arthritis (PsA) predominantly emerges in individuals previously diagnosed with psoriasis (PsO), offering a unique opportunity to study the transition from PsO to PsA. This progression provides a window to identify characteristics of PsO patients who may develop PsA, facilitating early intervention and potentially informing prevention and treatment strategies. This review evaluates a wide array of research focusing on various risk factors for PsA development. These factors span demographic characteristics, concomitant diseases and habits, characteristics of skin and nail psoriatic disease, and symptoms and imaging abnormalities associated with PsA. By summarising the existing literature, this review critically examines each risk factor, highlighting the strengths and limitations inherent in the studies. Each section of the review not only summarises the current state of knowledge but also includes an expert opinion, culminating in a final concluding remark. This integration allows physicians to utilise the confluence of established literature and ongoing clinical experience, facilitating a rationalised decision-making process that is deeply informed by both empirical evidence and practical insights.

Introduction: Biologic therapies are licensed for both psoriasis (PsO) and psoriatic arthritis (PsA) with some electronic medical record data suggest that IL (Interleukin)-23 blockers might be more protective in PsA prevention than TNF blockers; however, the findings have been inconsistent. Higher Psoriasis Area and Severity Index (PASI) scores have also been linked to an increased PsA risk. To clarify these unresolved issues we investigated biologic agents, methotrexate, phototherapy, and topical therapy for PsA prevention in patients with psoriasis., Methods: This retrospective cohort study analyzed data from 58,671 patients with psoriasis from the Israeli Meuhedet Health Services Organization database was evaluated for incident PsA. Patients were categorized on the basis of treatment: group 1, topical therapy; group 2, phototherapy; group 3, conventional disease-modifying antirheumatic drugs (cDMARDs; methotrexate); group 4, biologic DMARDs which was also stratified according to biologic class., Results: The PsA incidence rate was lower in the biologic agents' group versus the methotrexate group (HR 0.46 [95% CI 0.35-0.62]). The incidence rates per 100 person-years varied across biologic treatment groups, with the anti‑IL‑12/23 or anti‑IL‑23p19 group at 4.57, the anti-IL-17 group at 4.35, and the TNF inhibitor group at 2.55. No differences were found between various biological agents in terms of preventing PsA. The phototherapy group exhibited a higher PsA development rate than the topical therapy group (HR 1.85 [95% CI 1.65-2.07])., Conclusion: Biological agents are more effective than methotrexate in reducing incident PsA in patients with psoriasis. This lower rate of PsA on topical therapy compared to phototherapy supports the importance of psoriasis severity as a risk factor., (© 2024. The Author(s).)

Objectives: The direct impact of inflammatory conditions and their therapy with corticosteroids contribute to an increased risk of osteoporosis with associated fractures. Familial Mediterranean fever (FMF) is an autoinflammatory disorder not commonly treated with corticosteroids. Evidence regarding FMF association with osteoporosis and femur fractures is anecdotal. We aimed to evaluate the incidence and risk of osteoporosis and femoral neck fracture in FMF patients compared with the general population., Methods: A retrospective cohort study using the electronic database of Clalit Health Services of all FMF patients first diagnosed between 2000 and 2016 and controls was conducted including age- and sex-matched controls in a 1:1 ratio. Follow-up continued until the first diagnosis of osteoporosis or fracture. Risk for these conditions was compared using univariate and multivariate Cox regression models., Results: A total of 9769 FMF patients were followed for a median period of 12.5 years. Of these, 304 FMF patients were diagnosed with osteoporosis compared with 191 controls, resulting in an incidence rate (per 10 000 persons-years) of 28.8 and 17.8, respectively, and a crude hazard ratio of 1.62 (95% CI 1.35, 1.93; P < 0.001). Patients were diagnosed with osteoporosis at a considerably younger age than controls [60.1 (s.d. 12.4) vs 62.5 (s.d. 11.0) years; P = 0.028]. A total of 56 FMF patients were diagnosed with femoral neck fracture compared with 35 controls, resulting in an incidence rate of 5.3 and 3.3, respectively, and a crude HR of 1.60 (95% CI 1.05, 2.44; P < 0.05)., Conclusion: FMF patients are at increased risk for osteoporosis and consequently femur fracture. Our findings emphasize the importance of considering bone health in the management of FMF patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives : The objective of this study was to evaluate the real-world drug survival, adherence, and discontinuation risk of biologics disease-modifying anti-rheumatic drugs (bDMARDs) among patients with ankylosing spondylitis (AS). Methods : This was a retrospective study using a computerized database. Biologic-naïve and biologic-experienced AS patients who initiated treatment with bDMARDs (tumor necrosis factor alpha inhibitors {TNF-αis} or interleukin-17 inhibitor {IL-17i}) during 2015-2018 were included. Adherence was assessed using the proportion of days covered (PDC) method. Drug survival was analyzed using Kaplan-Meier estimates. Risk of discontinuation was estimated by the Cox proportional hazard model. Results : We identified 343 eligible patients utilizing 481 lines of therapy. The mean age was 44.6 years (SD ± 13.4), 57.7% were males, and 69.7% were biologic-naïve at baseline. The proportion of highly adherent patients (PDC ≥ 0.8) in the biologic-naïve group was 63.5% for golimumab, 69.2% for etanercept, and 71.6% for adalimumab ( p > 0.9). Among the biologic-experienced group, secukinumab had the highest proportion of adherent patients (75.7%) and etanercept the lowest (50.0%) reaching statistical difference ( p < 0.001). The Kaplan-Meier analysis did not show a significant difference in drug survival in either the biologic-naïve or the biologic-experienced groups ( p = 0.85). Multivariable analysis demonstrated a similar risk for discontinuation for etanercept, golimumab, and secukinumab compared with adalimumab, regardless of biologic-experience status. Conclusions : Adherence, drug survival, and risk for discontinuation were similar for all TNF-αis and the IL-17i SEC, regardless of biologic-experience status. As drug survival is an indirect measure of drug efficacy, n, in real-world settings, we believe caregivers can integrate these results into treatment considerations.

Introduction: The presence (vs absence) of enthesitis/dactylitis is associated with greater psoriatic arthritis (PsA) activity and reduced health-related quality of life. Risankizumab, an interleukin 23 antagonist, demonstrated superior treatment efficacy over placebo in patients with PsA, including enthesitis/dactylitis. Herein, we report the efficacy of risankizumab on complete resolution of enthesitis and/or dactylitis and improvements in patient-reported outcomes in patients with PsA., Methods: This integrated post hoc analysis of data from KEEPsAKE 1 and KEEPsAKE 2 included patients with baseline enthesitis (Leeds Enthesitis Index > 0) and/or dactylitis (Leeds Dactylitis Index > 0). Efficacy outcomes at weeks 24 and 52 included proportion of patients achieving enthesitis and/or dactylitis resolution and minimal clinically important differences (MCID) in pain, Health Assessment Questionnaire-Disability Index, and Functional Assessment of Chronic Illness Therapy-Fatigue., Results: Of 1407 patients, approximately 63%, 28%, and 20% had baseline enthesitis, dactylitis, and both enthesitis/dactylitis, respectively. At week 24, higher response rates were observed for risankizumab vs placebo for resolution of enthesitis, dactylitis, and both enthesitis/dactylitis (differences of 13.9%, 16.9%, and 13.3%, respectively; p < 0.05). By week 52, risankizumab treatment resulted in complete resolution of enthesitis, dactylitis, and both enthesitis and dactylitis in 55.0%, 76.1%, and 52.3% of patients; similar resolution rates occurred among patients who switched from placebo to risankizumab. Among risankizumab-treated patients who achieved resolution of enthesitis and/or dactylitis, MCIDs were also attained in patient-reported pain, disability, and fatigue at week 24 (all p < 0.05; except fatigue in patients with resolution of both enthesitis/dactylitis); responses were sustained through week 52., Conclusions: Higher proportions of risankizumab-treated (vs placebo-treated) patients achieved enthesitis and/or dactylitis resolution and meaningful improvements in patient-reported outcomes at week 24 and generally sustained responses at week 52. Thus, risankizumab may result in sustained alleviation of PsA-related pathognomonic musculoskeletal lesions of enthesitis/dactylitis., Gov Identifiers: NCT03675308, and NCT03671148., (© 2024. The Author(s).)

Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus., Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak., Findings: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response., Interpretation: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms., Funding: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists., Competing Interests: Declaration of interests The authors declare that they have no financial conflict of interests for this study., (Copyright © 2024. Published by Elsevier B.V.)

Objective: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA., Methods: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined., Results: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed., Conclusion: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA., Competing Interests: Competing interests: No support to any author for the present work. Outside the submitted work: LG: research grants: AbbVie, Biogen, Lilly, Novartis, UCB; consulting fees: AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB; non-financial support: AbbVie, Amgen, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB; membership on an entity’s Board of Directors or advisory committees: EULAR Treasurer. AK: speakers bureau, consultancy: AbbVie, Amgen, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer, UCB. RJOF: research grants: Medac, Lilly; consulting fees: Sanofi. DA: research grants: Galapagos, Lilly; consulting fees: AbbVie, Gilead, Janssen, Lilly, Merck, Novartis, Sanofi. XB: research grants: AbbVie, MSD, Novartis; consultancies: AbbVie, Amgen, Celltrion, Chugai, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, UCB; membership on an entity’s Board of Directors or advisory committees: ASAS President, EULAR President Elect. W-HB: honoraria: AbbVie, Almirall, BMS, Janssen, Leo, Eli Lilly, Novartis, UCB; expert testimony: Novartis; participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, Almirall, BMS, Janssen, Leo, Eli Lilly, Novartis, UCB. IBM: honoraria/consultation fees non-exec roles: NHS GGC Board Member, Evelo Board of Directors, Versus Arthritis Trustee Status; stock or stock options: Evelo, Cabaletta, Compugen, Causeway Therapeutics, Dextera. DGM: research grants: Janssen, AbbVie, Lilly, Novartis, UCB, BMS, Moonlake; consulting fees: Janssen, AbbVie, Lilly, Novartis, UCB, BMS, Moonlake, Celgene; honoraria: Janssen, AbbVie, Lilly, Novartis, UCB, BMS, Moonlake. KLW: research grants: BMS, Pfizer; consulting: Pfizer, AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, GlaxoSmithKline (GSK), Gilead, Novartis, Moderna, Regeneron, Roche, Sanofi, UCB Pharma. AB: speakers fees: AbbVie, Amgen, AlphaSigma, AstraZeneca, Angelini, Biogen, BMS, Berlin-Chemie, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Teva, UCB, Zentiva; consultancies: Akros, AbbVie, Amgen, AlphaSigma, Biogen, Boehringer Ingelheim, Lilly, Mylan, MSD, Novartis, Pfizer, Roche, Sandoz, Sobi, UCB. PVB: consulting fees: AbbVie, Janssen-Cilag, Pfizer; honoraria: AbbVie, Bausch Health, Celltrion Healthcare, Eli Lilly, Gedeon Richter, IBSA Pharma, Infomed, Janssen-Cilag, Novartis, Pfizer, Sandoz; payment for expert testimony: Gedeon Richter; other: President, Hungarian Association of Rheumatologists. GRB: honoraria and/or speaker fees: AbbVie, BMS, Janssen, Lilly, Novartis, Pfizer. JDC: honoraria: UCB. PC: research grants: AbbVie, Amgen, Biogen, Jansen, Lilly, Novartis, UCB; consulting fees: AbbVie, Amgen, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB. LE: consultation fee/advisory board: AbbVie, Novartis, Janssen, UCB, BMS, Eli Lilly; research/educational grants: AbbVie, Fresenius Kabi, Janssen, Amgen, UCB, Novartis, Eli Lilly, Sandoz, Pfizer. MLH: grant support: AbbVie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics BV, Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Bioepis, Sandoz, Novartis, Nordforsk; honoraria: Pfizer, Medac, Sandoz; advisory board: AbbVie; past-chair of the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies; cochair of EuroSpA, partly funded by Novartis. AI: research grants from AbbVie, Pfizer, Novartis; honoraria for lectures, presentations, speakers bureaus from AbbVie, Alfasigma, BMS, Celgene, Celltrion, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Sanofi Genzyme, Sobi; EULAR Board Member; EULAR Congress Committee, Education Committee and Advocacy Committee Advisor; EULAR Past President. LEK: consultancies: AbbVie, Amgen, Biogen, BMS, Celgene, Eli Lilly, Pfizer, UCB, Sanofi, GSK, Galapagos, Forward Pharma, MSD, Novartis, Janssen; has been representing rheumatology FOREUM scientific chair. RQ: consultancy and/or speaker’s honoraria from and/or participated in clinical trials and/or research projects sponsored by AbbVie, Amgen-Celgene, Eli Lilly, Novartis, Janssen, Pfizer, MSD, UCB. DM: honoraria: UCB, Janssen, GSK, AstraZeneca, AbbVie; support to meetings: Janssen. HM-O: grant support: Janssen, Novartis, UCB; honoraria and/or speaker fees: AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda, UCB. PJM: grant support: AbbVie, Acelyrin, Amgen, Bristol Myers Squibb, Eli Lilly, Genascence, Janssen, Novartis, Pfizer, UCB; consulting fees: AbbVie, Acelyrin, Aclaris, Alumis, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genascence, Inmagene, Janssen, Moonlake, Novartis, Pfizer, Takeda, UCB, Ventyx, Xinthera; honoraria: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB. PN: consulting fees and honoraria: AbbVie, Amgen, BMS, Lilly, Janssen, GSK, Novartis, UCB, Servatus; boards: Amgen, BMS, Janssen, GSK, Novartis, UCB; GRAPPA Steering Committee, Chair ASMPOC, ARA. LS: consulting fees: AbbVie, Almirall, Novartis, Janssen, Lilly, UCB, Pfizer, Bristol Myers Squibb, Boehringer Ingelheim; honoraria: AbbVie, Almirall, Novartis, Janssen, UCB, Pfizer, Takeda, Galderma, Biogen, Celgene, Celltrion, Lilly, Sanofi, Bristol Myers Squibb, Boehringer Ingelheim; support to attending meetings: AbbVie, Janssen, Lilly, Novartis, UCB, Galderma, Bristol Myers Squibb, Boehringer Ingelheim; participation in boards: AbbVie, Almirall, Novartis, Janssen, UCB, Pfizer, Galderma, Biogen, Lilly, Sanofi, Bristol Myers Squibb, Boehringer Ingelheim; GRAPPA Executive Board (elected), British Society for Medical Dermatology (BSMD) Committee. GS: honoraria: Novartis, Janssen. SJWS-W: grant support: Medical Research Council (MR/W027151/1). YT: research grants from Mitsubishi Tanabe, Eisai, Chugai, Taisho; speaking fees and/or honoraria from Eli Lilly, AstraZeneca, AbbVie, Gilead, Chugai, Boehringer Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol Myers, Pfizer, Taiho. FEVdB: consultancy honoraria from AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB. AZ: speakers bureau: AbbVie, Novartis, Janssen, Lilly, UCB, Amgen; paid instructor for AbbVie, Novartis, UCB. DvdH: consulting fees AbbVie, Argenx, Bayer, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, Takeda, UCB Pharma; Director of Imaging Rheumatology bv; Associate Editor for Annals of the Rheumatic Diseases; Editorial Board Member for Journal of Rheumatology and RMD Open; Advisor Assessment Axial Spondyloarthritis International Society. JSS: research grants from AbbVie, AstraZeneca, Lilly, Galapagos; royalties from Elsevier (textbook); consulting fees from AbbVie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; honoraria from Samsung, Lilly, R-Pharma, Chugai, MSD, Janssen, Novartis-Sandoz; participation in advisory board from AstraZeneca., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ on behalf of EULAR.)

Background: Axial spondyloarthropathy(AS) is a chronic inflammatory disease primarily affecting the axial skeleton, often characterized by sacroiliitis. While pulmonary embolism (PE), a potentially lethal condition, has been linked to several autoimmune diseases, limited data exist regarding PE risk among patients with AS. Methods: This retrospective cohort study utilized the Clalit Healthcare Services (CHS) database, including 5825 patients with AS and 28,356 matched controls. Follow-up began at the date of first AS diagnosis for patients and at the matched patient's diagnosis date for controls and continued until PE diagnosis, death, or study end date. Results: Prevalence of PE before AS diagnosis in patients compared to controls was 0.4% vs. 0.2% ( p < 0.01). The incidence rate of PE was 11.6 per 10,000 person-years for patients with AS and 6.8 per 10,000 person-years for controls. The adjusted hazard ratio (HR) for PE in patients with AS was 1.70 ( p < 0.001). Subgroup analysis demonstrated excess risk for PE in patients with AS regardless of gender and age, with variations among AS treatment categories. Discussion: Our findings highlight a significant association between AS and PE, indicating an increased risk in patients with AS independent of age and sex and suggests a subclinical level of inflammation. Preliminary results suggest a protective role of immunosuppressing drugs. Further research into the impact of treatment strategies should be conducted and could inform clinical management and reduce the life-threatening risk of PE in Patients with AS.

Objectives: To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study., Methods: Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0-6) and Dactylitis Severity Score (range, 0-60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0-100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test., Results: Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03)., Conclusion: In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients., Trial Registration: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT03158285; Registered: May 16, 2017. Key Points • At week 100, 65% and 76% of guselkumab-treated patients achieved enthesitis and dactylitis resolution (ER/DR). • Achieving ER was associated with achieving DR and vice versa through the end of study. • Achieving ER or DR was associated with durable and meaningful improvements in selected patient-reported outcomes., (© 2024. The Author(s).)

Objective: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD)., Methods: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series., Results: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation ( P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy., Conclusion: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain., (Copyright © 2024 by the Journal of Rheumatology.)

Objective: To investigate the prevalence of poly-refractory rheumatoid arthritis (RA) defined as failure of all biological (b)/targeted synthetic (ts)-disease-modifying drugs (DMARDs). To further investigate whether patients with persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA), determined by objective ultrasound (US) synovitis, have distinct clinical phenotypes in both EULAR difficult-to-treat RA (D2T-RA) and poly-refractory RA groups., Methods: A cross-sectional study of 1,591 patients with RA on b/tsDMARDs that evaluated D2T-RA criteria and subclassified as poly-refractory if inefficacy/toxicity to at least one drug of all classes. PIRRA was defined if US synovitis in one or more swollen joint and NIRRA if absent. Univariate tests and multivariate logistic regression were conducted to investigate factors associated with poly-refractory, PIRRA, and NIRRA phenotypes., Results: 122 of 1,591 were excluded due to missing data. 247 of 1,469 (16.8%) had D2T-RA and only 40 of 1,469 (2.7%) poly-refractory RA. This latter group had higher disease activity score 28 C-reactive protein (CRP) (median 5.4 vs 5.02, P < 0.05), CRP levels (median 13 vs 5 mg/l, P < 0.01), and smoking (ever) rates (20% vs 4%, P < 0.01) compared with other D2T patients. Smoking was associated with poly-refractory RA (odds ratio 5.067, 95% CI 1.774-14.472, P = 0.002). Of 107 patients with D2T-RA with recent US, 61 (57%) were PIRRA and 46 (43%), NIRRA. Patients with NIRRA had elevated body mass index (median 30 vs 26, P < 0.001) and higher fibromyalgia prevalence (15% vs 3%, P < 0.05), lower swollen joint count (median: 2 vs 5, P < 0.001), and lower CRP levels (5 vs 10, P < 0.01)., Conclusion: Only 2.7% of D2T-RA failed all classes of b/tsDMARDs. Among D2T-RA, less than 60% had objective signs of inflammation, representing a target for innovative strategies., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Nerve growth factor β (β-NGF) is a protein which is important to the development of neurons particularly those involved in the transmission of pain and is central to the experience of pain in osteoarthritis (OA). Direct NGF antagonism has been shown to reduce OA pain but is associated with rapidly progressive OA. The aim of the study is to investigate the ability of soluble neurotrophin receptors in the NGF pathway to modulate pain in OA., Methods: Synovial fluid (SF) was obtained from the knee joints of 43 subjects who underwent total knee arthroplasty. Visual analogue scale (VAS) pain scores were obtained prior to surgery. Customised-automated-ELISAs and commercial-ELISAs and LEGENDplex™ were used to measure soluble low-affinity nerve growth factor (LNGFR), soluble tropomyosin receptor kinase (TrkA), proNGF, β-NGF, other neurotrophins (NT) and cytokines including inflammatory marker TNF-α., Results: The VAS score positively correlated with β-NGF (r=0.34) and there was positive association trend with neurotrophin-3 (NT-3), BDNF and negative association trend with ProNGF. sLNGFR positively correlated with VAS (r=0.33). The β-NGF/soluble TrkA ratio showed a strong positive correlation with VAS (r=0.80). In contrast, there was no correlation between pain and the β-NGF/sLNGFR ratio (r=-0.08). TNF-α positively correlated with β-NGF (r=0.83), NT-3 (r=0.66), and brain-derived neurotrophic factor (BDNF) (r=0.50) and negatively with ProNGF (r= -0.74) and positively correlated with both soluble TrkA (r=0.62), sLNGFR (r=0.26)., Conclusions: This study suggests that endogenous or cleaved sLNGFR, but not soluble TrkA may participate in OA pain modulation thus supporting further research into soluble LNGFR as a therapeutic target in OA.

Objective: The aim was to assess the use and drug survival of IL-17Ai in a real-world cohort of axial SpA (axSpA) and PsA patients., Methods: Patients ever commenced on an IL-17Ai (secukinumab or ixekizumab) for axSpA or PsA at the Leeds Specialist Spondyloarthritis Service were identified. Demographics, IL-17Ai treatment length and reason for cessation were collected. Drug survival data were plotted as a Kaplan-Meier curve, with log rank test of median survival compared between axSpA and PsA. Cox regression analysis was performed to investigate the relationship between diagnosis and length of drug survival., Results: In total, 228 patients (91 axSpA and 137 PsA) were exposed to IL-17Ai. Drug survival for all patients at 12 months was 69% (95% Confidence Interval (CI) 63, 75%) and at 24 months 60% (95% CI 54, 67%). In axSpA and PsA, drug survival at 12 months was 63% (CI 54, 74%) and 73% (CI 66, 81%), respectively, and at 24 months it was 53% (CI 44, 65%) and 65% (CI 57, 75%), respectively. Median survival did not differ significantly between both diseases (log rank test 0.65). There was no association between diagnosis and survival (hazard ratio 0.92, 95% CI 0.63, 1.33), including when adjusting for age, previous biologic DMARD usage and sex (hazard ratio 0.89, 95% CI 0.61, 1.13)., Conclusion: This is the first study, to our knowledge, to analyse and compare real-world IL-17Ai drug survival in patients with axSpA and PsA from a single centre. We demonstrate that there is no difference in IL-17Ai survival rates and no relationship between diagnosis and drug survival. These results contribute to the body of real-world evidence confirming the role of IL-17Ai in the management of axSpA and PsA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Still's disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still's disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still's disease and MAS. Pathological entities associated with Still's disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still's disease courses were recognized. Newer proposals of alternative Still's disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still's disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management., (© 2024. Springer Nature Limited.)

Background: Hidradenitis suppurativa (HS) is a chronic debilitating disease with a significant burden of both organic and psychological comorbidities. It has been shown that certain telomere-related genes (TRGs) affect a wide range of diseases, including HS and its associated comorbidities, but their exact role in HS pathogenesis is still unknown., Objectives: To determine whether TRG methylomes can be used as biomarkers in HS., Methods: Using the Illumina HumanMethylation450 BeadChip array, we examined methylation variations associated with TRGs in HS cases and age-, sex- and ethnicity-matched healthy controls. The study utilized integrated bioinformatics statistical methods, such as a false discovery rate (FDR), the area under the receiver operating characteristic curve (AUC) and principal component analysis., Results: There were a total of 585 different differentially methylated CpG sites identified in 585 TRGs associated with HS (474 hypomethylated and 111 hypermethylated) (FDR p-value < 0.05). A number of these CpGs have been identified as being involved in increased pain sensitivity including EPAS1, AHR, CSNK1D, DNMT1, IKBKAP, NOS3, PLCB1 and PRDM16 genes; GABRB3 as a potential alcohol addiction marker; DDB1, NSMCE2 and HNRNPA2B1 associated with cancers. Pathway analysis identified 67 statistically significant pathways, including DNA repair, telomere maintenance, mismatch repair and cell cycle control (p < 0.001)., Conclusion: The disruption of TRGs leads to the shortening of telomeres, which is associated with HS progression, ageing, cellular senescence and an increased risk of various diseases, including cancer and associated comorbidities, such as metabolic syndrome, cardiovascular disease and inflammatory disorders. Further research is necessary to better understand the underlying mechanisms and establish causal links between TRGs and HS. The present study is the first effort to comprehend potential pathomechanisms of sporadic HS cases concentrating on PBMC methylome since ours., (© 2023 European Academy of Dermatology and Venereology.)

Bone void-filling cements are one of the preferred materials for managing irregular bone voids, particularly in the geriatric population who undergo many orthopedic surgeries. However, bone marrow mesenchymal stem/stromal cells (BM-MSCs) of older-age donors often exhibit reduced osteogenic capacity. Hence, it is crucial to evaluate candidate bone substitute materials with BM-MSCs from the geriatric population to determine the true osteogenic potential, thus simulating the clinical situation. With this concept, we investigated the osteogenic potential of shell nacre cement (SNC), a bone void-filling cement based on shell nacre powder and ladder-structured siloxane methacrylate, using older donor BM-MSCs (age > 55 years) and young donor BM-MSCs (age < 30 years). Direct and indirect cytotoxicity studies conducted with human BM-MSCs confirmed the non-cytotoxic nature of SNC. The standard colony-forming unit-fibroblast (CFU-F) assay and population doubling (PD) time assays revealed a significant reduction in the proliferation potential ( p < 0.0001, p < 0.05) in older donor BM-MSCs compared to young donor BM-MSCs. Correspondingly, older donor BM-MSCs contained higher proportions of senescent, β -galactosidase (SA- β gal)-positive cells (nearly 2-fold, p < 0.001). In contrast, the proliferation capacity of older donor BM-MSCs, measured as the area density of CellTracker TM green positive cells, was similar to that of young donor BM-MSCs following a 7-day culture on SNC. Furthermore, after 14 days of osteoinduction on SNC, scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS) showed that the amount of calcium and phosphorus deposited by young and older donor BM-MSCs on SNC was comparable. A similar trend was observed in the expression of the osteogenesis-related genes BMP2, RUNX2, ALP, COL1A1, OMD and SPARC. Overall, the results of this study indicated that SNC would be a promising candidate for managing bone voids in all age groups.

Objectives: To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks., Methods: In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes., Results: Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52., Conclusion: Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition., Trial Registration: ClinicalTrials.gov, NCT02745080., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Axial spondyloarthritis (axSpA) encompasses radiographic axial SpA (r-axSpA), formally designated as ankylosing spondylitis (AS) and non-radiographic axial SpA (nr-axSpA). The advent of MRI permitted the description of the "pre-radiographic" (nr-AxSpA) stage characterized by bone marrow oedema lesions, histologically an osteitis, not yet visible on X-rays. Most subjects with a diagnosis of nr-axSpA do not progress to r-axSpA and the risk of misdiagnosis of nr-axSpA is considerable because back pain related to malalignment, degenerative conditions or biomechanical stress including intense exercise may lead to positive MRI scans. Even when nr-axSpA or r-axSpA are accurately diagnosed only about 40-50% achieve the ASAS40 responses with licensed therapies. It is likely that spinal enthesitis/osteitis leading to structural damage and associated damage contributes to post inflammatory disc territory secondary pain responses. Things are complicated as the concept of refractory axSpA itself is not well defined since there is no gold standard test to capture the full burden of inflammatory disease and, in any event, MRI has not been systematically applied. Nevertheless, there is sufficient evidence to borrow from the refractory rheumatoid arthritis field to propose two types of refractory axial SpA- a persistent inflammatory refractory ax-SpA (PIRaxSpA) and non-inflammatory refractory ax-SpA (NIRaxSpA). Both axSpA refractoriness and misdiagnosis need careful considerations when evaluating treatment failure. The immunological basis for axSpA immunotherapeutics non-responses is still rudimentary beyond the knowledge of HLA-B27 positivity status, CRP elevation, and MRI bone oedema that represents osteitis being equated with responder status., Competing Interests: Declaration of Competing Interest None to disclose for this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To evaluate whether knee flexion contracture (FC) was associated with leg length inequality (LLI) and/or morbidity in knee osteoarthritis (OA)., Design: We accessed 2 databases: (1) the Osteoarthritis Initiative (OAI) cohort, including participants with, or at-risk of OA, and (2) the Ottawa Knee Osteoarthritis cross-sectional database (OKOA), including participants with primary advanced knee OA. Both included demographics, radiographic data, knee range of motion, leg length, pain, and function scales., Setting: Tertiary care academic rheumatology and orthopedic clinics., Participants: Patients with or at-risk of primary OA. We included 881 OAI and 72 OKOA participants (N=953)., Intervention: Not applicable., Main Outcome Measures: The primary outcome tested the association between the difference in knee extensions of the OA and contralateral knees (the knee extension difference, or KExD) and LLI. This was evaluated using bivariate regression, followed by a multivariable linear regression model., Results: OAI participants had less severe knee OA [Kellgren and Lawrence (KL) score 1.9±1.3] vs OKOA (KL score 3.4±0.6). The KExD correlated with LLI for both databases (OAI: R=0.167; P≤.001; OKOA: R=0.339; P=.004). Multivariable regression showed an effect of KExD on LLI in both databases (OAI: β=0.37[0.18,0.57]; P<.001, OKOA: β=0.73[0.20,1.26]; P=.007). When broken down by subgroup, the OAI moderate-severe OA group showed a significant effect of KExD on LLI (β=0.60 [0.34,0.85]; P<.001)., Conclusions: OA-related loss of knee extension was associated with LLI for those with moderate-severe OA. Because LLI correlates with worse knee OA symptoms, discovering an FC should cue clinicians to evaluate for LLI, an easily-treatable finding that may help reduce OA-associated morbidity for those approaching the need for arthroplasty., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The association between chronic inflammatory conditions and cardiovascular disease is well established. Considering FMF, few studies exist investigating the risk of ischaemic heart disease, and none address the risk of stroke. We aimed to evaluate the incidence and risk for stroke in FMF patients compared with the general population., Methods: A retrospective cohort study using the electronic database of Clalit Health Services (CHS), the largest health organization in Israel. All FMF patients diagnosed between 2000 and 2016 were included and matched with control according to age, gender and place of residence. Follow-up continued until the first diagnosis of stroke or death. The incidence of stroke was compared between the groups using univariate and multivariate models adjusting for cardiovascular risk-factors., Results: A total of 9769 FMF patients and a similar number of controls were followed up for a median period of 12.5 years. The mean age at the beginning of the follow-up was 25.7 years. In total, 208 FMF patients were diagnosed with stroke compared with 148 controls, resulting in an incidence rate (per 10 000 persons-years) of 19.8 (95% CI 17.2, 22.7) and 13.9 (95% CI 11.8, 16.4), respectively, and a crude HR of 1.42 (95% CI 1.15-1.76; P < 0.001). In a multivariate analysis, FMF patients who developed amyloidosis with related or non-related renal failure demonstrated significant stroke risk (HR = 2.16; 95% CI 1.38, 3.38; P < 0.001), as well as for those who did not develop these complications (HR = 1.32; 95% CI 1.04, 1.67; P < 0.05)., Conclusion: FMF patients are at increased risk for stroke regardless of known complications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Adult-onset Still's disease (AOSD) poses a not well estimated burden on patients and healthcare systems. To assess this burden, a systematic review (SR) was undertaken to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data. Searches of twelve databases, four conferences, and three key technology assessment and regulatory agency websites were conducted in August 2022. Reference lists of retrieved SRs published since 2017 were also checked. Overall, 16 studies were eligible for inclusion. Eight studies reported HRQoL outcomes, one of which also reported utilities data. Two studies reported direct costs outcomes, and seven reported healthcare resource use data. No indirect costs were identified. A range of outcomes were reported, thus limiting the comparability of results across studies. SF-36 data were impaired in AOSD on most scales, especially those concerning physical activity. Mean SF-36 data were lower across all subscales in patients with active AOSD compared with inactive AOSD. Biologic therapy showed improvements in the SF-36 physical health summary. Utility scores (one study) were significantly lower for AOSD than for healthy controls. Limited direct economic costs data were identified but were substantial where reported. Hospital length of stay ranged from 6.1 to 23.5 days. The SR showed there is a paucity of research reporting the HRQoL and cost burden of AOSD., Competing Interests: Declaration of Competing Interest PR, EF and DMcG did not receive any remuneration from Novartis related to this project. EF received honoraria for consultancy and lectures from Abbvie, Lilly, Galapagos, Pfizer, Roche/Chugai, Sobi, Novartis, Sanofi. DMcG received honoraria or grant funding Abbvie, Lilly, Pfizer, Sobi, Novartis, Sanofi. PR received speaker honoraria from Abbvie, BMS, Janssen, Novartis, Sobi outside this work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Since the original description of spondyloarthritis 50 years ago, results have demonstrated similarities and differences between ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA). HLA-B27 gene carriage in axial inflammation is linked to peri-fibrocartilaginous sacroiliac joint osteitis, as well as to spinal peri-entheseal osteitis, which is often extensive and which provides a crucial anatomical and immunological differentiation between the AS and PsA phenotypes. Specifically, HLA-B27-related diffuse bone marrow oedema (histologically an osteitis) and bone marrow fatty corners detected via magnetic resonance imaging, as well as radiographic changes such as sacroiliitis, vertebral squaring, corner erosions and Romanus lesions, all indicate initial bone phenotypes in HLA-B27 + axial disease. However, in much of PsA with axial involvement, enthesitis primarily manifests in ligamentous soft tissue as 'ligamentitis', with characteristic lesions that include para-syndesmophytes and sacroiliac joint bony sparing. Like axial PsA, diffuse idiopathic skeletal hyperostosis phenotypes, which can be indistinguishable from PsA, exhibit a thoracic and cervical spinal ligamentous soft-tissue tropism, clinically manifesting as syndesmophytosis that is soft-tissue-centric, including paravertebral soft-tissue ossification and sacroiliac soft-ligamentous ossification instead of joint-cavity fusion. The enthesis bone and soft tissues have radically different immune cell and stromal compositions, which probably underpins differential responses to immunomodulatory therapy, especially IL-23 inhibition., (© 2023. Springer Nature Limited.)