This study aims to provide an update of the European Alliance of Associations for Rheumatology (EULAR) rheumatoid arthritis (RA) management recommendations addressing the most recent insights. An International Task Force was formed with a wide expertise and solicited 2 systemic literature research activities on the safety and efficacy of disease-modifying antirheumatic drugs (DMARDs). New evidence was discussed, considering the update from 2022. A voting process was applied to each item. Levels of evidence and strengths of recommendation were assigned, and participants voted on the levels of agreement. The task force agreed on 5 overarching principles and reduced the number of recommendations to 9 concerning use of conventional synthetic DMARDs (methotrexate [MTX], leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b)DMARDs (tumour necrosis factor inhibitors [adalimumab, certolizumab pegol, etanercept, golimumab, infliximab], abatacept, rituximab, tocilizumab, sarilumab, including biosimilars) and targeted synthetic [ts]DMARDs (namely the Janus kinase inhibitors [JAKi] tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target), and tapering following clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were considered. Initially, MTX ideally in combination with short-term GCs is recommended; upon insufficient response after 3 to 6 months, a bDMARD should be added; after careful consideration of risks, including MACEs, malignancies and/or thrombo-embolic events, JAKi may also be considered. If the first bDMARD (or JAKi) fails, any other bDMARD (from another or the same class) or JAKi (considering risks) is recommended. With sustained remission, DMARDs may be tapered, but caution is required as stopping often leads to a flare. Levels of evidence and levels of agreement were high for most recommendations. These updated EULAR recommendations provide consensus on RA management based on currently available evidence regarding efficacy, safety, and cost.
This study aims to update the European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of Behçet's syndrome according to the updated EULAR standard operating procedures. The task force comprised 29 members from 11 countries, including 19 rheumatologists, 2 ophthalmologists, 1 dermatologist, 1 gastroenterologist, 1 neurologist, 1 health professional, 2 patient research partners, and 2 Emerging EUlar NETwork members. Research questions were proposed by the task force through a Delphi survey and formulated into patients, interventions, comparison, and outcomes (PICO) questions for the systematic literature review. The results of the systematic literature review were discussed among the task force members. Previous recommendations and overarching principles were modified, and new recommendations were developed as needed. The updated recommendations were voted, and the levels of evidence and levels of agreement were determined. The updated recommendations consist of 5 overarching principles and 12 recommendations that were tabulated according to organ involvement. Among the 12 recommendations, 1 was a new recommendation, 7 recommendations were modified, and only the wording was changed in 4 recommendations. The overarching principles focus on the importance of recognising the relapsing and remitting disease course and individualising treatment according to disease activity and prognostic risk factors, and emphasise the importance of a multidisciplinary approach, patient education, and shared decision making for optimal care. For mucocutaneous and joint involvement, colchicine is recommended as the first-line treatment modality. Apremilast and immunosuppressives such as tumour necrosis factor alpha (TNFα) inhibitors are recommended for refractory patients. For patients with organ involvement, more aggressive treatment with glucocorticoids and immunosuppressives is recommended for rapid induction of remission. Early use of monoclonal antibodies against TNFα is encouraged in patients with organ or life-threatening manifestations. These recommendations, which were updated based on new evidence and expert opinion, provide guidance for all stakeholders involved in the management of patients with Behçet's syndrome to improve the quality of care of these patients.
The identification of genetic risk factors could facilitate our understanding of the cause and pathogenesis of rheumatic diseases. Maps of susceptibility loci have been established for most complex diseases, including all major rheumatic diseases, but definitive causal variants have been identified only very infrequently. Here, we highlight the need to both position and confirm the role of causative polymorphisms in humans using experimental animals. The approach is best exemplified by the positional cloning of a causative single-nucleotide polymorphism (SNP) (rs201802280), which results in the substitution of arginine with histidine at position 90 in the NCF1 gene (neutrophil cytosolic factor 1, a component of the phagocyte NOX2 (Nicotinamide adenine dinucleotide phosphate oxidase 2) complex. This variant was independently identified and validated using 2 distinct approaches: by positioning the gene in animal models, followed by exon sequencing and validation of the identified SNPs, and by targeted resequencing and linkage disequilibrium mapping in multiethnic case-control studies. This causal SNP, located in a region with copy number variation, has emerged as a major susceptibility variant for multiple rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's disease, and systemic sclerosis. It represents the first major causal polymorphism conclusively linked to both increased susceptibility and disease severity across multiple rheumatic conditions, in both patients and animal models. The functional impact of the NCF1 variant has been explored mechanistically, and a viral infection has been identified as an interacting environmental factor contributing to lupus disease in animal studies. Importantly, the significance of the NCF1 polymorphism extends beyond rheumatic diseases-it has also been implicated in cancer, cardiovascular syndromes, infections, and physiological traits.
Pregnancy raises the risk of maternal and fetal complications in systemic lupus erythematosus (SLE) patients due to physiological and immunological changes, with infections standing out as a significant concern. It is important to conduct a comprehensive examination of the structure and trends in the scientific literature of this field. This bibliometric study analyzed publications on SLE-related infections during pregnancy using the Scopus database. The search was conducted on January 15, 2026, using the keywords “Systemic Lupus Erythematosus”, “Pregnancy”, and “Infection” in the title, abstract, and keyword fields. The analysis included an examination of publication distribution and trends over time using linear regression. Data on countries, authors, institutions, funding sources, journals, document types, and keywords of the articles were collected. A total of 994 publications were included in the analysis. The annual number of publications increased significantly over the years and the publication output peaked in 2024 (n = 73) (R² = 0.664, p < 0.001). In total, 71 countries contributed to the literature, with 28 classified as main active countries (≥ 1% of total output). The majority of document types were articles (n = 528) and reviews (n = 354). In terms of publication volume, the United States (n = 299), the United Kingdom (n = 101), and Italy (n = 83) were prominent, whereas in terms of citations per paper, Hungary (170.4), Greece (137.23), and the Netherlands (116.55) exhibited the highest impact. The most productive journals included Lupus (n = 36), Frontiers in Immunology (n = 20), and Annals of the Rheumatic Diseases (n = 14). This analysis reveals a significant upward trend in the scientific literature in recent years and the increasing clinical importance of the subject.
The pathogenic roles of the complement system in many human diseases have become increasingly understood, in large part through the results of informative clinical trials. In addition, based on biomarker studies in patients and results of murine models, there are an increasing number of indications under consideration for the use of therapeutics targeting different components of the pathway. Here, lessons learned from several of these studies are reviewed, with an emphasis on diseases of clinical and research interest to rheumatologists. Publications focused on the complement-related pathogenesis and clinical trials of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and rheumatoid arthritis (RA), in addition to studies relevant to other diseases, are summarised. Following translational studies demonstrating activation in affected tissues and blood from patients, the potential pathogenic roles of complement in AAV and RA were studied in murine models. These studies suggested in both diseases that complement alternative pathway generation of C5a is a primary driver of target organ damage. In AAV, clinical trials using a novel small molecular oral C5a anaphylatoxin receptor (C5aR1) antagonist revealed a substantial corticosteroid-sparing effect and initial evidence of clinical benefit. With regard to RA, although there is strong support through biomarker and murine model studies, intervention with C5 and C5aR1 inhibitors revealed only modest benefit, and additional work is necessary to determine if different targets or timing of intervention is necessary. Beyond AAV and RA, a substantial number of additional diseases cared for by rheumatologists exhibit evidence of complement activation in a potentially pathogenic manner. Inappropriate activation of the complement pathway mediates tissue inflammation and damage in many human diseases, including key ones cared for by rheumatologists.
This study aims to perform a systematic literature review (SLR) concerning the safety of synthetic and biological disease-modifying antirheumatic drugs (DMARDs) for the 2025 update of European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of rheumatoid arthritis (RA). Medline, Embase, Cochrane CENTRAL, and Web of Science were searched for observational and randomised controlled trials with a primary endpoint of DMARD safety on the conventional synthetic (cs-), biological (b-), and targeted synthetic-DMARDs, as well as glucocorticoids, published between January 14, 2022, and January 22, 2025. Separate searches on DMARD monitoring were conducted from database inception to January 22, 2025. A comparator group was required for inclusion. All safety outcomes were included. A total of 3837 articles were identified, with 321 selected for full-text review; 71 articles were included. Across the evidence base, infections were the most frequently assessed outcome: 13 studies examined serious or hospitalised infections, usually as composite endpoints of bacterial, opportunistic, and herpes zoster infection, while 1 addressed nonserious infections. Serious infections were more common with bDMARDs than csDMARDs. Janus kinase inhibitors (JAKis) showed a higher herpes zoster risk than bDMARDs. Tuberculosis risk was not increased with JAKis compared with bDMARDs, but was higher with infliximab and adalimumab compared with etanercept. Fifteen studies evaluated malignancy, split evenly between analyses of any malignancy and those excluding nonmelanoma skin cancer (NMSC); 2 focused on melanoma and 2 on NMSC. Increased NMSC was noted in patients with RA using DMARDs compared with the general population, with no link to a specific DMARD. Cardiovascular and thromboembolic events were reported in 20 studies. No consistent evidence of increased major adverse cardiovascular events risk with JAKis compared with bDMARDs was identified. Venous thromboembolism risk appeared elevated with JAKis compared with bDMARDs, driven mainly by pulmonary embolism. Fourteen studies reported retention and adverse event-related withdrawals, and 8 assessed other specific adverse events. Gastrointestinal perforation and demyelinating disease were each reported in 3 studies. No eligible articles were identified in searches on DMARD monitoring. There has been a notable increase in studies evaluating safety outcomes, with the majority of these being observational studies focusing primarily on malignancy, thromboembolic, and cardiovascular events, with most studies pertaining to JAKi safety. A substantial proportion of studies in this SLR relied on claims databases to evaluate safety outcomes, a practice that carries important methodological limitations for safety research. Surprisingly, not many studies looked into glucocorticoid safety outcomes over the past 3 years. This SLR, along with the SLR on efficacy of DMARDs, informed the 2025 update of the EULAR recommendations for management of RA with synthetic and biological DMARDs.
This study aimed to analyse structural and functional mitochondrial alterations, the release of mitochondrial DNA (mtDNA), and the activation of inflammatory signalling pathways that can be reversed by tofacitinib in the salivary glands (SG) of patients with Sjögren's disease (SjD). SG from patients with SjD and controls, as well as from mice with SjD treated with or without tofacitinib, were analysed. We determined the mitochondrial ultrastructure, the presence of mtDNA in the cytosol, and the levels and localisation of pattern recognition receptors (PRRs) that recognise mtDNA. The adenosine triphosphate (ATP) levels and oxygen consumption rate (OCR) were measured to evaluate mitochondrial respiration in frozen SG. We also evaluated the OCR in human submandibular gland cells incubated with interferon-gamma (IFN-γ), tofacitinib, or both. Increased mtDNA release into the cytosol was observed in SG epithelial cells of patients with SjD. This change was linked with increased PRR activation (cyclic GMP-AMP synthase, Z-DNA-binding protein 1, and nucleotide-binding oligomerisation domain-like receptor protein 3) and decreased mitochondrial transcription factor A (TFAM). Similar mitochondrial ultrastructural alterations and increased PRR activation were observed in the SG of the SjD mouse model. These changes were reversed by tofacitinib. Interestingly, increased activity of electron transport chain complexes was observed in SG of patients with SjD, which could be modulated by IFN-γ, as observed in vitro. We also found that tofacitinib stabilised mitochondrial function at basal conditions in vitro, counteracting the mitochondrial adaptations induced by IFN-γ. Taken together, these results suggest that mitochondrial alterations are linked with inflammation and support the potential use of tofacitinib in patients with SjD.
The primary objective of this randomised, active-controlled, international, multicentre, phase IV clinical trial was to demonstrate noninferiority of the response of ultrasound-assessed synovitis to baricitinib treatment, alone and in combination with methotrexate (MTX), compared with etanercept with MTX in rheumatoid arthritis (RA). Adult patients with active RA and inadequate response to MTX were randomised into 3 parallel treatment groups: baricitinib monotherapy, baricitinib plus MTX, and etanercept plus MTX. The patients underwent clinical, ultrasound, and laboratory assessments at baseline, 4, 12, and 24 weeks. Ultrasound synovitis was scored 0 to 3 in B-mode, Doppler mode, and a combination of both modes. The primary endpoint was the change in the Global European Alliance of Associations for Rheumatology-Outcome Measures in Rheumatology Synovitis Score (GLOESS) for bilateral wrist and metacarpophalangeal joints at week 12. Noninferiority was stated if the changes in the baricitinib groups were above the lower limit of the noninferiority range, defined as 80% of changes observed in the etanercept plus MTX group. Changes in serum concentrations of different mediators were analysed at 24 weeks. One hundred fifty patients (109 women and 41 men) were randomised. All clinical and ultrasound variables showed significant improvement starting from week 4 across the 3 treatment arms (P < .050). Noninferiority of baricitinib (monotherapy and plus MTX) was confirmed against etanercept with MTX for GLOESS at week 12 (P < .050). Changes in metalloprotease-3 concentration significantly correlated with changes in all ultrasound scores. The response of ultrasound-assessed synovitis to baricitinib, alone or in combination with MTX, was noninferior to that of etanercept with MTX.
Systemic sclerosis (SSc) is an autoimmune disease that transitions from vasculopathy as an initiating pathogenic event to tissue fibrosis. The mechanisms of these transitions remain, however, poorly understood, mainly because complex multicellular human models of SSc vasculopathy are lacking. We aimed to develop a complex multicellular human model of SSc vasculopathy and use it to investigate the mechanisms underlying this process. Blood vessel organoids (BVOs) were derived from induced pluripotent stem cells of patients with SSc and healthy controls. Organoids were exposed to serum from patients with SSc with clinically manifest microvasculopathy or healthy donors. Structural and molecular changes were evaluated using confocal imaging, transcriptomic (RNA sequencing), epigenetic (assay for transposase-accessible chromatin sequencing), and spatial proteomic (codetection by indexing) profiling. Serum immunoglobulin G (IgG) was selectively depleted or enriched to investigate antibody contributions. Therapeutic interventions included bosentan and the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). SSc-derived BVOs exposed to SSc serum exhibited profound angiogenic defects, characterised by reduced vessel integrity, loss of endothelial-pericyte interactions, and induction of endothelial-to-mesenchymal transition (EndMT). Epigenetic and transcriptional profiling revealed upregulation of fibrosis-related genes and loss of endothelial markers. Spatial proteomic data confirmed EndMT at the protein level and demonstrated shifts in endothelial and pericyte subpopulation as well as alterations in their interactions reminiscent of those seen in tissues of patient with SSc. IgG depletion from SSc serum restored vascular structure, and transfer of SSc IgG to healthy serum phenocopied the pathological phenotype, implicating autoantibodies in endothelial injury. Both bosentan and DAPT partially reversed vascular abnormalities and downregulated EndMT markers. This study establishes BVOs as a complex human model of SSc vasculopathy and demonstrates in a multiomic approach that they recapitulate disease-specific vascular dysfunction and its transition to fibrosis. We show that genetic susceptibility and pathogenic autoantibodies synergise in driving microvascular injury in SSc. Furthermore, we provide evidence that SSc BVOs are a promising platform for evaluating therapies that prevent the transition from vasculopathy to fibrosis, and present Notch/γ-secretase inhibition as a potential novel target in SSc vasculopathy.
This study aims to estimate the extent of the reduction in healthy working life expectancy (HWLE), from age 50, for people with rheumatic and musculoskeletal diseases (RMDs) in 19 countries across Europe and highlight the need to target extending working lives through interventions and policy. Data were from 2 longitudinal studies (Survey of Health, Ageing and Retirement in Europe [2004-2022], English Longitudinal Study of Ageing [2002-2023]) that collect information in people aged 50 years and over. 'Healthy' and 'working' were defined as no limiting long-standing illness and employment/self-employment, respectively. RMDs were identified from self-report of ever having received a doctor diagnosis of arthritis or rheumatism. Age-adjusted discrete time 3-state models were fitted using IMaCh software, a maximum likelihood modelling programme using interpolation of Markov Chains, to estimate HWLE from transition probabilities between each healthy and working state based on RMD status (overall, by sex, education, and physical activity), stratified by 19 countries. In 6 countries, HWLE in the population with RMDs was around 50% or less than for the population without RMDs. The lowest HWLE for populations with RMDs was in Austria 2.60 (1.49, 3.71) years which was 42.9% of HWLE for the population without RMDs. HWLE was lower in populations with RMDs with lower than upper secondary education in all countries and in populations with RMDs categorised as physically inactive in 16 countries. The differences observed in HWLE demonstrate the substantial societal burden associated with RMDs. However, differences by country, sex, education and physical activity indicate that there are opportunities for interventions and policies to increase HWLE.
Calcium pyrophosphate deposition (CPPD) disease is a common form of arthritis affecting older individuals. This disease is characterised by high levels of pyrophosphate in articular cartilage, resulting in calcium pyrophosphate crystal formation in humans and inflammatory and degenerative arthritis. A loss-of-function mutation in the TNFRSF11B locus (also known as CCAL1), which encodes osteoprotegerin (OPG) causes familial CPPD. OPG acts as a decoy receptor for RANKL, thereby inhibiting osteoclast differentiation and activity. CPPD currently lacks any animal models. The goal of this study was to develop a murine model of early CPPD by incorporating the TNFRSF11B gene mutation in mice and determining its effects on bones, joints and CPPD biomarkers. We used CRISPR/Cas9 editing to generate mice carrying the TNFRSF11B mutation (Opgmt). Joint and bone phenotypes, bone remodelling biomarkers and key CPPD biomarkers were assessed in wild type (WT; Opgwt/wt), Opgwt/mt and Opgmt/mt mice at 6 and 12 months of age. Male and female mice carrying Opgmt displayed osteopenia and high bone remodelling markers at 6 and 12 months of age. This phenotype was concurrent with increased osteoclast numbers and activity. Female Opgmt/mt mice also displayed significant osteoarthritis features by 12 months of age, including articular cartilage loss in the lateral compartment of the knee based on Mankin structural damage scores. Additionally, biomarkers pathognomonic of CPPD disease, such as pyrophosphate, transforming growth factor (TGF)-β1 levels and ENPP1 activity, were significantly elevated in the joints of both 6- and 12-month-old female mice with OPGmt. Mice carrying Opgmt display bone and joint phenotypes characteristic of early-stage CPPD disease in humans. Opgmt mice represent a novel preclinical model of early CPPD, ideal for exploring potential therapies targeting the disease prior to the development of major joint damage.
This systematic literature review (SLR) updated evidence on the efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) to inform the 2025 update of the European Alliance of Associations for Rheumatology (EULAR) management recommendations for rheumatoid arthritis (RA). Medline (PubMed), Embase (OVID), Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomised controlled trials (RCTs) of conventional-synthetic, biological, and targeted-synthetic DMARDs (csDMARDs, bDMARDs, tsDMARDs), as well as GCs and biosimilars, published from 14 January 2022 to 22 January 2025. Additional searches on DMARDs, GCs, and antifibrotics for RA-associated interstitial lung disease (RA ILD), and on DMARDs and GCs for preventing RA in at-risk individuals, were conducted from database inception to 22 January 2025. A total of 12,567 references were identified; 390 full-texts were reviewed, and 72 studies were included. Phase 3-4 RCTs evaluated csDMARDs (hydroxychloroquine, iguratimod, leflunomide, and methotrexate), bDMARDs (abatacept, otilimab, and ozoralizumab), and tsDMARDs (ivarmacitinib, peficitinib, and tofacitinib). Twelve novel compounds were assessed in phase 2 RCTs, and 3 articles investigated GCs. Strategic trials compared conventional therapies with bDMARD- or tsDMARD-based strategies and explored precision-medicine approaches such as synovial biopsy-guided treatment and therapeutic drug monitoring. Additional evidence addressed DMARD tapering. Two RCTs assessed antifibrotics (nintedanib and pirfenidone) for RA ILD, and 7 studies evaluated DMARDs for RA prevention in at-risk populations. This SLR, together with the safety review, informed the 2025 update of the EULAR RA management recommendations. Although few phase 3 trials on novel agents were available, strategic and head-to-head studies provided important insights that enabled further refinement of the established treatment algorithm.
Lupus nephritis (LN) is a common, potentially fatal manifestation of systemic lupus erythematosus. We aimed to gain new insights into the immune responses underlying LN and their relation to the histologic heterogeneity observed in this disease, focusing on myeloid cells. We used single-cell RNA-sequencing (scRNA-seq) data of dissociated kidney samples from 156 patients with LN and 30 healthy individuals. We applied spatial transcriptomics (ST), utilising a gene panel designed to capture all myeloid subsets identified in the scRNA-seq data, to profile kidney samples acquired from 6 patients with LN and 2 controls. We generated a catalogue of the myeloid subsets found in LN kidneys. Our analyses indicated that an increase in irreversible tissue damage, as measured by the National Institutes of Health chronicity index (CI), is associated with a gradual switch of the local immune response from one dominated by monocytes and macrophages to one featuring expanded CD4 T, GZMK+ CD8 T, B, and dendritic cells, with a parallel decrease in the interferon response. In proliferative/mixed LN only, the degree of active inflammation correlates with the expansion of disease-specific macrophage (DMac) subsets, which later contract as the CI increases. Trajectory analysis of the scRNA-seq data suggested that DMacs arise from both infiltrating monocytes and tissue-resident macrophages; this was supported by the ST data, as well as cell cultures. DMacs are implied to interact with parietal epithelial cells, promoting the development of glomerulosclerosis. We suggest a detailed picture of the changes in the kidney immune mechanisms in LN as this disease progresses.
The Axial Involvement in Psoriatic Arthritis (AXIS) cohort aimed at evaluating the frequency of and clinical and imaging features of axial involvement in psoriatic arthritis (PsA). AXIS (NCT04434885) is a prospective, multicentre, cross-sectional study conducted in 19 countries, by the Assessment of SpondyloArthritis International Society and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. Participants with a diagnosis of PsA meeting ClASsification criteria for Psoriatic ARthritis with musculoskeletal symptom duration ≤10 years and no prior exposure to biological or targeted synthetic disease-modifying antirheumatic drugs were consecutively included. Standardised clinical, laboratory, and imaging assessments (radiography and magnetic resonance imaging of the axial skeleton, including sacroiliac joints [SIJs] and spine), were performed. Imaging was reviewed locally and centrally to detect axial involvement. The presence of axial involvement was determined by local investigator judgement before and after central-imaging review. Among 409 participants, axial involvement was identified in 153 (37.4%) based on the investigator's initial assessment and was decreased to 112 (27.4%) in the final evaluation after incorporating central-imaging review. Participants with axial involvement were younger (45.2 ± 13.8 vs 47.6 ± 12.6 years), more often male (56.3% vs 51.5%), and had a higher frequency of human leukocyte antigen (HLA)-B*27 positivity (22.4% vs 10.8%), inflammatory back pain (IBP) (74.7% vs 43.4%), and elevated C-reactive protein (CRP) (52.7% vs 37.4%). Active inflammatory and structural imaging changes were highly discriminative between participants with and without axial involvement. The central review identified imaging signs of axial involvement (active inflammation or structural lesions) in 95 participants (23.2%). Axial involvement was identified in 27.4% of participants with PsA after final diagnostic assessment, with associated features including HLA-B*27 positivity, IBP, elevated CRP, and imaging changes in SIJ or spine.
There is growing evidence of microbial involvement in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). However, it remains unclear whether different PsA phenotypes exhibit distinct microbial profiles. Furthermore, up to 4% of patients with PsA have comorbid IBD, which often remains undiagnosed. We hypothesised that the gut microbiome distinguishes PsA subphenotypes and serves as a biomarker of IBD in patients with PsA independent of faecal calprotectin (fCAL). We obtained samples from 192 patients with axial or peripheral PsA and no prior diagnosis of IBD enrolled in the EISER study. Patients with elevated fCAL and subclinical IBD symptoms underwent colonoscopy with intestinal biopsy. Stool samples were used to measure fCAL, and gut microbiome was characterised using shotgun metagenomics. Serum samples were used for cytokine profiling. Axial PsA had lower alpha diversity and loss of several commensals compared with peripheral PsA, as well as a depletion of microbial biotin and arginine metabolism and higher levels of IL-23, IL-17F, and IL-8. Five subjects had newly diagnosed IBD which was characterised by a depletion of tryptophan and vitamin B6 metabolism. They also showed significant enrichment of several taxa compared to non-IBD and with a larger effect size than fCAL. Our results identify a distinct microbiome and immune profile in axial PsA, with lower microbiome diversity, a depletion of commensals and protective microbial mechanisms, and higher levels of some proinflammatory cytokines. In patients with newly diagnosed IBD, we identified microbial taxa associated with the condition yet independent of fCAL, the current clinical standard.
Tofacitinib is a Janus kinase inhibitor studied in different categories of juvenile idiopathic arthritis (JIA). This post hoc analysis evaluated the impact of tofacitinib on the growth of patients with JIA and on biomarkers of growth hormone (GH) function and bone metabolism. The analysis included 225 patients, primarily with polyarticular-course JIA, receiving long-term tofacitinib (median [IQR] follow-up 3.6 [1.9-4.6] years). Height velocities (cm/y) and height Z-scores (based on age- and sex-matched reference data) were calculated. Biomarkers were measured in serum from 137 patients with JIA completing 18 weeks of open-label treatment with tofacitinib. This population of patients with JIA had a baseline height distribution similar to the general population. During treatment with tofacitinib, patients experienced height velocities that appeared greater (patients ≤12 years) or as expected (patients >12 years) relative to the reference for their ages. Height Z-scores were largely stable during treatment with tofacitinib. In patients in puberty and a height Z-score less than --1.0 at baseline, an increase in height Z-score (P < .05) was detected after 24 months of treatment. Tofacitinib treatment did not impact levels of insulin-like growth factor (IGF)-1, IGF binding protein 3 and osteocalcin in the overall population, but in patients aged 6 to 12 years, IGF-1 levels increased with tofacitinib from baseline to 18 weeks. This post hoc analysis of patients with JIA indicated normal or higher than expected growth velocity during long-term treatment, with tofacitinib with catch-up growth during puberty and, overall, no concerning changes in biomarkers of GH signalling.
The objective of this study was to describe the musculoskeletal ultrasound features of asymptomatic hyperuricaemia using the Outcome Measures in Rheumatology (OMERACT) gout semiquantitative scoring system and examine relationships between ultrasound lesions. Participants with serum urate ≥0.48 mmol/L, no previous gout flares, and no subcutaneous tophi (n = 269) underwent a standardised ultrasound examination of bilateral patellar tendons, knee, first and second metatarsophalangeal joints (MTPs), and Achilles tendon. Double contour, tophus, and aggregates were scored according to the OMERACT gout ultrasound semiquantitative scoring system (0-3, with score >1 indicating a definite finding), together with erosion, synovial hypertrophy, and power Doppler activity in the scanned joints. In addition to elementary lesion sum scores, the sum of the semiquantitative double contour scores and tophus scores was calculated for each participant (semiquantitative double contour-tophus [SQDT] sum score, maximum 60). There were 38.7% of participants with at least 1 definite double contour and/or tophus on ultrasound. The median (IQR) SQDT sum score was 2 (0-4). Double contour scores contributed most to the SQDT sum score, followed by first MTP tophus scores. Double contour was associated with synovial hypertrophy at the first and second MTP, and tophus was associated with erosion, synovial hypertrophy, and power Doppler activity at the first MTP. Definite ultrasound features of gout can be identified in more than one-third of people with asymptomatic hyperuricemia. However, the amount of monosodium urate crystal deposition on ultrasound, assessed using the OMERACT gout ultrasound scoring system, is low. In asymptomatic hyperuricemia without clinical evidence of gout, ultrasound features of gout are associated with subclinical joint damage and inflammation.
This study aimed to evaluate the efficacy and safety of intravenous (IV) efgartigimod in adults with Sjögren's disease (SjD). We conducted a randomised, double-blinded, placebo-controlled, phase 2, proof-of-concept multicentre study (hereafter referred to as RHO). Participants were randomised 2:1 to receive efgartigimod IV 10 mg/kg or placebo once weekly for 24 weeks. The primary outcome was the proportion of Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) responders on ≥3 of 5 items (systemic disease activity, patient-reported symptoms, tear and salivary gland function, and serology) at week 24. Secondary outcomes included the proportion with candidate Sjögren's Tool for Assessing Response (cSTAR) score ≥5 at week 24 and safety. No formal statistical hypothesis was tested. Thirty-four participants were randomised to efgartigimod (N = 23) or placebo (N = 11); 31 were included in the efficacy analysis. A numerically higher proportion of efgartigimod-treated participants responded to ≥3 items of CRESS at week 24 compared with placebo (45.5% vs 11.1%; treatment difference 34.4%). More specifically, efgartigimod scored higher on 4 of 5 CRESS items. Similarly, a numerically higher proportion of efgartigimod-treated participants scored ≥5 on the cSTAR at week 24 (efgartigimod, 54.5% vs placebo, 33.3%). Treatment-emergent adverse events were reported in 87.0% of efgartigimod-treated participants compared with 63.6% of those on placebo; all were grade 1 or 2 in severity. Data from the RHO study support proof of concept for efgartigimod in SjD. Further evaluation in a phase 3 study of efgartigimod in individuals with SjD is warranted. The trial was registered with ClinicalTrials.gov (NCT05817669).
No app-based nonpharmacological intervention has yet demonstrated to meaningfully improve disease activity, functional status, and disease-specific quality of life in axial spondyloarthritis (axSpA). We evaluated Axia, a CE-marked smartphone application designed for axSpA, that combines personalised exercise therapy, patient education, and disease management, supported by gamification for long-term adherence. To evaluate its clinical efficacy, a 12-week monocentric randomised controlled interventional trial was conducted involving 200 patients with axSpA with stable pharmacotherapy. Patients were randomised (1:1) to either using Axia (intervention group [IG]) or standard of care (control group [CG]). A total of 186 participants (mean age 50.61 years, 66% females, 56% with radiographic axSpA, mean Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] 5.17, and 58% received biologicals or Janus kinase inhibitors) completed the study (95 in the IG and 91 in the CG). Compared to CG, participants in the IG demonstrated significant improvements in BASDAI (analysis of covariance [ANCOVA]-estimated group difference: -1.508, P < .001), Bath Ankylosing Spondylitis Functional Index (-1.139; P < .001), and Ankylosing Spondylitis Quality of Life questionnaire (-2.297; P < .001), all exceeding minimal clinically important difference thresholds. A significantly higher proportion of patients in the IG achieved an Assessment of Spondyloarthritis International Society (ASAS)20 response compared to the CG (51% vs 9%; P < .001), and the ASAS40 response rate was also higher (23% vs 3%; P < .001). No concerning safety signals were observed. These findings support the potential of Axia as a safe and effective nonpharmacological intervention to further improve the state of care of patients with axSpA in addition to conventional anti-inflammatory pharmacotherapy.
This study aimed to assess the noninferiority of spacing a tumour necrosis factor (TNF) inhibitor or reducing the methotrexate dose with continued treatment in patients with rheumatoid arthritis. The SORAIRO trial was a multicentre, open-label, randomised, noninferiority study. Patients who had been in remission or low disease activity based on the Clinical Disease Activity Index (CDAI) in the preceding phase III trial of ozoralizumab, a next-generation TNF inhibitor, were enrolled. The precalculated sample size was 141. Patients were randomised into continued treatment, ozoralizumab spacing, or methotrexate dose reduction groups. The primary endpoint was a noninferiority of low disease activity maintenance at week 48 with a prespecified noninferiority margin of -18%. A total of 144 patients were analysed. The mean age was 58.2 years, 75.0% were female, and the mean CDAI was 2.70 with 61.8% in remission. The low disease activity at week 48 was 97.9% in the continued treatment group, 79.2% in the ozoralizumab spacing group (difference, -21.6; 95% CI, -39.9 to -5.7), and 72.7% in the methotrexate dose reduction group (difference, -30.4; 95% CI, -54.0 to -10.5). In the baseline remission subgroup, remission maintenance rates were comparable in the 3 groups (77.4%, 76.7%, 79.2%, respectively). No significant differences were demonstrated in changes in the Health Assessment Questionnaire Disability Index and modified total Sharp score. Adverse events occurred in 68.0%, 59.2%, and 58.0%, respectively. Treatment tapering may not be feasible in patients with low disease activity, whereas both extending the TNF inhibitor interval and reducing the methotrexate dose may be reasonable options for patients in remission.