To perform a systematic literature review to inform a Task Force formulating EULAR points to consider on the initiation of targeted therapies in patients with IA and a history of cancer.

Specific research questions were defined within the Task Force before formulating the exact research queries with a librarian. We included studies reporting a relative risk measure of patients with a history of cancer initiating a targeted therapy or a conventional synthetic disease-modifying antirheumatic drug (csDMARD), regardless of the time since diagnosis of cancer. All relevant studies included in PubMed or Embase up to 15 July 2022 were included. Two reviewers independently performed standardised article selection, data extraction, synthesis and risk of bias assessment.

14 published articles and one ACR abstract fulfilled the inclusion criteria. All studies were high-quality observational studies, representing a median follow-up from treatment initiation of 4.52 years among 4428 patients and 15 062 patient-years of follow-up for new or recurrent cancer.

All patients had a history of cancer, most frequently solid cancer, most frequently receiving treatment for rheumatoid arthritis and most frequently treated with tumour necrosis factor-alpha inhibitors. Across these studies, the overall HR of cancer recurrence was 0.92 (95% CI 0.74 to 1.15) for patients receiving a targeted therapy versus a csDMARD.

Overall, the targeted therapies and clinical contexts covered by the included studies were not associated with an increased risk of cancer recurrence as compared with csDMARDs.

To develop points to consider (PTC) to assist rheumatologists when initiating a targeted therapy in the context of a previous malignancy.

Following EULAR standardised operating procedures, a task force met to define the research questions for a systematic literature review and to formulate the overarching principles (OPs) and the PTC.

The group formulated five OPs; seven PTC were formulated concerning the initiation of targeted therapies in patients with active IA and a previous malignancy in remission and one PTC concerning patients with active IA who were not in cancer remission. Major themes included (a) the need to assess the individualised risk of cancer recurrence based on the characteristics of the patient, cancer and the underlying disease; (b) the importance of engaging with specialists caring for cancer and defining treatment based on a shared decision between the patient and the rheumatologist; (c) the value of initiating without delay an appropriate targeted therapy for the treatment of the IA in patients in remission of their cancer; (d) the proposal to use Janus kinase inhibitors and abatacept with caution and in the absence of therapeutic alternatives, based on the absence of any data concerning their use in the context of previous malignancy.

The 2024 EULAR points to consider provide guidance on the management of targeted therapies in patients with IA and a previous malignancy.

Systematic literature review and Grading of Recommendations, Assessment, Development and Evaluations-based appraisal of evidence, two Delphi surveys and three digital and in-person consensus meetings with a multidisciplinary expert panel and patient representatives.

A consensus disease definition was developed and the term ‘chronic non-bacterial osteitis’ (CNO) is proposed to describe adults with sterile bone inflammation. For initial imaging evaluation of adults with suspected CNO, the panel recommends MRI or otherwise CT combined with nuclear imaging. Whole-body imaging at initial evaluation can be considered for diagnostic and prognostic purposes. Suggested first-line treatment in adults with active CNO includes non-steroidal anti-inflammatory drugs/cyclooxygenase 2-inhibitors. Second-line treatment preferably consists of intravenous bisphosphonates, and otherwise tumour necrosis factor-α inhibitors. Choice between them should be individualised, considering the presence of additional inflammatory features. The panel further discusses outcome measures, follow-up and management of adverse events and complications.

These expert consensus recommendations are intended to support healthcare professionals worldwide in their care for adults with CNO. They also lay the groundwork for establishing international patient registries, translational research lines and multicentre trials, all of which are urgently required.

Patients were randomised (1:1:1) to receive either placebo (n=188), ivarmacitinib 4 mg (n=189) or ivarmacitinib 8 mg (n=189) once daily, with background csDMARDs allowed. After 24 weeks, patients on placebo switched to ivarmacitinib 4 mg for an additional 28 weeks, while those on ivarmacitinib continued their initial dosage. The primary endpoint was the proportion of patients achieving a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24.

At week 24, ACR20 response rates were significantly higher in the ivarmacitinib 4 mg (70.4%) and 8 mg (75.1%) groups compared with the placebo group (40.4%; both p<0.0001). Both ivarmacitinib doses achieved numerically higher Disease Activity Score 28-joint count C reactive protein of <2.6/≤3.2 response rates compared with placebo. Improvements in efficacy and patient-reported outcomes were sustained through 52 weeks and were noted in patients who switched from placebo after week 24. During the placebo-controlled period, treatment-emergent adverse events (TEAEs) occurred in 81.5% and 90.5% of patients in the ivarmacitinib 4 mg and 8 mg groups, versus 79.3% in the placebo group. Infection-related TEAEs were slightly higher in the ivarmacitinib groups.

Ivarmacitinib may offer a potential therapeutic option for patients with RA who have an inadequate response to csDMARDs, with a safety profile that was generally manageable over 1 year of treatment and similar to other JAK inhibitors.

NCT04333771.

Pharmacodynamic effects of 2 and 4 mg cenerimod were evaluated in the phase 2b clinical trial (CARE) in moderate to severe patients with SLE (NCT03742037).

Blood samples were collected at baseline and after 6 months of treatment with cenerimod or placebo from CARE. The gene expression signatures for type 1 interferon (IFN-1), IFN- and plasma cells were used to assess dose-dependent pharmacodynamic effects of cenerimod. Cell-type deconvolution was performed to estimate cell abundance.

Cenerimod 4 mg reduced IFN-associated protein and gene signature biomarkers after 6 months compared with placebo. A larger decrease of IFN proteins was evident in IFN-1 high patients compared with IFN-1 low patients. The median IFN-1 score in the IFN-1 high patients was reduced after 6 months of cenerimod 4 mg and the transition from IFN-1 low to high status compared with placebo was prevented. Cenerimod 4 mg exhibited a larger effect size on the pharmacodynamic biomarkers IFN-1, IFN- and plasma cells compared with cenerimod 2 mg.

This study further characterised the mechanism of action of cenerimod in patients with SLE and substantiated the scientific rationale for cenerimod 4 mg in the phase 3 clinical trials in moderate to severe SLE (OPUS-1/–2).

In the multicentre PsA Research Consortium (PARC) study, we applied factor analysis of mixed data to reduce dimensionality and collinearity, followed by hierarchical clustering on principal components. We then evaluated the transition of PsA clusters and their response to new immunomodulatory therapy and tumour necrosis factor inhibitor (TNFi).

Among 627 patients with PsA, three clusters were identified: mild PsA and psoriasis only (PsO) (Cluster 1, 47.4%), severe PsA and mild PsO (Cluster 2, 34.3%) and severe PsA and severe PsO (Cluster 3, 18.3%). Among 339 patients starting or changing, significant differences in response were observed (mean follow-up of 0.7 years, SD 0.8), with Cluster 3 showing the largest improvements in cDAPSA and PsAID. No differences were found among those starting TNFi (n=218). cDAPSA remission and PsAID patient acceptable symptom state were achieved in 10% and 54%, respectively. Clusters remained stable over time despite treatment changes, though some transitions occurred, notably from Cluster 3 to milder clusters.

Data-driven clusters with distinct therapy responses identified in this real-world study highlight the extensive heterogeneity in PsA and the central role of psoriasis and musculoskeletal severity in treatment outcomes. Concurrently, these findings underscore the need for better outcome measures, particularly for individuals with lower disease activity.

We conducted a retrospective, multicentre study comparing PEXIVAS redGC with standGC in patients with AAV. The primary composite outcome was the occurrence of death, ESKD, AAV progression before remission or relapse within the 12 months following induction. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Factors associated with the occurrence of the primary outcome were estimated.

A total of 234 patients were included. The primary composite outcome occurred in 42/126 (33%) patients with redGC versus 20/108 (19%) with standGC. In unweighted multivariable analysis and in weighted analysis, redGC was independently associated with the primary outcome but not with death or ESKD. Among redGC-treated patients, those with serum creatinine>300 µmol/L were more likely to achieve the primary outcome. RTX-treated patients who received redGC were more likely to experience death or ESKD and to achieve the primary outcome.

In this study of patients with AAV primarily treated with RTX, redGC was associated with an increased risk of the primary outcome consisting of death, ESKD, AAV progression before remission or relapse.

RNA-sequencing was performed in the blood of active SLE patients at baseline and following 6 months of belimumab treatment (n=45 paired samples). Clinical response was determined according to the SLE Responder Index (SRI)-4 and Lupus Low Disease Activity State (LLDAS). Weighted correlation network analysis (WGCNA) was used to uncover gene module trait associations. Reversibility of SLE susceptibility and severity gene signatures was assessed. Machine learning was used to build models predictive of response.

Belimumab induced widespread transcriptome changes with downregulation of pathways related to B cells, type I/II interferon, IL-6/STAT3 and neutrophil activation. These effects were more pronounced among patients with LLDAS+ compared with to SRI-4+/LLDAS– response, with amelioration of the SLE ‘susceptibility’ signature observed in the former group. Unsupervised analysis unveiled gene modules enriched in neutrophil degranulation, type I interferon signalling and cytokine production to correlate positively with response at 6 months. Using neural networks, a set of 50 genes (including CCL4L2, CARD10, MMP15 and KLRC2) predicted response to belimumab with a cross-validated 84% specificity (test set). Lack of response was linked to perturbations of the cell cycle checkpoints, PI3K/Akt/mammalian target of rapamycin and TGF-beta signalling pathways.

Belimumab treatment ameliorates multiple innate and adaptive immunity dysregulations of SLE and may reverse the disease signature, consistent with the drug effects on reducing activity and preventing flares. Fingerprints of innate immunity correlate with robust improvement whereas DNA damage response with less responsive disease to BAFF inhibition.

The PRESS trial is a multicentre, 33-week, open-label, three-arm, non-inferiority designed, randomised controlled trial. SLE patients with sustained clinically inactive disease who were maintained on low-dose GC plus HCQ therapy were screened and qualified patients were randomly assigned to three groups: drug-free group (both GC and HCQ withdrawal); HCQ group (discontinued GC but maintained HCQ); dual maintenance group (both GC and HCQ continued). The primary endpoint was to compare the proportion of patients experiencing a relapse as defined by the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index flare index by 33 weeks. Two parallel non-inferiority analyses were performed (drug-free group vs dual maintenance group and HCQ group vs dual maintenance group).

From 3 November 2016 to 13 August 2021, 333 participants complied with the protocol after randomisation were analysed. The relapse rates in the three groups were 26.1%, 11.2% and 4.7%, respectively. Compared with dual maintenance group, drug-free group failed to achieve non-inferiority significance (relapse rate difference 21.4%; 95% CI 12.3% to 30.5%; P_{non-inferiority}=0.238), whereas HCQ group achieved non-inferiority (relapse rate difference 6.5%; 95% CI –0.5% to 13.5%; P_{non-inferiority}=0.034). HCQ group also exhibited fewer relapses than drug-free group (p=0.006). Adverse events were similar among all three groups.

GC withdrawal may be feasible in sustained clinically inactive SLE patients. HCQ maintenance can exert a protective role in preventing disease relapse after GC withdrawal.

NCT02842814.

A task force of 26 people from 10 European countries followed the EULAR Standardised Operating Procedures to establish overarching principles (OAPs) and PtC based on a literature review and expert consensus. Level of evidence (LoE), grade of recommendation (GoR) and level of agreement (LoA) were determined.

Two OAPs and seven PtC were formulated. The OAPs highlight the importance of personalised transitional care in rheumatology, ideally based on shared decision-making and incorporate interactive education to empower young individuals in managing their physical activity and pain. The PtC emphasise the clinical importance of patient education in these areas to improve readiness to transfer from paediatric to adult care. For two PtC, the GoR was moderate (grade B), based on individual cohort study (LoE 2b). For the remaining five PtC, the GoR was weak (grade D), based on expert opinion (LoE 5). The LoA among the task force was high, ranging from 9.4 to 9.8, except for one PtC that was 8.7.

These EULAR PtC establish guidance on best practices for delivering patient education in physical activity and self-management of pain during transitional care in rheumatology. The adoption of these PtC in clinical settings is recommended to standardise and optimise transitional care across European healthcare systems. Additionally, the task force expects that these PtC will drive future research and potentially shape policies across Europe.

We searched MEDLINE for all Cochrane reviews and for systematic reviews published since April 2015. RCTs were eligible if they included patients with IA receiving b/tsDMARD, compared with any comparator arm. Harms were evaluated based on number of withdrawals due to adverse events (WDdtAEs), total withdrawals (WDs), serious adverse events (SAEs) and deaths. Data were extracted for 48 trial/patient characteristics and meta-regression analyses were performed to relate the relative risk ratio (RRR) of harms to the trial characteristics.

A total of 284 trials (from 245 reviews) with 97 607 patients were included, contributing 490 comparisons for the primary analysis. Overall, the relative risk of WDdtAEs was lower when trials used active comparators (RRR, 0.74 (95% CI 0.58 to 0.94)) and higher when requiring raised inflammatory markers at enrolment (RRR, 1.25 (1.01 to 1.55)). Our meta-regression analyses suggested that trials with eligibility criteria for minimum tender/swollen joint count and maximum disease duration decreased the risk of WDs, while previous b/tsDMARDs use at the time of enrolment increased the risk of SAEs.

Most study characteristics do not affect the reported harm measures. However, a trend was observed where trials selecting patients with higher baseline disease activity found a higher risk ratio of WDdtAEs and SAEs, but also a lower risk of WDs, compared with trials not selecting patients with a high disease activity.

CRD42020171124.

We set up a framework to monitor T cells in paired bronchoalveolar lavage fluid, blood and inflamed synovium tissue samples from 17 new-onset treatment naïve anticitrullinated protein antibody+RA patients. T cell receptor (TCR) repertoire of index-sorted tissue residing in T cells was determined by single-cell TCR sequencing coupled with deep immunophenotyping.

A significant enrichment of CD4+ and CD8+ T cells was seen in synovial samples from smoking versus non-smoking patients, along with an increase in expanded T cell clonotypes. This was particularly pronounced among SE+smokers, suggestive of a synergic gene-smoke effect. Strikingly, identical TCR clonalities were present in matched lung and joint samples of RA smokers, the majority being also detectable in circulation. This was mirrored by an increased clustering of lung and synovium TCRs across patients, suggesting a shared specificity by conserved motifs. The lung-joint shared T cell clonotypes showed a restricted TCR gene usage and exhibited a particular 4-1BB+CD57 hi effector profile within the inflamed synovium.

The data indicate a profound interplay between a strong MHC predisposition, smoking and induction of autoimmunity by shaping the TCR repertoire.

Individuals at risk of RA were defined by the presence of anticyclic citrullinated protein (anti-CCP) antibodies and new musculoskeletal symptoms without clinical synovitis. Baseline sampling included 124 participants (30 progressed to RA), with longitudinal sampling of 19 participants (5 progressed to RA) over 15 months at five timepoints. Gut microbiome taxonomic alterations were investigated using 16S rRNA amplicon sequencing and confirmed with shotgun metagenomic DNA sequencing on 49 samples.

At baseline, CCP+ at risk progressors showed significant differences in Prevotellaceae abundance compared with non-progressors, contingent on intrinsic RA risk factors and time to progression. Longitudinal sampling revealed gut microbiome instability in progressors 10 months before RA onset, a phenomenon absent in non-progressors. This may indicate a late microbial shift before RA onset, with Prevotellaceae contributing but not dominating these changes. Structural changes in the gut microbiome during arthritis development were associated with increased amino acid metabolism.

These data suggest conflicting reports on Prevotellaceae overabundance are likely due to sampling within a heterogeneous population along a dynamic disease spectrum, with certain Prevotellaceae strains/clades possibly contributing to the establishment and/or progression of RA. Gut microbiome changes in RA may appear at the transition to clinical arthritis as a late manifestation, and it remains unclear whether they represent a primary or secondary phenomenon.

The aim of this new SLR was to provide the most up-to-date literature to underpin contemporary EULAR recommendations for the management of SSc.

30 searches for 30 interventions (including several outcomes/clinical questions), and 1 dedicated search (with several interventions) for calcinosis were prioritised by the task force. Three types of questions were defined: type I questions, unchanged as compared with the previous recommendations; type II questions exploring interventions already mentioned in the previous recommendations but with new outcomes; type III questions for new interventions.

14 490 abstracts were retrieved from the databases on 31 March 2022 and 2021 abstracts were retrieved on 11 October 2022. 483 new full texts were evaluated and 172 new articles were included for the first search and 9 for the second search. The majority of the questions covered by this SLR explored new interventions (40% of type III questions) or new outcomes (26% of type II questions). New interventions included targeted therapies such as abatacept, Janus kinase inhibitors or nintedanib, and updated questions incorporated the results from key game-changing randomised controlled trials including trials on tocilizumab, mycophenolate or rituximab in SSc-interstitial lung disease.

This SLR provides and summarises the highest level of evidence for the new EULAR recommendations for the treatment of SSc, providing an unprecedented comprehensive overview of recent knowledge on SSc treatments and participating in defining the future research agenda.

This case–control study used the Mass General Brigham (MGB) and Mayo Clinic (MC) Biobanks for discovery and replication, respectively. We matched criteria-confirmed incident RA cases to four non-RA controls on age, sex and health record history. Genetic exposures included the top 11 RA risk alleles, and a validated human leucocyte antigen (HLA) genetic risk score (GRS). We identified seven respiratory diseases by codes. Using logistic regression models adjusting for potential confounders, we estimated Rs with 95% CIs for the interactions between genetic and respiratory exposures for RA risk.

We identified 653 RA cases and 2607 controls in MGB, and 428 incident RA cases and 1712 non-RA controls in MC (mean age 64, 69% female). Respiratory diseases were associated with an increased risk of RA (OR 1.34, 95% CI 1.05, 1.71). Six out of 11 non-HLA RA risk alleles interacted strongly with specific respiratory diseases for RA risk, including NFKBIE and sinusitis (OR 5.49, 95% CI 1.56, 19.4 MGB; 5.26, 95% CI 2.00, 13.86 MC) and FAM167A and acute sinusitis for seronegative RA (OR 6.00, 95% CI 2.09, 17.24 MGB; 4.90, 95% CI 1.71, 14.1 MC). The RA HLA GRS interacted synergistically with interstitial lung disease for RA risk (OR 5.41, 95% CI 2.71, 10.8 in MC), with DPB1*02:01, DRB1*16:01 and DRB1*04:04 best predicting RA (positive predictive value 61%).

Several genetic-respiratory disease interactions strongly drive RA onset. If confirmed, these novel associations may reflect RA endotypes that can facilitate individualised prevention, diagnosis and treatment.

We used single-cell and spatial transcriptomics to profile synovial cells and spatial gene expressions of synovial tissues to identify phenotypic changes in patients with osteoarthritis, RA in sustained remission and active state. Immunohistology, multiplex immunofluorescence and flow cytometry were used to identify synovial fibroblasts subsets. Deconvolution methods further validated our findings in two cohorts (PEAC and R4RA) with treatment response. Cell coculture was used to access the potential cell-cell interactions. Adoptive transfer of synovial cells in collagen-induced arthritis (CIA) mice and bulk RNA sequencing of synovial joints further validate the cellular functions.

We identified a novel tissue-remodelling CD45^–CD31^–PDPN⁺ITGA5⁺ synovial fibroblast population with unique transcriptome of POSTN, COL3A1, CCL5 and TGFB1, and enriched in immunoregulatory pathways. This subset was upregulated in active and lympho-myeloid type of RA, associated with an increased risk of multidrug resistance. Transforming growth factor (TGF)-β1 might participate in the differentiation of this subset. Moreover, ITGA5⁺ synovial fibroblasts might occur in early stage of inflammation and induce the differentiation of CXCL13^hiPD^–1^hi peripheral helper T cells (TPHs) from naïve CD4⁺ T cells, by secreting TGF-β1. Intra-articular injection of ITGA5⁺ synovial fibroblasts exacerbates RA development and upregulates TPHs in CIA mice.

We demonstrate that ITGA5⁺ synovial fibroblasts might regulate the RA progression by inducing the differentiation of CXCL13^hiPD^–1^hi TPHs and remodelling the proinflammatory microenvironments. Therapeutic modulation of this subpopulation could therefore be a potential treatment strategy for RA.

The Vascular Occlusion for optimizing the Functional Improvement in patients with Knee Osteoarthritis randomised controlled trial enrolled 120 patients with KOA at Ghent University Hospital, randomly assigning them to either a traditional exercise programme or a BFR-enhanced programme over 24 sessions in 12 weeks. Assessments were conducted at baseline, 6 weeks, 12 weeks and 3 months postintervention using linear mixed models with Dunn-Sidak corrections for multiple comparisons. Primary outcome was the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire at 3 months follow-up with knee strength, Pain Catastrophizing Scale questionnaire and functional tests as secondary outcomes. Analysis followed an intention-to-treat approach (NCT04996680).

The BFR group showed greater improvements in KOOS pain subscale (effect size (ES)=0.58; p=0.0009), quadriceps strength (ES=0.81; p<0.0001) and functional tests compared with the control group at 12 weeks. At 3 months follow-up, the BFR group continued to exhibit superior improvements in KOOS pain (ES=0.55; p=0.0008), symptoms (ES=0.59; p=0.0004) and quality of life (QoL) (ES=0.66; p=0.0001) with sustained benefits in secondary outcomes. Drop-out rates were similar in both groups.

Incorporating BFR into traditional exercise programmes significantly enhances short-term and long-term outcomes for patients with KOA demonstrating persistent improvements in pain, symptoms, QoL and functional measures compared with conventional exercise alone. These findings suggest that BFR can provide the metabolic stimulus needed to achieve muscle strength and functional gains with lower mechanical loads. Reduced pain and increased strength support a more active lifestyle, potentially maintaining muscle mass, functionality and QoL even beyond the supervised intervention period.

NCT04996680.

Immune responses to Epstein-Barr nuclear antigen-1 (EBNA1) and the Ro52/Ro60/La and Sm/U1RNP autoantigens and peptides were examined by immunoassay in patient 1, healthy and disease controls.

Anti-Ro52 and anti-Ro60 autoantibodies were present 7 days after primary infection and underwent IgM to IgG switching, suggesting that EBV infection promoted their production. More than 7 months after primary infection, new and increasing levels of antibodies against EBNA1 and the U1RNP autoantigen appeared concomitantly. These antibodies bound homologous peptide sequences shared by EBNA1, SmB' and the U1-C (U1RNP) protein, consistent with induction by molecular mimicry. Although Ro60 and EBNA1 crossreact immunologically, we found that anti-Ro60/anti-Ro52 antibody production was stimulated by acute EBV infection long before the onset of anti-EBNA1. Unexpectedly, a subset of healthy control sera had anti-SmB' peptide antibodies that were not correlated with anti-EBNA1 peptide antibodies. In contrast, anti-SmB' and EBNA1 peptide antibody levels correlated in anti-Sm/U1RNP⁺ lupus sera.

Primary EBV infection can promote anti-Ro60/anti-Ro52 and anti-U1RNP responses, though by different mechanisms. Some healthy individuals produce anti-SmB' peptide autoantibodies independently of a response to EBNA1.

The Strategies for glucocorticoid TApering in Rheumatoid arthritis (STAR) study was a double-blind, double-placebo randomised controlled trial including patients with RA receiving a stable dose of glucocorticoid 5 mg/day for ≥3 months and were in LDA for ≥3 months. Patients were randomly assigned in a 1:1 ratio to either replace prednisone with 20 mg/day of hydrocortisone for 3 months, then reduce to 10 mg/day for 3 months before discontinuation or to taper prednisone by 1 mg/day every month until complete discontinuation, contingent on maintaining LDA. The primary outcome was the percentage of patients achieving glucocorticoid discontinuation at 12 months. Other secondary outcomes were proportion of flares, need for additional glucocorticoid use, disease activity, patient-reported outcomes and the results of adrenocorticotropic hormone (ACTH) stimulation tests.

Of the 102 patients randomised in the trial (mean age 62.4 years, 70.6% females), 53 had hydrocortisone replacement and 49 tapered prednisone. At 12 months, 29 patients (55%) in the hydrocortisone replacement group and 23 patients (47%) in the prednisone tapering group achieved glucocorticoid discontinuation (p=0.4). No difference was observed between groups in the secondary outcomes. No cases of acute adrenal insufficiency were observed; however, 17 patients still had an abnormal ACTH stimulation test at 12 months, with no differences between arms.

A hydrocortisone replacement strategy was not superior to a prednisone tapering strategy for achieving glucocorticoid discontinuation success in patients with RA in LDA.

NCT02997605.

We applied IMC to deconvolute the heterogeneity of 49 969 cells including 6501 fibroblasts at the single-cell level, to analyse their spatial distribution and to characterise their cellular niches in skin sections of patients with SSc and controls in situ.

We identified 13 different subpopulations of fibroblasts in SSc and control skin, the proportion increases in five fibroblast subpopulations (myofibroblasts, FAP^high, S1PR⁺, Thy1⁺;ADAM12^high;PU.1^high and ADAM12⁺;GLI1⁺ fibroblasts) and decreases in three subpopulations (TFAM^high, PI16⁺;FAP⁺ and Thy1⁺;ADAM12^low fibroblasts). Several fibroblast subpopulations demonstrated spatial enrichment and altered cellular interactions in SSc. The proportion of S1PR⁺-fibroblast positively correlated with more extensive skin fibrosis, whereas high numbers of PI16⁺;FAP^–-fibroblasts were associated with milder skin fibrosis. The frequency of aberrant cellular interaction between S1PR⁺ and ADAM12⁺;GLI1⁺-fibroblasts also positively associated with the extent of skin fibrosis in SSc.

Using IMC, we demonstrated profound changes in composition and localisation of the majority of fibroblast subpopulations in SSc skin. These findings may provide a rationale for specific targeting of deregulated fibroblast subpopulations in SSc. Quantification of S1PR⁺-fibroblast and PI16⁺;FAP^–-fibroblasts may offer potential for patient stratification according to severity of skin fibrosis.

A cohort of 206 patients with SSc enrolled in the PRECISESADS cross-sectional study was examined. Patients were stratified based on their anti-centromere (ACA) and anti-SCL70 (SCL70) antibody statuses. Comprehensive omics analyses including transcriptomic, flow cytometric, cytokine and metabolomic data were analysed to characterise the differences between these patient groups.

Patients with SCL70 antibodies showed severe clinical features such as diffuse cutaneous sclerosis and pulmonary fibrosis and were biologically distinguished by unique transcriptomic profiles. They exhibit a pro-inflammatory and fibrotic signature associated with impaired tissue remodelling and increased carnitine metabolism. Conversely, ACA-positive patients exhibited an immunomodulation and tissue homeostasis signature and increased phospholipid metabolism.

Patients with SSc display varying biological profiles based on their serological status. The findings highlight the potential utility of serological status as a discriminating factor in disease severity and suggest its relevance in tailoring treatment strategies and future research directions.

We performed single-cell RNA/B cell receptor (BCR)/T cell receptor (TCR) sequencing analysis on sorting-purified B and T cells from the kidney and paired peripheral blood of patients with active LN, and the periphery of matched controls. Flow cytometry, Assay for Transposase Accessible-sequencing, multiplexed immunohistochemistry and functional studies were performed to validate the transcriptomic results.

High infiltrations of intrarenal atypical B cells (ABCs) and antibody-secreting cells (ASCs) were identified in the B cell compartment. The single-cell BCR repertoire analysis revealed strong clonal expansion of intrarenal ASCs dominated by IGHG1 and IGHG3 isotypes, accompanied by lower frequencies of heavy-chain and light-chain somatic mutations, compared with the peripheral ASCs. Notably, a unique expansion of IGHG4-59 and clonal overlap between ABCs and ASCs was found in kidney-specific clonotypes. In the T cell compartment, we identified granzyme K (GZMK)⁺ CD8 T cells as the dominant kidney-associated T cells which shared inflammation- and stress-related gene pathways with ABCs. Intrarenal GZMK⁺ CD8 T cells highly expressed IFNG and displayed strong communication with ABCs via the type II interferon (IFN) pathway. Intrarenal GZMK⁺ CD8 T cells and ABCs were largely co-localised within the tertiary lymphoid structure, and GZMK⁺ CD8 T cells potentially contributed to the differentiation of ABCs via IFN- and interleukin-21.

Our study revealed a potent extrafollicular B cell response linked with overactivation of GZMK⁺ CD8 T cells in the kidney of patients with LN, which may lead to innovative treatments for LN.

We conducted a phase 3, multicentre, prospective, randomised, active-controlled, parallel-group study to evaluate the efficacy and safety of either infliximab (IFX) or adalimumab (ADA) in patients with BS. Adults patients with BS presenting with active mucocutaneous manifestations, occurring while on therapy with either azathioprine or cyclosporine for at least 3 months prior to study entry, were eligible. Participants were randomly assigned (1:1) to receive IFX or ADA for 6 months. The primary study outcome was the time to response of manifestations over 6-month anti-TNF alpha agents’ treatment.

42 patients underwent screening visits, of whom 40 were randomly assigned to the IFX group (n=22) or to the ADA group (n=18). All patients at the time of randomisation had active mucocutaneous manifestations and a smaller proportion had concomitant vital organ involvement (ie, six and three patients with ocular and neurological involvement, respectively). A total of 14 (64%) responders in the IFX group and 17 (94%) in the ADA group were observed. Retention on treatment was 95% and 94% in the IFX and in the ADA group, respectively. Quality of life resulted to be significantly improved in both groups from baseline, as well as Behcet’s Disease Current Activity Form assessment. We registered two adverse events (one serious) in the ADA group and three non-serious adverse events in the IFX group.

The overall results of this study confirm the effectiveness of both IFX and ADA in achieving remission in patients with BS affected by mucocutaneous involvement.

An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds.

The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers.

These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years.

This was a phase I, randomised, placebo-controlled, two-part, proof-of-mechanism and proof-of-concept study. In part A, healthy participants were randomised 3:1 to receive GSK3858279 as either single intravenous (0.1–10 mg/kg) doses, a subcutaneous (3 mg/kg up to 240 mg maximum) dose, or placebo, to evaluate safety and tolerability. In part B, participants with knee OA pain were randomised 1:1 to receive weekly subcutaneous 240 mg GSK3858279, or placebo, for 8 weeks, to assess safety and change from baseline (CFB) in average and worst knee pain intensity. Exploratory endpoints included CFB in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and stiffness scores.

GSK3858279 demonstrated greater median CFB (95% credible interval (CrI)) in average and worst knee pain intensity versus placebo (average, –1.18 (–2.15, –0.20); worst, –1.09 (–2.29, 0.12)) at week 8. Median CFB (95% CrI) for GSK3858279 versus placebo in WOMAC pain and function scores were –1.41 (–2.35, –0.46) and –1.29 (–2.28, –0.29), respectively, at week 8. Overall, 72% (26/36; part A) and 88% (21/24; part B) of participants receiving GSK3858279 experienced adverse events (AEs); with nasopharyngitis being the most common in part A and injection site reactions in part B. No serious AEs or deaths were observed.

GSK3858279 improved pain intensity and WOMAC pain and function scores in adults with knee OA pain and demonstrated favourable safety and tolerability in both healthy participants and adults with knee OA pain.

Single-nucleus RNA sequencing of 82 924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analyses were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status.

We identified multiple subclusters of fibroblasts, macrophages, adipocytes and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles and computationally identified putative cell–cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of naïve, profibrotic stimuli-treated and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFPs.

Overall, by employing a multiomic approach, this study provides the first comprehensive map of the cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as key cells contributing to transcriptomic and metabolic differences related to KOA disease, sex or obesity.

Peripheral blood mononuclear cells from patients with anti-HMGCR+IMNM (n=10) and dermatomyositis (DM; n=10) were stimulated with HMGCR protein and peptides identified using a natural antigen processing assay (NAPA; n=6). CD4⁺T-cell activation was assessed by CD154 upregulation via flow cytometry. T-cell receptor β(TCR) sequencing was performed on paired HMGCR-reactive T-cells and muscle biopsy tissue (n=5).

CD4⁺T-cell responses to HMGCR protein were higher in patients with anti-HMGCR+IMNM compared with DM (median 0.06 vs 0.00, p=0.0059). These responses were enriched in Th1-Th17 cells, and when present, they positively correlated with anti-HMGCR antibody levels (r²=0.89, p=0.0012). NAPA revealed convergent presentation of seven HMGCR core peptides, with substantial overlap in the peptide repertoires between patients. These HMGCR peptides elicited robust CD4⁺T-cell responses, with 9/10 anti-HMGCR+IMNM patients responding to at least one peptide, compared with 1/10 DM (p=0.0003). Analysis of HMGCR-reactive TCRs β yielded antigen-reactive motifs that were enriched in muscle biopsies (projection score 0.03 vs 0.63, p=0.007).

HMGCR-antigen-reactive CD4⁺T-cells are present in the circulation and target tissue of patients with anti-HMGCR+IMNM, suggesting an active role for these cells in the pathogenesis of anti-HMGCR+IMNM.

21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting.

The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits.

Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide.

Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA.

Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4⁺ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as ‘expected’ whereas the ‘non-expected’ group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group’s 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend.

Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.

The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety.

The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index.

The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX.

NCT03505008.

1946 GCA patients with clinicodemographic data at GCA presentation were included. Associations between pre-existing CV-related traits (including Polygenic Risk Scores (PRS) for CV traits) and cranial ischaemic complications were tested. A model for cranial ischaemic complications was optimised using an elastic net approach. Positional gene mapping of associated PRS was performed to improve biological understanding.

In a sample of 1946 GCA patients (median age=71, 68.7% female), 17% had cranial ischaemic complications at presentation. In univariable analyses, 10 variables were associated with complications (likelihood-ratio test p≤0.05). In multivariable analysis, the two variables with the strongest effects, with or without PRS in the model, were anticoagulant therapy (adjusted OR (95% CI)=0.21 (0.05 to 0.62), p=4.95x10^–3) and age (adjusted OR (95% CI)=1.60 (0.73 to 3.66), p=2.52x10^–3, for ≥80 years versus <60 years). In sensitivity analyses omitting anticoagulant therapy from multivariable analysis, age and hypertension were associated with cranial ischaemic complications at presentation (hypertension: adjusted OR (95% CI)=1.35 (1.03 to 1.75), p=0.03). Positional gene mapping of an associated transient ischaemic attack PRS identified TEK, CD96 and MROH9 loci.

Age and hypertension were risk factors for cranial ischaemic complications at GCA presentation, but in this dataset, anticoagulation appeared protective. Positional gene mapping suggested a role for immune and coagulation-related pathways in the pathogenesis of complications. Further studies are needed before implementation in clinical practice.

We assessed different definitions of early OA using data from Multicenter Osteoarthritis (MOST) Study participants who were followed up longitudinally. We defined early OA as having at least minimal knee pain (WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain ≥3/20) with different levels of pre-radiographic OA. For MRI, we required knee pain and used MRI definitions with combinations of cartilage damage, osteophytes, bone marrow lesions and meniscus damage.

The primary outcome, worsening OA at 2 or 5 years, combined structural (Kellgren and Lawrence grade ≥2 with joint space narrowing ≥1) and symptom (WOMAC pain ≥6 with increase ≥2 from baseline) outcomes. We also examined structural and symptom outcomes separately.

For worsening OA at 2 years, we included 750 participants (mean age 65 years, 60% female, 90% white, mean body mass index 29.2 kg/m²). Fewer than 10% of early OA knees had the combined outcome at 2 or 5 years. At 2 years, for several early OA definitions, roughly 20% of knees had either structural or symptom worsening outcomes. Two-year trials of either, but not both, outcomes would need to recruit over 1200 patients.

Most knees with early OA are stable and do not progress. Some painful knees experience worse pain but not structural progression and vice versa. Trial testing treatments to prevent OA illness or disease will be challenging.

Baseline SIJ MRI scans were collected from two prospective randomised controlled trials in patients with non-radiographic (nr-) and radiographic (r-) axSpA (RAPID-axSpA: NCT01087762 and C-OPTIMISE: NCT02505542) and were centrally evaluated by two expert readers (and adjudicator in case of disagreement) for the presence of inflammation by the 2009 Assessment of SpondyloArthritis International Society (ASAS) definition. Scans were processed by the deep-learning algorithm, blinded to clinical information and central expert readings.

Pooling the patients from RAPID-axSpA (n=152) and C-OPTIMISE (n=579) yielded a validation set of 731 patients (mean age: 34.2 years, SD: 8.6; 505/731 (69.1%) male), of which 326/731 (44.6%) had nr-axSpA and 436/731 (59.6%) had inflammation on MRI per central readings. Scans were obtained from over 30 scanners from 5 manufacturers across over 100 clinical sites. Comparing the trained algorithm with the human central readings yielded a sensitivity of 70% (95% CI 66% to 73%), specificity of 81% (95% CI 78% to 84%), positive predictive value of 84% (95% CI 82% to 87%), negative predictive value of 64% (95% CI 61% to 68%), Cohen’s kappa of 0.49 (95% CI 0.43 to 0.55) and absolute agreement of 74% (95% CI 72% to 77%).

The algorithm enabled acceptable detection of inflammation according to the 2009 ASAS MRI definition in a large external validation cohort.

SGECs from SjD patients and controls were analysed for m⁶A writers METTL3 and METTL14 expression using RNA-seq, quantitative PCR and immunohistochemistry. Functional assays assessed the impact of METTL3 knockdown or pharmacological inhibition on proinflammatory gene expression and immune cell interactions (using transwell and coculture systems). Mechanistic studies examined METTL3-mediated m⁶A modifications in double-stranded RNA (dsRNA) formation through immunofluorescence. Unsupervised clustering identified patterns of interferon activation in salivary glands and their correlation with m⁶A writers.

METTL3 and METTL14 were elevated in SGEC from SjD patients in comparison to controls. Paradoxically, inhibiting METTL3 increased proinflammatory gene expression, enhancing SGEC’s ability to attract immune cells and activate B cells. Conversely, inhibiting the eraser FTO had the opposite effect. METTL3-mediated m⁶A modifications prevented dsRNA formation and IFN signalling activation. SGEC from SjD showed insufficient METTL3 upregulation compared with controls in response to inflammatory triggers, indicating a limited capacity to regulate the inflammatory response. SjD patients with elevated disease activity and higher interferon signature exhibit reduced METTL3 expression.

Impairment of m⁶A modifications in SGEC in response to inflammatory triggers favour the formation of dsRNA, potentially amplifying the interferon loop and contributing to SjD pathogenesis.

Association of NCF1-H90 with SSc was performed in case–control cohorts, bleomycin (BLM)-treated Ncf1-R90 C57BL/6 wildtype and Ncf1-H90 knock-in (KI) littermates. Peripheral blood mononuclear cell (PBMC) subsets were analysed by cytometry by time-of-flight.

The NCF1-H90 allele is associated with risk for diffuse cutaneous SSc (dcSSc) in Chinese and European Americans, and lung fibrosis in Chinese patients with SSc (OR=2.09, p=7.96E–10). Low copy number of NCF1 associated with lung fibrosis in European Americans (OR=4.33, p=2.60E–2). BLM-treated KI mice demonstrated increased pulmonary fibrosis, exhibiting activated type I interferon signature, elevated Spp1, Ccl2, Arg1, Timp1 and Il6 expression, enriched macrophage scores in lung tissues. In a longitudinal observation cohort, homozygous H90 patients with SSc at baseline had increased anti-nuclear antibody titres, anti-topoisomerase antibody seropositivity and anti-centromere antibody seronegativity, increased incidence of lung fibrosis and Gender-Age-lung Physiology index, elevated modified Rodnan Skin Score (mRSS) and elevated plasma osteopontin (OPN, SPP1), CCL2, ARG1, TIMP-1 and IL-6. These H90 patients with SSc sustained elevated mRSS during follow-up years with decreased survival. The 0, 1 and 2 copies of H90 carriage in SSc PBMCs exhibited dose-dependent increases in profibrotic CD14⁺CD68⁺CD11b⁺Tim3⁺monocytes. Elevated OPN, CCL2 and ARG1 in CD68⁺CD11b⁺monocyte-derived macrophages from H90 patients were decreased after co-culturing with anti-CCL2 antibody.

Low NCF1 activity increases the risk for the development of dcSSc and lung fibrosis via expanding profibrotic SPP1⁺MoMs in a CCL2-dependent manner, contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc.

This cross-sectional study analysed responses to 30 LBP-related questions, covering self-management, risk factors and treatment. The questions were developed by experienced clinicians and researchers and were piloted with a group of consumer representatives with lived experience of LBP. The inquiries were inputted in prompt form into ChatGPT 3.5, Bing, Bard (Gemini) and ChatGPT 4.0. Responses were evaluated in relation to their accuracy, readability and presence of disclaimers about health advice. The accuracy was assessed by comparing the recommendations generated with the main guidelines for LBP. The responses were analysed by two independent reviewers and classified as accurate, inaccurate or unclear. Readability was measured with the Flesch Reading Ease Score (FRES).

Out of 120 responses yielding 1069 recommendations, 55.8% were accurate, 42.1% inaccurate and 1.9% unclear. Treatment and self-management domains showed the highest accuracy while risk factors had the most inaccuracies. Overall, LLM-chatbots provided answers that were ‘reasonably difficult’ to read, with a mean (SD) FRES score of 50.94 (3.06). Disclaimer about health advice was present around 70%–100% of the responses produced.

The use of LLM-chatbots as tools for patient education and counselling in LBP shows promising but variable results. These chatbots generally provide moderately accurate recommendations. However, the accuracy may vary depending on the topic of each question. The reliability level of the answers was inadequate, potentially affecting the patient’s ability to comprehend the information.

We analysed metagenomic datasets from patient cohorts with six autoimmune conditions—SLE, IBD, multiple sclerosis, myasthenia gravis, Graves’ disease and ankylosing spondylitis—contrasting these with CRC metagenomes to delineate disease-specific microbial profiles. The study focused on identifying predictive biomarkers from species profiles and functional genes, integrating protein-protein interaction analyses to explore effector-like proteins and their targets in key signalling pathways.

Distinct microbial signatures were identified across autoimmune disorders, with notable overlaps between SLE and IBD, suggesting shared microbial underpinnings. Significant predictive biomarkers highlighted the diverse microbial influences across these conditions. Protein-protein interaction analyses revealed interactions targeting glucocorticoid signalling, antigen presentation and interleukin-12 signalling pathways, offering insights into possible common disease mechanisms. Experimental validation confirmed interactions between the host protein glucocorticoid receptor (NR3C1) and specific gut bacteria-derived proteins, which may have therapeutic implications for inflammatory disorders like SLE and IBD.

Our findings underscore the gut microbiome’s critical role in autoimmune diseases, offering insights into shared and distinct microbial signatures. The study highlights the potential importance of microbial biomarkers in understanding disease mechanisms and guiding treatment strategies, paving the way for novel therapeutic approaches based on microbial profiles.

NCT02394964.

Cost-effectiveness was assessed using the TREAT EARLIER trial. 236 patients with CSA with subclinical joint inflammation were randomised to 1-year treatment with methotrexate, or placebo, and followed for 2 years. Cost-effectiveness was analysed by computing costs and effects. For costs, both a societal perspective (healthcare-productivity and work-productivity costs) and a healthcare perspective (healthcare costs only) were used. For effects, quality adjusted life years (QALYs) were used.

Treatment increased QALYs by 0.041 (95% CI –0.050 to 0.091), and reduced costs with –4809 (95% CI –12 382 to 2726) over the course of 2 years using a societal perspective, with a probability of 88.1% that treatment was cost-effective. From a healthcare perspective, the cost-difference between treatment and placebo was estimated at –418 (95% CI –1198 to 225).

A fixed treatment course in individuals with arthralgia at-risk for RA and MRI-detected subclinical joint inflammation resulted in better work productivity, lower healthcare costs and improved quality of life over the course of 2 years; with the largest gain in productivity costs. This is the first evidence that methotrexate treatment aiming at secondary prevention in arthralgia at-risk for RA is cost-effective.

Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages.

Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19⁺ and CD20⁺ B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells.

This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.

We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-β was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-β-induced pathogenic molecules was investigated in vitro.

Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-β upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-β-induced pathogenic molecules in both myoblasts and myotubes.

We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-β-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.

We developed a cell-specific and cytotoxic systematic evolution of ligands by exponential enrichment (CSCT-SELEX) method to screen the therapeutic aptamers without prior knowledge of the surface signatures of RA-FLSs. The molecular targets and mechanisms of action of the screened aptamers were determined by pull-down assays and RNA sequencing. The therapeutic efficacy of the screened aptamers was examined in arthritic mouse models.

We obtained an aptamer SAPT8 that selectively recognised and killed RA-FLSs. The molecular target of SAPT8 was nucleolin (NCL), a shuttling protein overexpressed on the surface and involved in the tumor-like transformation of RA-FLSs. Mechanistically, SAPT8 interacted with the surface NCL and was internalised to achieve lysosomal degradation of NCL, leading to the upregulation of proapoptotic p53 and downregulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) in RA-FLSs. When administrated systemically to arthritic mice, SAPT8 accumulated in the inflamed FLSs of joints. SAPT8 monotherapy or its combination with tumour necrosis factor (TNF)-targeted biologics was shown to relieve arthritis in mouse models.

CSCT-SELEX could be a promising strategy for developing cell-targeting and cytotoxic aptamers. SAPT8 aptamer selectively ablates RA-FLSs via modulating NCL-p53/Bcl-2 signalling, representing a potential alternative or complementary therapy for RA.

We developed autoML models integrating clinical, biochemical, X-ray and MRI data. Using two data sets within the OA Initiative—the Foundation for the National Institutes of Health OA Biomarker Consortium for training and hold-out validation, and the Pivotal Osteoarthritis Initiative MRI Analyses study for external validation—we employed two distinct definitions of clinical outcomes: Multiclass (categorising OA progression into pain and/or radiographic) and binary. Key predictors of progression were identified through advanced interpretability techniques, and subgroup analyses were conducted by age, sex and ethnicity with a focus on early-stage disease.

Although the most reliable models incorporated all available features, simpler models including only clinical variables achieved robust external validation performance, with area under the precision-recall curve (AUC-PRC) 0.727 (95% CI: 0.726 to 0.728) for multiclass predictions; and AUC-PRC 0.764 (95% CI: 0.762 to 0.766) for binary predictions. Multiclass models performed best in patients with early-stage OA (AUC-PRC 0.724–0.806) whereas binary models were more reliable in patients younger than 60 (AUC-PRC 0.617–0.693). Patient-reported outcomes and MRI features emerged as key predictors of progression, though subgroup differences were noted. Finally, we developed web-based applications to visualise our personalised predictions.

Our novel tool’s transparency and reliability in predicting rapid knee OA progression distinguish it from conventional ‘black-box’ methods and are more likely to facilitate its acceptance by clinicians and patients, enabling effective implementation in clinical practice.

Individual participant data were analysed from three studies of people with gout. The time periods for the analysis were selected to identify study participants with serial DECT scans of both feet over a 12-month epoch of stable urate-lowering therapy and serum urate concentrations. Data from 251 study participants were analysed using a mixed models analysis of covariance approach according to mean serum urate cut-points and mean serum urate bands.

For all mean serum urate cut-points assessed (0.24, 0.30, 0.36, 0.42 and 0.48 mmol/L), reductions in DECT urate volumes were observed below the cut-point. Increased DECT urate volumes were observed at or above the 0.48 mmol/L mean serum urate cut-point. Differences in the change in DECT volume were observed for the 0.42 mmol/L cut-point (p=0.0044) and the 0.48 mmol/L cut-point (p<0.0001). Significantly reduced DECT urate volumes were observed for the mean serum urate bands<0.24 mmol/L and 0.24–0.29 mmol/L and increased DECT urate volume was observed for the mean serum urate band≥0.48 mmol/L.

Over 1 year, MSU crystal dissolution, as measured by DECT, occurs with mean serum urate bands of<0.24 mmol/L and 0.24–0.29 mmol/L while MSU crystal formation occurs with mean serum urate≥0.48 mmol/L.

We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR<60 mL/min/1.73 m²) and stage G3b (eGFR<45 mL/min/1.73 m²). Results were adjusted for relevant time-fixed and time-varying covariates.

31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m²) contributed 234 973 visits and 146 778 person-years of follow-up. Multivariable mixed-effect linear model showed an average annual eGFR decline during follow-up in the TA-CDAI-remission group of –0.83 mL/min/1.73 m² and estimated additional annual declines (95% CI) of –0.09 (–0.15 to –0.03) in low, –0.17 (–0.23 to –0.10) in moderate and –0.18 (–0.27 to –0.08) mL/min/1.73 m² in high disease activity patients. Compared with TA-CDAI remission, adjusted HRs (95% CI) for CKD stage G3a during follow-up were 1.15 (1.01 to 1.30) in low, 1.22 (1.06 to 1.40) in moderate and 1.27 (1.05 to 1.52) in high disease activity; for CKD stage G3b, 1.22 (0.84 to 1.76) in low, 1.66 (1.12 to 2.45) in moderate and 1.93 (1.16 to 3.20) in high disease activity.

Higher RA disease activity was associated with accelerated eGFR decline and increased risk of clinically relevant kidney dysfunction. Future intervention studies should attempt to replicate the association between RA disease activity and eGFR.