The Lancet Rheumatology

BackgroundJuvenile idiopathic arthritis (JIA) shows recognised sex differences, but their impact on treatment and early outcomes remains uncertain. This study assesses sex-specific patterns in onset, phenotype, treatment timing, and short- and medium-term outcomes in JIA. MethodsData were drawn from the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort of 1,789 children presenting with a new episode of arthritis. Demographics, subtype distribution, clinical features, and 6- and 12-month outcomes were stratified by sex. Cox, Kaplan-Meier, and linear regression models assessed associations between sex and treatment initiation and 12-month outcomes. ResultsThe cohort was predominantly female (64.3%), with a median age at symptom onset of 6.8 years. Girls were younger than boys at onset (6.1 vs 7.8 years, p<0.0001) and diagnosis (7.0 vs 9.1 years, p<0.0001) and demonstrated a distinct bimodal age distribution. Diagnostic delay was short and comparable (median 4.4 months, p=0.8932). At diagnosis, girls had slightly higher active joint counts (p=0.0080, while inflammatory markers were similar except in psoriatic JIA, where females had higher ESR and CRP. After adjustment, sex was not associated with time to methotrexate (HR 0.89, 95% CI 0.74-1.06) or biologic initiation (HR 0.91, 95% CI 0.72-1.16). Outcomes at 6- and 12-month were largely comparable, with only ESR showing a modest male-favoured improvement at 12 months (p=0.0480). ConclusionsSex shaped age at onset and subtype distribution but did not independently influence treatment timing or early outcomes, underscoring the value of sex-aware analyses while confirming broadly comparable short-term trajectories in JIA. Evidence before this studyRecent evidence on sex effects in JIA is genuinely mixed: several cohorts have reported that girls, despite more severe onset, show greater resolution of objective inflammation, while a newer, large network analysis found females had poorer outcomes across composite disease activity and pain, pointing to potential inequities or phenotype-driven differences. In parallel, boys, especially in enthesitis-related arthritis (ERA), often exhibit more persistent activity and risk of damage. Overall, the picture is controversial: sex appears to shape biology, trajectory, and patient-reported burden in different ways across subtypes and settings, reinforcing the need for sex-stratified analyses, careful adjustment for confounders, and precision approaches that integrate biomarkers, subtype, and social context in JIA care. Added value of this studyThe study establishes that, although sex is closely linked to JIA subtype distribution and baseline clinical features, it does not independently determine the timing of methotrexate or biologic initiation within a UK inception cohort. By analysing one of Europes largest prospective multicentre datasets, it provides strong evidence that treatment decisions appear to be guided by disease characteristics rather than demographic bias. Within the context of the UK National Health Service (NHS), where universal access to paediatric rheumatology care is a core principle, this study provides important epidemiological evidence on sex and equity in JIA. Although clear sex differences were observed in age at onset, subtype distribution, and certain diagnostic features, these did not translate into disparities in treatment timing or medium-term disease burden. The absence of sex-based differences in 6 and 12-month outcomes, despite variation in baseline presentation, suggests that the NHS model of coordinated, guideline-driven care may help buffer against inequities that might otherwise emerge in systems with variable access. These findings reinforce the value of population-based cohorts in evaluating equity within healthcare delivery and highlight that, in this setting, sex does not appear to drive differential treatment or short-term clinical trajectories. Implications of all the available evidence.This study underscores sex as an important biological variable in JIA. Although treatment initiation was equitable and disease-driven, baseline phenotype differences and isolated effects on 12-month outcomes highlight how sex interacts with JIA subtype and initial disease burden. Prior work shows that females often present earlier with higher inflammatory burden, while males are more frequently affected by ERA, a subtype linked to treatment resistance and poorer long-term outcomes. Yet published findings remain inconsistent, with some cohorts reporting better resolution of inflammation in females and others suggesting poorer outcomes. Our findings suggest that coordinated and guideline-driven care may minimise sex-related disparities in JIA, even when underlying biological or phenotypic differences exist. The comparable medium-term trajectories observed across sexes support equitable paediatric rheumatology care in the UK and highlight the need to continue monitoring for structural or access-related inequities beyond clinical measures.

ObjectivesTo investigate COVID-19 breakthrough infection after third mRNA vaccine dose among patients with RA by immunomodulator drug class, and we hypothesized that CD20 inhibitors (CD20i) would have higher risk for breakthrough COVID-19 vs. TNF inhibitors (TNFi). MethodsWe performed a retrospective cohort study investigating breakthrough COVID-19 among RA patients at Mass General Brigham in Boston, MA, USA. Patients were followed from the date of 3rd vaccine dose until breakthrough COVID-19, death, or end of follow-up (18/Jan/2023). Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate breakthrough COVID-19 risk by immunomodulator drug class. We used propensity score (PS) overlap-weighting to compare users of CD20i vs. TNFi. ResultsWe analyzed 5781 patients with RA that received 3 mRNA vaccine doses (78.8% female, mean age 64.2 years). During mean follow-up of 12.8 months, 1173 (20.2%) had breakthrough COVID_19. Use of CD20i (adjusted HR 1.74, 95%CI 1.30-2.33) and glucocorticoid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) were each associated with breakthrough COVID-19 compared to TNFi use. In the PS overlap-weighted analysis, CD20i users also had higher breakthrough COVID-19 risk than TNFi users (HR 1.62, 95%CI 1.02-2.56). A sensitivity analysis excluding patients with cancer or interstitial lung disease yielded similar findings. ConclusionsWe identified CD20i and glucocorticoid monotherapy as risk factors for breakthrough COVID-19 among patients with RA after a 3rd vaccine dose. This contemporary study highlights the real-world impact of blunted immune responses in these subgroups and the need for effective risk mitigation strategies. What is already known about this topicO_LIPatients with RA are at increased risk for COVID-19 breakthrough infection after two vaccine doses so a third dose is recommended to complete the initial series. C_LIO_LISome immunomodulator medications, particularly CD20 inhibitors, can impact vaccine immunogenicity and waning. C_LI What this study addsO_LICD20 inhibitor use was associated with increased risk of COVID-19 breakthrough infection in people with RA who received 3 vaccine doses compared to TNF inhibitor use. C_LIO_LIGlucocorticoid monotherapy was also associated with increased risk of COVID-19 breakthrough infection. C_LI How this study might affect research, practice or policyO_LIPatients with RA who are using CD20 inhibitors or glucocorticoid monotherapy should be prioritized for risk mitigation strategies after the initial vaccine series of 3 mRNA doses. C_LIO_LIThe impact of additional vaccine doses, timing of medication dosing, and other protective measures will need further study. C_LI

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that causes debilitating swelling and destruction of the joints. People with RA are treated with drugs that actively suppress one or more parts of their immune system, and these may alter their response to vaccination against SARS-CoV-2. In this study, we analyzed blood samples from a cohort of RA subjects after receiving a 2-dose mRNA COVID-19 vaccine regimen. Our data show that individuals on the CTLA4-Ig therapy abatacept have reduced levels of SARS-CoV-2-neutralizing antibodies after vaccination. At a cellular level, these subjects show reduced activation and class-switching of SARS-CoV-2-specific B cells, as well as reduced numbers and impaired helper cytokine production by SARS-CoV-2-specific CD4+ T cells. Individuals on methotrexate showed similar but less severe defects in vaccine response, whereas individuals on the B cell-depleting therapy rituximab had a near-total loss of antibody production after vaccination. These data define a specific cellular phenotype associated with impaired response to SARS-CoV-2 vaccination in RA subjects on different immune-modifying therapies, and help inform efforts to improve vaccination strategies in this vulnerable population.

BackgroundRheumatoid Arthritis (RA) is a chronic rheumatological condition which causes inflammation of both the joint lining and extra-articular sites. It affects around 1% of the UK population and, if not properly treated, can lead joint damage, disability, and significant socioeconomic burden. The risk of long-term damage is reduced if treatment is started in an early disease stage with treatment in the first 3 months being associated with significantly improved clinical outcomes. However, treatment is often delayed due to long referral waits and challenges in identifying early RA in primary care. We plan to use large primary care datasets to develop and validate an RA risk prediction model for use in primary care, with the aim to provide an additional mechanism for early diagnosis and referral for treatment. MethodsWe identified candidate predictors from literature review, expert clinical opinion, and patient research partner input. Using coded primary care data held in Clinical Practice Research Datalink (CPRD) Aurum, we will use a time to event Cox proportional hazards model to develop a 1-year risk prediction model for RA. This will be validated first in CPRD GOLD and then independently in the Secure Anonymised Information Linkage dataset. We will also conduct a sensitivity analysis for the same model at 2-5-year risk, with a secondary outcome of RA and initiation of a disease modifying drug, and with the addition of laboratory test results as candidate predictors. DiscussionThe resulting risk prediction model may provide an additional mechanism to distinguish early RA in primary care and reduce treatment delays through earlier referral.

ObjectiveVaccination decreases the risk of severe COVID-19 but its impact on post-acute sequelae of COVID-19 (PASC) is unclear among patients with systemic autoimmune rheumatic diseases (SARDs) who may have blunted vaccine immunogenicity and be vulnerable to PASC. MethodsWe prospectively enrolled SARD patients from a large healthcare system who survived acute infection to complete surveys. The symptom-free duration and the odds of PASC (any symptom lasting [&ge;] 28 or 90 days) were evaluated using restricted mean survival time and multivariable logistic regression, respectively, among those with and without breakthrough infection ([&ge;] 14 days after initial vaccine series). ResultsAmong 280 patients, the mean age was 53 years, 80% were female, and 82% were white. The most common SARDs were inflammatory arthritis (59%) and connective tissue disease (24%). Those with breakthrough infection had more upper respiratory symptoms, and those with non-breakthrough infection had more anosmia, dysgeusia, and joint pain. Compared to those with non-breakthrough COVID-19 infection (n=164), those with breakthrough infection (n=116) had significantly more symptom-free days over the follow-up period (+28.9 days, 95% CI: 8.83, 48.89; p=0.005) and lower odds of PASC at 28 and 90 days (aOR 0.49, 95% CI: 0.29, 0.83 and aOR 0.10, 95% CI: 0.04, 0.22, respectively). ConclusionVaccinated patients with SARDs were less likely to experience PASC compared to those not fully vaccinated. These findings support the benefits of vaccination for patients with SARDs and suggest that the immune response to acute infection is important in the pathogenesis of PASC in SARD patients. Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIPost-acute sequelae of COVID-19 (PASC) affects 20-50% of COVID-19 survivors, though the impact of vaccination on the risk and severity of PASC is unclear, especially among those with systemic autoimmune rheumatic diseases (SARDs) who may have impaired responses to vaccines and be particularly vulnerable to PASC. C_LI What this study adds?O_LIIn this prospective cohort of SARD patients recovering from COVID-19, we found that those with breakthrough vs non-breakthrough infection had more symptom-free days over the follow-up period (adjusted difference +28.9 days, 95% CI: 8.38, 48.89; p=0.005) and a lower odds of PASC at 28 days (aOR 0.49, 95% CI: 0.29, 0.83) and at 90 days (aOR 0.10, 95% CI: 0.04, 0.22). C_LIO_LIPatient-reported pain and fatigue scores were lower, reflecting less severe pain and fatigue, in those with breakthrough infection compared to those with non-breakthrough infection. C_LI How this study might affect research, practice, or policy?O_LIThis study extends our understanding of the benefits of vaccination against COVID-19 in patients living with SARDs and reinforces the importance of vaccinating this vulnerable population. C_LIO_LIOur findings suggest that the initial immune response to acute SARS-CoV-2, as influenced by vaccination, affects PASC risk but this requires further study. C_LI

ObjectivesWe aimed to estimate how rheumatology healthcare use has changed since the COVID-19 pandemic and determine demographic characteristics associated with observed changes in healthcare use. MethodsUsing three primary and secondary care electronic health record datasets in England (with the approval of NHS England), Scotland, and Wales, we identified individuals with a diagnosis of rheumatoid arthritis (RA) before 01/04/2019. We determined the proportion of people with rheumatology hospital outpatient appointments each month (April 2019-December 2022 (Wales and Scotland), April 2019-November 2023 (England)) and quantified changes using interrupted time-series analysis. We used logistic regression to determine characteristics associated with having fewer appointments compared to 2019. ResultsWe identified 145,065, 3,813 and 13,637 individuals coded with RA in England, Scotland, and Wales, respectively. At the start of the COVID-19 pandemic the number of rheumatology outpatient appointments dropped sharply across all nations. In England and Scotland, the percentage of monthly appointments has continued to decline. In Wales, while there was a gradual recovery, rheumatology services have not returned to pre-pandemic levels. In contrast, the number of appointments for all other specialist outpatient appointments have recovered in all nations. Ethnic minorities, those living in more deprived areas and urban areas had fewer appointments after the start of the pandemic compared to 2019. ConclusionFor the first time, we compared healthcare use across three UK nations and found that rheumatology outpatient appointments had not recovered to pre-COVID-19 pandemic levels, particularly in Scotland and England. Certain patient groups had fewer appointments during the study period. Key messagesO_LIRheumatology outpatient appointments remain below pre-pandemic levels, particularly in England and Scotland, unlike other specialties. C_LIO_LIEthnic minorities, deprived communities, and urban residents had fewer rheumatology appointments post-pandemic than in 2019. Rheumatology services need data-driven strategies to provide better support, tailored to local community needs. C_LI

ObjectivesIdentifying causal biomarkers of rheumatoid arthritis (RA) to improve treatment and monitor disease progression remains a critical but elusive goal. To search for putatively causal protein biomarkers of RA, we designed an integrative genomic strategy utilizing Mendelian randomization (MR), which allows for causal inference between an exposure and an outcome by incorporating genetic variants associated with an exposure (circulating protein level) and inferring its effect on the outcome (rheumatoid arthritis). MethodsWe utilized genetic variants associated with 71 cardiovascular disease-related proteins measured in nearly 7000 Framingham Heart Study participants in conjunction with variants associated with RA in a genome-wide association study (GWAS) from the UK Medical Research Council Integrative Epidemiology Unit (19,234 cases, 61,565 controls) to identify putatively causal proteins for RA. In addition, we applied MR to study circulating rheumatoid factor (RF) levels using GWAS of RF from the UK Biobank (n=30,565) as the outcome. ResultsWe identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1 standard deviation increment in inverse-rank normalized sRAGE level=0.482; 95% confidence interval 0.374-0.622; p=1.85x10-08) and RF levels ({beta} [change in RF level per sRAGE increment]=-1.280; SE=0.434; p=0.003). ConclusionsBy integrating GWAS of 71 cardiovascular disease-related proteins, RA, and RF, we identified sRAGE as a putatively causal protein protective for both RA ad RF levels. These results highlight the AGER/RAGE axis as a promising new target for RA treatment.

The efficacy of nucleic acid-based vaccines against SARS-CoV-2 varies across individuals, partly due to genetic factors influencing neutralizing antibody production. In patients with systemic autoimmune diseases (SADs), this response may be further altered by immune dysregulation. We conducted a genome-wide association study (GWAS) to identify genetic variants associated with post-vaccination anti-SARS-CoV-2 IgG antibody levels and to assess whether these associations differ between SAD patients and healthy individuals. The study included 165 participants (138 with SADs, 27 healthy controls), all of whom received nucleic-acid based vaccines. Antibody levels targeting the spike protein receptor-binding domain (RBD) and nucleocapsid were measured between one and twelve months after vaccination. GWAS results were meta-analyzed with data from a previously published GWAS of 1,076 healthy individuals. We identified a novel association near RACGAP1 (rs706785; {beta}meta=-0.30, Pmeta=3.85x10-{square}) and replicated a known association at HLA-DRB1 position 71 ({beta}meta=-0.23, Pmeta=1.94x10-11). No significant interactions were observed between genotype and disease status. This study highlights both MHC and non-MHC genetic contributions to SARS-CoV-2 vaccine responses and suggests these effects are consistent across SAD patients and healthy individuals, supporting standard vaccination strategies for individuals with systemic autoimmune conditions.

ObjectiveRheumatic disease patients on certain immunomodulators are at increased risk of impaired humoral response to SARS-CoV-2 vaccines. We aimed to identify factors associated with breakthrough infection among patients with rheumatic diseases. MethodsWe identified patients with rheumatic diseases being treated with immunomodulators in a large healthcare system who received at least two doses of either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccines or one dose of the Johnson & Johnson-Janssen (J&J) vaccine. We followed patients until SARS-CoV-2 infection, death, or December 15, 2021, when the Omicron variant became dominant in our region. We estimated the association of baseline characteristics with the risk of breakthrough infection using multivariable Cox regression. ResultsWe analyzed 11,468 patients (75% female, mean age 60 years). Compared to antimalarial monotherapy, multiple immunomodulators were associated with higher risk of infection: anti-CD20 monoclonal antibodies (aHR 5.20, 95% CI: 2.85, 9.48), CTLA-4 Ig (aHR 3.52, 95% CI: 1.90, 6.51), mycophenolate (aHR 2.31, 95% CI: 1.25, 4.27), IL-6 inhibitors (aHR 2.15, 95% CI: 1.09, 4.24), JAK inhibitors (aHR 2.02, 95% CI: 1.01, 4.06), and TNF inhibitors (aHR 1.70, 95% CI: 1.09, 2.66). mRNA-1273 recipients had a lower risk of breakthrough infection compared to BNT162b2 recipients (aHR 0.66, 95% CI: 0.50, 0.86). There was no association of sex, body mass index, smoking status, race, or ethnicity with risk of breakthrough infection. ConclusionAmong patients with rheumatic diseases, multiple immunomodulators were associated with increased risk of breakthrough infection. These results highlight the need for additional mitigation strategies in this vulnerable population.

Background.Autoimmune disease patients on immunosuppressants exhibit reduced humoral responses to primary COVID-19 vaccination. Booster vaccine responses and the effects of holding immunosuppression around vaccination are less studied. We evaluated the efficacy and safety of additional vaccination in mycophenolate mofetil/mycophenolic acid (MMF/MPA)-, methotrexate (MTX)-, and B cell-depleting therapy (BCDT)-treated autoimmune disease patients, including the impact of withholding MMF/MPA and MTX. Methods.In this open-label, multicenter, randomized trial, 22 MMF/MPA-, 26 MTX-, and 93 BCDT-treated autoimmune disease patients with negative or suboptimal antibody responses to initial COVID-19 vaccines (BNT162b2, mRNA-1273, or AD26.COV2.S) received a homologous booster. MMF/MPA and MTX participants were randomized (1:1) to continue or withhold treatment around vaccination. The primary outcome was the change in anti-Wuhan-Hu-1 receptor-binding domain (RBD) concentrations at 4 weeks post-additional vaccination. Secondary outcomes included adverse events, COVID-19 infections, and autoimmune disease activity through 48 weeks. Results.Additional vaccination increased anti-RBD concentrations in MMF/MPA and MTX patients, irrespective of whether immunosuppression was continued or withheld. BCDT-treated patients also demonstrated increased anti-RBD concentrations, albeit lower than MMF/MPA- and MTX-treated cohorts. COVID-19 infections occurred in 30-46% of participants, were predominantly mild, and included only two non-fatal hospitalizations. Additional vaccination was well-tolerated, with low frequencies of severe disease flares and adverse events. Conclusion.Additional COVID-19 vaccination is effective and safe in immunosuppressant-treated autoimmune disease patients, regardless of whether MMF/MPA or MTX is withheld. Trial Registration. ClinicalTrials.gov (NCT#05000216)

ObjectivesClonal hematopoiesis (CH), defined by acquired mutations in hematopoietic stem cells, has been linked to many inflammatory diseases of aging. We investigated whether CH subtypes such as clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alteration (mCA) are associated with the risk of incident rheumatoid arthritis (RA) and whether complement modifies these associations. MethodsCHIP was ascertained in NIH AllOfUs, Vanderbilt BioVU, and the UKBiobank; mCA was detected in UKBiobank. A consistent phenotyping algorithm was applied across biobanks to identify seropositive RA (SPRA) and seronegative RA (SNRA). Age-scale survival models assessed the effect of CH on risk of incident RA. Effect modification was tested with interaction models with genetically predicted complement protein levels. ResultsAmong 612,989 eligible participants, 30,840 had CHIP, 2,110 had incident SPRA, and 1,310 had incident SNRA. CHIP was associated with an increased risk of incident SPRA (HR 1.29; CI 1.05-1.57; p=1.3x10-2) driven primarily by DNMT3A-mutated CHIP (HR 1.42, CI 1.1-1.82, p=7.1x10-3) but no risk of SNRA. In UKBiobank, autosomal mCA and mosaic loss of Y (mLOY) were associated with an increased risk of incident SPRA (HR 2.12 and 2.85; CI 1.18-3.8 and 1.57-5.19; p=1.2x10-2 and 6.1x10-4), but no risk of SNRA. Higher genetically predicted levels of C1r and C1s attenuated the CHIP-SPRA association. ConclusionsDNMT3A-CHIP, autosomal mCA and mLOY are novel risk factors for incident SPRA but not SNRA, supporting a serostatus-specific link between somatic mutation in epigenetic regulators and RA, with the classical complement pathway as a potential modifier of this risk.

ObjectivePatients with immunological diseases exhibit distinct comorbidity patterns, categorized into low comorbidity, polyautoimmunity, and polyinflammation clusters. This retrospective cohort study aimed to validate these profiles in rheumatoid arthritis (RA), examine their longitudinal trajectories, and assess their impact on treatment persistence. MethodsRA patients receiving targeted therapies, and their associated treatments, were identified from the French pharmacy dispensing database LRx. Comorbidity clusters were assigned using a multinomial regression model, and state sequence analysis with hierarchical clustering was used to define temporal trajectories. Cox regression models evaluated DMARD persistence across trajectories. ResultsAmong 15,189 RA patients (maximum follow-up: 10 years), initial comorbidity profiles included low comorbidity (61.9%), polyautoimmunity (24.7%), and polyinflammation (13.4%). Four trajectory patterns emerged: stable low comorbidity (50%), dominant polyautoimmune (31%), stable polyinflammatory (9%), and low comorbidity switching to polyinflammation (polyinflammation switchers, 10%). The prevalence of polyautoimmunity and polyinflammation increased with age by 2.5% and 3.8% per decade, respectively. Patients with stable polyinflammation had the lowest classical synthetic DMARD persistence (HR: 1.79 [1.33-2.42], reference: polyinflammation switchers). Stable low comorbidity patients had the highest biological and targeted synthetic DMARD persistence (polyinflammation switchers aHR: 1.32 [1.09-1.60], reference: stable low comorbidity). ConclusionComorbidity trajectories in RA influence DMARD persistence, reflecting distinct etiopathological subgroups with potential theranostic relevance.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint destruction along with extra-articular morbidity and early mortality. Abatacept (CTLA-4 Ig), a blocker of lymphocyte co-stimulation, has become a well-accepted biologic treatment with proven efficacy in established-RA and for preventing disease onset in predisposed individuals. To investigate the immunologic implications of abatacept treatment, we conducted a prospective, open-label trial with multi-omic single-cell analyses of lymphocytes and BCR repertoire profiling at predefined intervals. Treatment-induced low-disease activity correlated with coordinated depletion of circulating peripheral helper cells (Tph), late-activated naive cells (late-aNAV), and of CD27-IgD- (Double negative, DN) Zeb2+CD11c+ T-box transcription factor 21 (Tbet+) DN2 unconventional memory B cells, implicated in the tertiary lymphoid structures responsible for the propagation of pathologic autoimmune responses and joint destruction. Among B-cell subsets, DN2 had the greatest representation of molecular machinery for antigen-uptake, processing, and presentation. Among memory B-cell subsets, DN2 had the lowest representation of somatically generated N-glycosylation sites and somatic hypermutation. Yet abatacept induced DN2 cells to express elevated CXCR4 levels, which normalized upon drug withdrawal, suggesting that abatacept treatment may cause these cells to traffic out of pathologic synovial infiltrates. In conclusion, we have documented that abatacept affects the circulating immune cellular drivers of disease activity, Tph, late-aNAV and DN2. Therapeutic depletion of these pathologic lymphocyte subsets is associated with clinical benefits that can persist after therapy cessation. Hence, levels of these subsets may serve as surrogates for the overall burden of disease and potential response to abatacept therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/26348386v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@b44131org.highwire.dtl.DTLVardef@241f4eorg.highwire.dtl.DTLVardef@18361f6org.highwire.dtl.DTLVardef@9470b7_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryMulti-omics analyses showed costimulatory blockade depletes trafficking DN2 B cells and Tph cells that correlates with rheumatoid disease response.

Autoimmune diseases (ADs) are a group of more than 80 heterogeneous disorders that occur when there is a failure in the self-tolerance mechanisms triggering self-attacking autoantibodies. Most autoimmune disorders are polygenic and associated with genes in the human leukocyte antigen (HLA) region. However, additional non-HLA genes are also found to be associated with different ADs, and often these are also implicated in more than one disorder. Previous studies have observed associations between various health-related and lifestyle phenotypes and ADs. Polygenic risk scores (PRS) allow the calculation of an individuals genetic liability to a phenotype and are estimated as the sum of the risk alleles weighted by their effect sizes in a genome-wide association study (GWAS). Here, for the first time, we conducted a comparative PRS-PheWAS analysis for 11 different ADs (Celiac Disease, Juvenile Idiopathic Arthritis, Multiple Sclerosis, Myasthenia Gravis, Primary Sclerosing Cholangitis, Psoriasis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Type 1 Diabetes, Vitiligo Early Onset, Vitiligo Late Onset) and 3,281 outcomes available in the UK Biobank that cover a wide range of lifestyle, socio-demographic and health-related phenotypes. We also explored the genetic relationships of the studied ADs, estimating their genetic correlation and performing cross-disorder GWAS meta-analyses for the identified AD clusters. In total, we observed 554 outcomes significantly associated with at least one disorder PRS, and 300 outcomes were significant after variants in the HLA region were excluded from the PRS calculations. Based on the genetic correlation and genetic factor analysis, we observed five genetic factors among studied ADs. Cross-disorder meta-analyses in each factor revealed genome-wide significant loci that are pleiotropic across multiple ADs. Overall, our analyses confirm the association of different factors with genetic risk for ADs and reveal novel observations that warrant further exploration.

ObjectiveGenome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with juvenile idiopathic arthritis (JIA), the majority of which are located in non-coding regions such as enhancers. This presents a challenge for pinpointing causal variants and their target genes. Interpreting these loci requires functional genomics data from disease-relevant tissues, which has been lacking for JIA. This study seeks to fill that gap and elucidate the biological mechanisms underlying JIA susceptibility. MethodsWe performed low-input whole genome promoter Capture Hi-C (PCHi-C) and ATAC-seq on CD4+ T cells from three JIA oligoarthritis patients. To link JIA-associated SNPs to potential causal genes, we integrated PCHi-C data with JIA GWAS summary statistics using our Bayesian prioritisation algorithm, Capture Hi-C Omnibus Gene Score (COGS). ATAC-seq was used to further annotate JIA GWAS loci in CD4+ T cells. We then employed CRISPR activation and interference (CRISPRa/i) in Jurkat cells to validate the prioritised SNPs and their corresponding genes. ResultsChromatin interactions between JIA-associated SNPs and gene promoters were identified in 19 of 44 non-MHC JIA loci, linking 61 known and novel target genes to the disease. Through COGS, we prioritised seven putative causal genes for JIA: RGS14, ERAP2, HIPK1, CCR4, CCRL2, CCR2, and CCR3. SNPs within promoter-interacting regions (PIRs) of these genes were further validated using CRISPRa/i to confirm their roles in regulating gene expression. ConclusionsThis study provides insights into the genetic architecture of JIA by integrating genomic and epigenomic data, identifying disease-related genes, functionally validating risk SNPs, and highlighting candidate drugs for repurposing. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSRecent genome-wide association studies in JIA have identified genetic loci associated with disease risk. However, the precise mechanisms by which these variants contribute to disease pathology remain unclear, as most do not directly alter protein-coding genes. It has been proposed that non-coding SNPs can affect genes that are important in disease through disruption of enhancer-mediated regulatory mechanisms that control their expression, with enhancers exerting their effects through chromatin interactions. Functional characterisation of risk loci is essential to delineate causal SNPs and target genes in JIA. What this study addsThis study is the first to utilise low-input Promoter Capture Hi-C to map long-range chromatin interactions in CD4+ T cells from JIA patients, alongside ATAC-seq to assess chromatin accessibility within the same samples. It identifies 61 potential target genes at JIA-associated loci and validates the regulatory roles of some of these through CRISPR activation and interference. This work enhances our understanding of how genetic variants modulate gene expression in immune cells, shedding light on key pathways involved in JIA pathogenesis. How this study might affect research, practice or policyHighlights new potential causal genes in JIA which can help understand the pathological mechanisms in JIA, and suggests the potential to repurpose CCR2/CCR5 inhibitors in JIA.

BackgroundThe success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. MethodsBlood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FindingsOf 1265 patients, high risk of HI (high HI5-NEWS2) (n=367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n= 455, 36.0%). An intermediate risk group (n= 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p=0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p=0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p=0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p =0.31). InterpretationThe HI5-NEWS2 measured at COVID-19 diagnosis, strongly predicts mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention. FundingNo external funding.

IntroductionThere is limited information on the effectiveness of COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). Methods136 consecutive patients with rheumatic diseases who never had a diagnosis of COVID-19 previously, and had completed vaccination with either the ChAdOx1 or BBV152 vaccines were recruited. Their IgG antibody titres to the Spike protein were estimated 1 month after the second dose. Results102 patients had AIRD while the 34 had non-AIRD. Lesser patients with AIRD (92/102) had positive antibodies titres than ones with non-AIRD(33/34) [p<0.001]. Amongst patients who received the ChAdOX1 vaccine, the AIRD group had lower antibody titres. Although the AIRD patients receiving BBV152 had similarly lower titres numerically, this did not attain statistical significance probably due to lesser numbers. Comparing the two vaccines, 114(95%) of those who received ChAdOx1 (n=120) and 11(68.7%) of those who received BBV152(n=16) had detectable antibodies [p=0.004]. Antibody titres also were higher in ChAdOx1 recipients when compared to BBV152. To validate the findings, we estimated antibody titres in 30 healthy people each who had received either vaccine. All 30 who had received ChAdOX1 and only 23/30 of those who had received BBV152 had positive antibodies (p=0.011). ConclusionIn this preliminary analysis, patients with AIRD had lower seroconversion rates as well as lower antibody titres as compared to patients with non-AIRD. Also,the humoral immunogenicity of the BBV152 vaccine appears to be less than that of the ChAdOX1 vaccine. Validation using larger numbers and testing of cellular immunity is urgently required.

ObjectiveTo assess the comparative efficacy and safety of approved biologic disease-modifying antirheumatic drugs (bDMARDs), biosimilars, and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) for patients with rheumatoid arthritis (RA) who had inadequate responses to methotrexate (MTX). Results53 eligible studies were identified and 44 studies were included in a network meta-analysis. Using Surface Under the Cumulative Ranking Curve (SUCRA), tofacitinib (10 mg bid) with MTX [Relative risk (RR) 95% confidence interval (CI) 4.65 (2.98-7.27)] and tofacitinib (10 mg bid) [RR (95%CI)1.96 (1.27-3.03)] were ranked highest among tsDMARDs for increasing remission rate at 24-26 weeks and 48-52 weeks, respectively. For bDMARDs, tocilizumab (8 mg/kg) with MTX was ranked with highest treatment effect for remission at both 24-26 and 48-52 weeks [RR (95%CI) 3.06 (2.27-4.12); RR (95%CI) 2.52 (1.94-3.28)]. For safety, baricitinib (4 mg) and tofacitinib (5 mg bid) with MTX likely showed an increased risk of HZ with statistical significance [for baricitinib, RR (95%CI) 3.52 (1.38-9.02) at 24-26 weeks, and RR (95%CI) 4.20 (1.22-14.48) at 48-52 weeks, and for tofacitinib, RR (95%CI) 5.38 (1.00-28.91) at 48-52 weeks]. No statistically significant safety concerns for serious infection, tuberculosis (TB), cancer, and cardiovascular (CV) events were identified. ConclusionsFor RA patients who failed MTX, bDMARDs, biosimilars, and tsDMARDs monotherapy and combination therapy with MTX provided better treatment outcomes than MTX monotherapy with modest safety concerns within 24-52 weeks. A scarcity of longer-term effects and post-market surveillance necessitates further analyses using long-term patient-level data to improve the medication profile. Rheumatology key messagesO_LIFor RA patients who failed MTX and other conventional DMARDs, different types of DMARDs are available. C_LIO_LIAt dose- and time point-specific levels, tofacitinib (10 mg bd) showed the highest probability to be the most effective in achieving remission at 24-26 weeks. C_LIO_LIAn increased risk of herpes zoster was found for baricitinib (4 mg) and tofacitinib (5 mg bid) with MTX. C_LI

BackgroundCOVID-19 outcomes, in the context of immune-mediated inflammatory diseases (IMIDs), are incompletely understood. Reported outcomes vary considerably depending on the patient population studied. It is essential to analyse data for a large population, while considering the effects of the pandemic time period, comorbidities, long term use of immunomodulatory medications (IMMs), and vaccination status. MethodsIn this retrospective case-control study, patients of all ages with IMIDs were identified from a large U.S. healthcare system. COVID-19 infections were identified based on SARS-CoV-2 NAAT test results. Controls without IMIDs were selected from the same database. Severe outcomes were hospitalisation, mechanical ventilation (MV), and death. We analysed data from 1 March 2020 to 30 August 2022, looking separately at both pre-Omicron and Omicron predominant periods. Factors including IMID diagnoses, comorbidities, long term use of IMMs, and vaccination and booster status were analysed using multivariable logistic regression (LR) and extreme gradient boosting (XGB). FindingsOut of 2 167 656 patients tested for SARS-CoV-2, there were 290 855 with confirmed COVID-19 infection: 15 397 patients with IMIDs and 275 458 controls (patients without IMIDs). Age and most chronic comorbidities were risk factors for worse outcomes, whereas vaccination and boosters were protective. Patients with IMIDs had higher rates of hospitalisation and mortality compared with controls. However, in multivariable analyses, few IMIDs were rarely risk factors for worse outcomes. Further, asthma, psoriasis and spondyloarthritis were associated with reduced risk. Most IMMs had no significant association, but less frequently used IMM drugs were limited by sample size. XGB outperformed LR, with the AUROCs for models across different time periods and outcomes ranging from 0{middle dot}77 to 0{middle dot}92. InterpretationFor patients with IMIDs, as for controls, age and comorbidities were risk factors for worse COVID-19 outcomes, whereas vaccinations were protective. Most IMIDs and immunomodulatory therapies were not associated with more severe outcomes. Interestingly, asthma, psoriasis and spondyloarthritis were associated with less severe COVID-19 outcomes than those expected for the population overall. These results can help inform clinical, policy and research decisions. FundingPfizer, Novartis, Janssen, NIH MeSHD001327, D000086382, D025241, D012306, D000071069

There is increasing evidence for an autoimmune aetiology in post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). SARS-CoV-2 has now become the main trigger for ME/CFS. We have already conducted two small proof-of-concept studies of IgG depletion by immunoadsorption (IA) in post-infectious ME/CFS, which showed efficacy in most patients. This observational study aims to evaluate the efficacy of IA in patients with post-COVID-19 ME/CFS. The primary objective is to assess the improvement in functional ability. Due to the urgency of finding therapies for post-Covid-Syndrome (PCS), we report here the interim results of the first ten patients with seven responders defined by an increase of between 10 and 35 points in the Short-Form 36 Physical Function (SF36-PF) at week four after IA. The results of this observational study will provide the basis for patient selection for a randomised controlled trial (RTC) including sham apheresis and for a RTC combining IA with B-cell depletion therapy.