Annals of the Rheumatic Diseases

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.

Immune checkpoint inhibitor-induced myotoxicity (ICI-M) comprises myocarditis, myositis, and myasthenia gravis-like syndrome, demanding rapid recognition and therapy. Using immunophenotyping and transcriptomics analysis from blood and muscle, we identified distinct CD38hi and KIR+ CD8 T cells in ICI-M. Abatacept rescued patients and altered the composition and clonality of these cells. Dynamics of CD38hi and KIR+ CD8 T cells effectively supported therapeutic monitoring, offering personalized treatment in life-threatening irAEs.

ObjectiveAxial Spondyloarthritis (AxSpA) is a common inflammatory arthritis with HLA-B*27 as the major genetic risk. Recent discoveries of AxSpA-specific T cell receptor (TCR) motifs and the self and bacterial peptides that they recognize support a pathogenic role of CD8+ T cells. Despite of previous work on synovial fluid, the characteristics of CD8 cells in joint tissue are currently unknown. MethodSynovial tissues from 5 AxSpA patients were used for single cell RNA sequencing (scRNA-seq). Paired TCR sequencing was carried out for 2. The abundance of KIR+CD8+ T cells in the blood from 9 AxSpA patients and 10 healthy controls was measured using flow cytometry. The expression of naive and memory T cell markers (CCR7, CD45RA and CD45RO) were compared between KIR+ and KIR- CD8 cells. ResultsWe observed conventional, TRAV1-2+ mucosal-associated invariant T (MAIT) cell and MKI67+ proliferating cell populations in synovium. Following sub-clustering of conventional CD8+ T cells, HLA-DR+ tissue resident memory (TRM), circulating, KIR+ and FCGR3A+ (encoding CD16) cell subsets were observed. HLA-DR+ TRM and KIR+ cells were clonally expanded and exhibited distinct transcriptional features, enriched for T cell activation pathways and natural killer (NK) cell-mediated cytotoxicity pathway respectively. Lastly, KIR+CD8+ T cells were increased in AxSpA blood and enriched for CD45RA+CCR7- TEMRA cells. ConclusionHere we present the very first transcriptomic profiling of CD8+ T cells in synovium tissue and highlight potential roles of HLA-DR+ TRM and KIR+ cells in AxSpA pathology. This study adds novel insights to the disease mechanisms and offers new therapeutic opportunities.

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

Although different chronic arthritic diseases are defined by clinical factors like gender, psoriasis and auto-antibodies, the biology of inflamed joints while comparing the different diseases remains neglected. Here, after curating an inflamed joint derived T-cell receptor (TCR) database, our new TRIASSIC tool identified 66303 significantly convergent TCR clonotypes. Clustering TCR clonotypes showed that synovial fluid convergence clusters (SFCCs) characterized HLA-B27+ mediated diseases (spondyloarthritis, SpA, and enthesitis-related juvenile idiopathic arthritis, JIA-ERA), Lyme arthritis and oligoarticular JIA. Single-cell transcriptomics and bulk proteomics showed upregulated interferon type I and II and TNF- pathways in oJIA. Adult and juvenile psoriatic arthritis, (JIA-)PsA, was characterized by upregulated HSP expression in monocytes and TXNIP in T-cells. We discovered an abundance of CCL5 expressing CD8+ T-cells in SF from HLA-B27+ JIA-ERA and SpA patients. JIA-ERA patients showed upregulation of CD74 and LGALS1 in Th1 and Th17 cells and IGHV7-4.1 in B-cells. oJIA patients shared a TRBV28 RG-motif on CXCL13 producing helper T-cells. Rheumatoid arthritis and (JIA-)PsA patients carried EBV-reactive cytotoxic CD8+ T-cells. Annexin signalling was shown to be important in the intercellular communication for all arthritis groups. Collectively, our work showed that chronic arthritis is characterized by both disease-specific and broadly shared mechanisms.

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

ObjectivesTo describe our experience with a coronavirus disease 2019 (COVID-19) outbreak within a large rheumatology department, early in the pandemic. MethodsSymptomatic and asymptomatic healthcare workers (HCWs) had a naso-oropharyngeal swab for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were followed clinically. Reverse transcription polymerase-chain reaction (RT-PCR) was repeated to document cure, and serological response was assessed. Patients with risk contacts within the department in the 14 days preceding the outbreak were screened for COVID-19 symptoms. Results14/34 HCWs (41%; 40{+/-}14 years, 71% female) tested positive for SARS-CoV-2, and 11/34 (32%) developed symptoms but were RT-PCR-negative. Half of RT-PCR-positive HCWs did not report fever, cough, or dyspnoea before testing, which were absent in 3/14 cases (21%). Mild disease prevailed (79%), but 3 HCWs had moderate disease requiring further assessment, which excluded severe complications. Nevertheless, symptom duration (28{+/-}18 days), viral shedding (31{+/-}10 days post-symptom onset, range 15-51) and work absence (29{+/-}28 days) were prolonged. 13/14 (93%) of RT-PCR-positive and none of the RT-PCR-negative HCWs had a positive humoral response, with higher IgG-index in individuals over 50 years (14.5{+/-}7.7 vs 5.0{+/-}4.4, p=0.012). Of 617 rheumatic patients, 8 (1.3%) developed COVID-19 symptoms (1/8 hospitalisation, 8/8 complete recovery), following a consultation/procedure with an asymptomatic (7/8) or mildly-symptomatic (1/8) HCW. ConclusionsA COVID-19 outbreak can occur among HCWs and rheumatic patients, swiftly spreading over the presymptomatic stage. Mild disease without typical symptoms should be recognised, and may evolve with delayed viral shedding, prolonged recovery, and adequate immune response in most individuals. O_LSTKey messagesC_LSTO_LIHigh infection rates have been reported in healthcare workers (HCWs) dealing with COVID-19 patients. Less is known about potential transmission by pre/asymptomatic carriers, which may be important in the context of rheumatology practice, among both HCWs and patients. C_LIO_LIA COVID-19 outbreak in a rheumatology department affected 41% of HCWs, with fast spreading throughout the presymptomatic stage. C_LIO_LIMild disease without typical symptoms was common, especially in early phases, evolving with delayed viral shedding (unto 51 days), prolonged recovery (average one month), and adequate immune response (93%) in most individuals. C_LIO_LITransmission by mostly asymptomatic HCWs occurred to a minority of patients with rheumatic and musculoskeletal diseases (RMDs), who had a globally favourable outcome. C_LIO_LIAsymptomatic and mild disease forms among HCWs should be recognised. Assertive infection control measures and testing strategies are warranted to prevent subclinical contagion between HCWs and patients with RMDs. C_LI

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.

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and have long been considered to contribute to pathogenesis. In this study, we sequenced the plasmablast antibody repertoires of RA patients and functionally characterized their encoded ACPAs. Recombinantly expressed monoclonal ACPAs bound citrullinated autoantigens, as well as autocitrullinated peptidylarginine deiminase 4 (PAD4). Using the collagen antibody induced arthritis (CAIA) mouse model, we demonstrated that the recombinant ACPAs significantly reduced paw thickness and arthritis severity as compared to isotype-matched control antibodies. Treatment with recombinant ACPAs also significantly reduced bone erosions, synovitis, and cartilage damage in histologic analysis of paws. This amelioration was observed for all the ACPAs tested and was independent of citrullinated antigen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model, implying that ACPAs anti-inflammatory effects were more preventative than therapeutic. This study highlights a potential protective role for ACPAs in RA.

ObjectivesMyositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins. MethodsConfocal immunofluorescence microscopy was used to localize antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to study the transcriptomic profiles of 668 samples from patients with myositis, disease controls, and healthy controls. Antibodies from myositis patients were introduced into cultured myoblasts by electroporation and the transcriptomic profiles of the treated myoblasts were studied by bulk RNA sequencing. ResultsIn patients with myositis autoantibodies, antibodies accumulated inside myofibers in the same subcellular compartment as the autoantigen. Each autoantibody was associated with effects consistent with dysfunction of its autoantigen, such as the derepression of genes normally repressed by Mi2/NuRD in patients with anti-Mi2 autoantibodies, the accumulation of RNAs degraded by the nuclear RNA exosome complex in patients with anti-PM/Scl autoantibodies targeting this complex, and the accumulation of lipids within myofibers of anti-HMGCR-positive patients. Internalization of patient immunoglobulin into cultured myoblasts recapitulated the transcriptomic phenotypes observed in human disease, including the derepression of Mi2/NuRD-regulated genes in anti-Mi2-positive dermatomyositis and the increased expression of genes normally degraded by the nuclear RNA exosome complex in anti-PM/Scl-positive myositis. ConclusionsIn myositis, autoantibodies are internalized into muscle fibers, disrupt the biological function of their autoantigen, and mediate the pathophysiology of the disease.

BackgroundPain is one of the most prevalent and distressing symptoms in juvenile idiopathic arthritis (JIA) and often persists despite treatment. Damage-associated molecular patterns (DAMPs), such as high mobility group box 1 (HMGB1) and S100A8/A9, have been implicated in inflammatory activation and nociceptive sensitization, but their associations with pain are not fully characterized in JIA. MethodsPlasma and paired synovial fluid (SF) samples were obtained from patients with oligoarticular and polyarticular JIA from the Juvenile Arthritis Biobank (JABBA). A discovery cohort (n = 79) was used to investigate associations between biomarkers and pain, and these associations were subsequently examined in a validation cohort (n = 38). Levels of HMGB1, S100A8/A9, IL-6, IL-8, C2C, and TRAP5b were measured using ELISA. Associations between biomarkers and patient-reported pain scores were assessed using multivariable linear regression analyses. ResultsPlasma and SF levels of most biomarkers did not show significant correlations, except for TRAP5b, which demonstrated a moderate correlation. In the discovery cohort, as multivariable linear regression analyses, both CRP and SF HMGB1 ({beta} = 1.14, 95% CI: 0.21-2.08; {beta} = 1.54, 95% CI: 0.06-3.01 respectively in fully adjusted model) were independently associated with higher pain scores. SF S100A8/A9 ({beta} = 1.00, 95% CI: 0.10-1.89) was additionally associated with pain in fully adjusted models. Sensitivity analyses confirmed the robustness of these findings. These associations were further supported in the validation cohort. ConclusionsPain in JIA is associated with both systemic CRP and local alarmin markers, with SF HMGB1 showing a particularly robust association. These findings highlight the importance of local joint HMGB1 in pain mechanisms and suggest a potential role for DAMP-mediated pathways in persistent pain in JIA.

ObjectiveTo investigate accumulating single nucleotide variants (SNVs) in synovium of patients with early, pre-treatment rheumatoid arthritis (RA). MethodsI leveraged RNA-seq dataset derived from patients with RA deposited in database. To capture synovium-specific mutations, I applied standardized SNVs-calling method to paired synovium and blood samples per individual. ResultsDe novo mutational signatures constructed by non-negative matrix factorization reflected continuous relationship of synovial histology, namely lymphoid-myeloid (Lymphoid), diffuse myeloid (Myeloid) and pauci-immune fibroid (Fibroid). Using COSMIC signature, defective DNA damage repair-associated mutational signature was associated with the level of inflammation in synovitis. Further, pathway analysis based on specific genes harboring SNVs in each histological group represent different types of synovitis, with differing pathogenic process and inflammatory environment. ConclusionThis data will promote our understandings about pathogenic status of synovitis, and suggests evidence that stratified treatments would be optimal according to histological subgroup.

About two thirds of rheumatoid arthritis (RA) patients develop anti-citrullinated protein antibodies (ACPA), which are a characteristic of the disease and sparsely observed in other clinical settings or in the healthy population. ACPA are used as a diagnostic criterion and often develop prior to diagnosis. Therefore, ACPA titers are important in the identification of individuals at risk of developing RA. Interestingly, the titers and target cross-reactivity of ACPA increase by time of diagnosis, suggesting a causality between anti-citrulline reactivity and the development of RA. However, only 50% of ACPA-positive at-risk individuals will progress to a clinical RA diagnosis. This observation suggests that there are different types of ACPA and that their relationship with RA development is more complex than presently assumed. To address the biological effect of ACPA in the establishment and development of inflammatory arthritis, we made use of the collagen antibody-induced arthritis (CAIA) model of passive arthritis. Using seven unique patient derived monoclonal ACPA, we observed that ACPA are predominantly anti-inflammatory, with some clones (C03 and BVCA1) completely inhibiting disease development. We have also identified a clone (C04) as having a disease-prone effect, by increasing and sustaining disease prevalence. This clone had previously been reported as being pro-inflammatory in a different model of joint inflammation. The anti-inflammatory effects of C03 were dependent on Fc{gamma}R, since neither F(ab)2 or a mutated Fc-null GRLR-C03 clone could mediate disease protection. Most importantly, mice receiving polyclonal ACPA enriched from RA sera were also partially protected from disease. Looking at the cell and tissue of origin of the ACPA clones, their V(D)J sequences, Fc glycosylation pattern and fine-specificities, we could not identify a common feature between anti-inflammatory ACPA distinguishing them from those without the properties. Together, our data demonstrates that circulating ACPA in RA patients are predominantly anti-inflammatory, emphasizing the need to study ACPA repertoires in order to determine their influence on the clinical outcome of the patient or at-risk individual.

The human gut microbiota is recognized as a modulator of inflammatory diseases and has been linked to interindividual differences in therapy responsiveness. However, the robustness of disease-specific microbiome signatures across closely related diseases is rarely compared. Here, we compared treatment-naive microbiota composition and functional potential across rheumatic diseases, including rheumatoid arthritis (RA) and spondyloarthritis subforms, to identify disease-specific biomarkers. While we failed to define robust disease-specific microbiota signatures, we identified microbial signatures linked to methotrexate (MTX) responsiveness for the two rheumatic diseases RA and psoriatic arthritis (PsA), for which MTX is the first-line treatment. Notably, the signatures were distinct, i.e., we could define a signature based on the relative abundance of microbial species for RA, yet the signature for PsA was based on the relative abundance of microbial pathways. Together this supports the previously recognized value of microbiota to predict treatment responses to MTX in RA and identifies distinct signatures predicting MTX responsiveness for PsA.

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)

BackgroundADP-ribosylation factor-like protein 15 (ARL15) is a rheumatoid arthritis (RA) susceptibility gene identified through GWAS. Previous studies suggested a role for ARL15 in synovial fibroblast (SF) pathogenicity, but its contribution to inflammatory arthritis remains unclear. We investigated the inflammatory role of ARL15 and its therapeutic potential in RA. MethodsARL15 was overexpressed in MH7A cells followed by bulk RNA sequencing and pathway enrichment analyses. Therapeutic relevance was evaluated in collagen-induced arthritis (CIA) mouse model using anti-ARL15 monoclonal antibodies, ARL15-targeting siRNA, or isoquinoline. Arthritis scores, histopathology, micro-CT and serum cytokines were assessed. Publicly available single-cell RNA sequencing (scRNA-seq) datasets were analyzed to determine ARL15 expression in RASF subsets. ResultsARL15 overexpression induced a pro-inflammatory transcriptional program characterized by upregulation of IL1A, IL1B, IL6, IL8, CXCL1, CXCL10, and CCL20. Gene set enrichment analysis revealed activation of IL6-JAK-STAT, TNF, interferon-response, and KRAS signaling pathways, with suppression of oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. In CIA mice, ARL15 inhibition significantly reduced arthritis severity, inflammatory infiltrates, and joint destruction while preserving cartilage and bone integrity. Serum TNF-, IL-6, and IL-1{beta} levels were markedly decreased following ARL15 blockade. Combination monoclonal antibody treatment demonstrated the greatest therapeutic benefit. scRNA-seq analysis showed broad ARL15 expression across RA fibroblast populations, with enrichment in inflammatory lining and SF subsets. ConclusionsARL15 is a pro-inflammatory regulator of SF activation and arthritis progression. Integrated transcriptomic, single-cell, and in vivo analyses identify ARL15 as a therapeutic target for RA and support further translational development of ARL15 based therapies.

ObjectivesTo assess whether baseline ESR-CRP difference (D score) is associated with discontinuation due to loss of efficacy during Janus kinase inhibitor therapy after biologic failure in rheumatoid arthritis. MethodsSingle-centre retrospective cohort of 24 patients with rheumatoid arthritis who initiated a Janus kinase inhibitor after inadequate response to at least one biologic DMARD. D score was ESR (mm/h) minus CRP (mg/L). The primary outcome was discontinuation due to loss of efficacy; other discontinuations were censored. Kaplan-Meier curves and Cox models were used. ResultsSeven patients discontinued due to loss of efficacy. After dichotomisation at the median D score (20.3; n = 12 per group), 1-year LOE-free persistence was 90.9% in the high D group and 43.2% in the low D group (log-rank p = 0.004). The hazard ratio per 10-unit increase was 0.47 (95% CI 0.29 to 0.76; p = 0.002) and 0.41 after age adjustment (0.22 to 0.74; p = 0.003). ConclusionsBaseline D score was associated with lower risk of discontinuation due to loss of efficacy. Larger studies are needed. Key messagesO_LILoss-of-efficacy discontinuation tended to cluster in patients with low ESR and low CRP at baseline. C_LIO_LIHigher baseline D score was associated with fewer loss-of-efficacy discontinuations during JAK inhibitor therapy. C_LIO_LID score from ESR and CRP may complement post-biologic treatment decisions, pending external validation. C_LI

BackgroundRheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by a heterogeneous clinical course with periods of remission and flare. Although biologic DMARDs (bDMARDs) have revolutionized RA treatment by enabling sustained disease control, their long-term use is associated with adverse effects and high costs, making dose tapering an attractive but clinically challenging strategy. The lack of reliable biomarkers to predict flare risk limits safe implementation of treatment de-escalation. This study aimed to identify novel circulating protein biomarkers associated with flare risk in RA patients undergoing bDMARDs tapering, useful to enable biomarker-guided treatment optimization strategies. MethodsA discovery proteomic analysis using mass spectrometry was performed on baseline serum samples from a subset of the OPTIBIO clinical trial (n=44), followed by validation in the full cohort (n=194) using ELISA. Functional pathway analysis explored biological processes associated with candidate biomarkers. In parallel, anti-cytokine autoantibodies were profiled using multiplex immunoassays. Logistic and Cox regression models were used to assess associations with flare risk. Predictive models integrating biomarkers and clinical variables were evaluated using receiver operating characteristic (ROC) analysis, sensitivity and specificity metrics, and decision curve analysis to assess clinical utility. ResultsMass spectrometry identified 806 proteins, of which 87 were differentially expressed at baseline between patients who flared and those who maintained remission during follow-up within the intervention (tapering) arm. Functional enrichment analysis highlighted immune-regulatory and innate immune pathways. Among the candidates, V-set immunoglobulin-domain-containing 4 (VSIG4) was validated as a biomarker associated with increased flare risk. Anti-interferon-{gamma} (anti-IFN{gamma}) autoantibodies were also associated with flare. A combined model including VSIG4, anti-IFN{gamma}, and the clinical variable DAS28-CRP improved predictive performance compared with clinical variables alone (AUC 0.76 vs 0.66), achieving significantly higher sensitivity. Decision curve analysis demonstrated higher net benefit of the combined model, indicating improved clinical decision-making. In a secondary analysis focused on patients with prolonged remission, representing the most suitable candidates for safe treatment tapering, the model performance further improved (AUC 0.84). ConclusionIntegration of novel serum proteomic and autoantibody biomarkers with clinical parameters improves prediction of flare during biologic tapering in RA and provides clinically relevant benefit for patient stratification. These findings support further development of biomarker-driven approaches for personalized treatment optimization strategies.

Genomics-driven drug discovery framework holds promise in developing novel therapeutic targets. Here, we leveraged large-scale genomic data including genome-wide association studies (GWAS), rare variant burden tests in exome sequencing studies (Exome), and protein quantitative trait loci (pQTL), to prioritize potential therapeutic targets and identify opportunities for drug repositioning in rheumatoid arthritis (RA). We found that prioritized genes covering two approved RA treatment targets (IL6R and CD86), and five targets tested in clinical trials for RA. Eighteen proteins were identified as having causalities with RA risk, three out of them showed strong support for colocalization. Bromodomain-containing protein 2 (BRD2) was nominated as one of the most promising candidates for clinical translation as its wide expression in joint synovial tissues and validation in observational analyses associating with RA incidence. Collectively, our systematic screening of candidate drug targets from different genetically informed approaches, and provided a comprehensive insight into therapeutic strategies for RA.

Synovial fibroblasts (SF) drive joint pathology in rheumatoid arthritis (RA). Difficult-to-treat RA frequently exhibits a fibroblast-rich synovial pathotype, enriched in DKK3{square} and CD34{square} SF, highlighting a critical therapeutic gap. Through multicohort transcriptomic analysis of synovial tissues and mechanistic in vitro studies, we identified SF as principal targets of Janus kinase (JAK) inhibition in RA. We demonstrated that JAK inhibitors (JAKi) can target multiple core aspects of fibroblast pathobiology - therapeutic refractoriness, cartilage destruction, and inflammation - offering a mechanistic rationale for JAKi superiority in difficult-to-treat RA. JAK1 was the dominantly expressed JAK across synovial pathotypes and SF subsets, including DKK3{square} and CD34{square} populations. A STAT1-interferon type I gene program was enriched in matrix-destructive PRG4{square} SF, consistent with JAKi efficacy in erosive RA. In contrast, canonical IL-6 signaling predominated in IL6-expressing inflammatory CXCL12high and HLA-DR+ SF, and was reproduced in cytokine-stimulated cultured SF, underscoring the autocrine nature of synovial IL-6 signaling. These data inferred a heightened JAKi sensitivity of PRG4{square}, CXCL12high, and HLA-DR+ SF subsets, informing precision therapeutic strategies. We uncovered a strong synergy between TNF and IL-6 trans-signaling, profoundly amplifying fibroblast inflammation. In high and synergistic cytokine milieu, STAT1/3 phosphorylation and IL-6 secretion persisted in SF despite tofacitinib treatment, revealing tofacitinibs functional ceiling. This could explain reduced tofacitinib efficacy and adherence in patients with high baseline arthritis activity. Finally, inflamed SF partially uncoupled STAT3 activation from sustained JAK1 phosphorylation, limiting inflammatory output. Similar uncoupling in tofacitinib-treated SF, likely drove rapid STAT1/3 reactivation following tofacitinib washout. These data aligned with JAKi withdrawal complications and clinical recommendations for gradual JAKi tapering. Collectively, our study identifies SF as key cellular targets of JAK inhibition and delineates cytokine- and drug-driven mechanisms that may constrain the efficacy and safety profiles of JAKi in RA.