Human bone marrow mesenchymal stromal/stem cells (BM-MSCs) are widely used in clinical trials and tissue engineering, yet their native microenvironment remains poorly understood. Here we introduce a tissue-clearing protocol, DeepBone, for human bones and integrate it with simultaneous mRNA and protein detection. Using this protocol, we spatially map BM-MSCs relative to key bone microenvironment components, including human blood capillaries, adipocytes, sinusoids and bony trabeculae. Quantitative analysis reveals that the native microenvironment of human BM-MSCs in young bone is enriched in vasculature, sinusoids, bone matrix and adipocytes. In contrast, in aged bone, BM-MSCs show no preferential association with bone or adipocytes. Proliferative BM-MSCs are predominantly found along blood vessels. Moreover, we identify a specialized microenvironment for BM-MSCs in young bone, characterized by sinusoids coiled around trabeculae and enriched by R-type vessels. These findings provide insights into the native niches of BM-MSCs, offering a foundation for the development of tissue engineering strategies that mimic their physiological context.

Osteoporosis is characterized by an imbalance in bone remodeling, resulting in bone loss and increased fracture risk. Inflammatory diseases, such as rheumatoid arthritis, are strongly associated with secondary osteoporosis due to inflammation-induced bone loss. Pro-inflammatory cytokines, particularly TNF-α, disrupt bone homeostasis by promoting osteoclastogenesis and inhibiting osteoblast function. The Wnt signaling pathway is essential for bone formation and is suppressed in inflammatory conditions. WNT16, an osteoblast-derived ligand, increases bone mass mainly by inhibiting osteoclast differentiation but has also been found to stimulate osteoblast activity. Here we demonstrate that TNF-α downregulates Wnt16 mRNA expression in primary osteoblasts, suggesting that inflammation may impair WNT16 expression and thereby reduce bone mass. To evaluate whether pharmacological or genetical elevation of WNT16 levels can mitigate inflammation-induced bone loss, we examined the effect of WNT16 in three mouse models of local and systemic inflammation. In a knee arthritis model, intra-articular delivery of WNT16 liposomes failed to prevent local bone loss. Similarly, although osteoblast-specific WNT16 overexpression increased the overall bone mass, it did not protect against either local calvarial bone loss or systemic bone loss induced by Toll-like receptor 2 (TLR2) activation. Furthermore, in a model of systemic inflammation induced by Staphylococcus aureus, WNT16 overexpression did not preserve vertebral trabecular bone, despite increased baseline bone mass. These findings demonstrate that WNT16, although increasing the overall bone mass, is insufficient to counteract inflammation-driven bone loss.

BACKGROUND:Pain, fatigue, and impaired health-related quality of life are common manifestations of rheumatoid arthritis. The aim of this study was to compare the effects of active conventional treatment with three different biological disease-modifying antirheumatic drugs (DMARDs) on patient-reported outcomes after 48 weeks, in patients with early rheumatoid arthritis using data from the NORD-STAR trial. METHODS:NORD-STAR was an investigator-initiated open-label randomised controlled trial done at 29 rheumatology centres across Denmark, Finland, Iceland, Norway, Sweden, and the Netherlands. Newly diagnosed patients aged 18 years or older, with rheumatoid arthritis (according to the 2010 American College of Rheumatology-European Allience of Associations for Rheumatology classification criteria for rheumatoid arthritis), symptom duration less than 24 months and who were naïve to DMARDs were randomly assigned (1:1:1:1) to receive active conventional treatment, certolizumab pegol, abatacept, or tocilizumab. The patient-reported outcomes assessed at baseline and weeks 4, 8, 12, 16, 24, 32, 40, and 48 included pain, patient's global assessment of disease activity, Health Assessment Questionnaire Disability Index, Fatigue, Short Form-36 (reflecting health-related quality of life, morning stiffness, and patient's acceptable symptom state). Linear mixed regression and logistic regression analyses were adjusted for sex, country, baseline patient-reported outcomes values, anti-citrullinated protein antibody status, and treatment group. Proportions of patients reporting improvements greater than or equal to the minimal clinically important difference (MCID) were assessed. There was lived experience involvement in the design and implementation of the study. This trial was registered with ClinicalTrials.gov, NCT01491815, and EudraCT, 2011-004720-35. FINDINGS:Between Dec 14, 2012, and Dec 11, 2018, 812 patients were enrolled and randomly assigned; after exclusion of 17 patients not receiving tocilizumab due to administrative issues, the intention-to-treat population consisted of 795 patients (200 [25%] received active conventional treatment, 203 [26%] received certolizumab pegol plus methotrexate, 204 [26%] received abatacept plus methotrexate, and 188 [24%] received tocilizumab plus methotrexate). 547 (69%) of 795 patients were female, 248 (31%) were male, the mean age was 54 years (SD 15). Between baseline and week 48 large and clinically relevant improvements in patient-reported outcomes were observed in all treatment groups. At 48 weeks the biological DMARD groups had larger improvements in pain, fatigue, physical component score, and bodily pain of SF-36 compared with the active conventional treatment group. For pain, improvement exceeding MCID was reported by 155 (76%) of 203 patients with certolizumab pegol plus methotrexate and 162 (79%) of 204 patients with abatacept plus methotrexate compared with 136 (68%) of 200 patients in the active conventional treatment group. In the group of patients with tocilizumab and methotrexate 132 (70%) of 188 patients reported pain improvement exceeding MCID. The absolute differences between the biological DMARD groups and the active conventional treatment group were otherwise generally marginal. INTERPRETATION:All treatment groups showed substantial improvements in patient-reported outcomes over time. Biological DMARDs produced somewhat greater gains in pain, fatigue, and physical quality of life measures than conventional treatments, though overall differences between groups were small. The results highlight that early treatment and effective disease control in rheumatoid arthritis lead to strong patient-reported benefits regardless of therapy type. FUNDING:Stockholm County Council, Swedish Medical Research Council, Swedish Rheumatism Association, Academy of Finland, Finska Läkaresällskapet, South-Eastern Health Region Norway, HUS Institutional grant, Icelandic Society for Rheumatology, Interregional grant from all health regions in Norway, NordForsk, Regionernes Medicinpulje, The Research Fund of University Hospital Reykjavik, UCB, Bristol Myers Squibb.

Post-translationally modified proteins are crucial autoantigens in autoimmune diseases, with citrullinated proteins being key targets of autoantibodies in rheumatoid arthritis (RA). However, accurate citrullinome profiling and autoantigen identification remain limited by insufficient detection methods and computational tools. Here we develop Iseq-Cit (internal standard-assisted enrichment-free approach for high-throughput quantitative analysis of citrullinome), for global citrullinome profiling in individuals at RA risk and in patients with RA across a longitudinal cohort, requiring less than 1% of the sample input needed for conventional methods. We find that plasma citrullinome profiles closely correlate with RA development and severity. Moreover, we develop models integrating clinical indicators and citrullination data, achieving high accuracy in predicting treatment response. To evaluate the RA-sera reactivity of identified citrullinated peptides, we train a bidirectional gated recurrent unit model using 67,399 RA-sera negative and 8,816 RA-sera positive peptides. External validation through enzyme-linked immunosorbent assays confirms 84.2% accuracy in predicting RA-sera reactivity of citrullinated peptides, yielding 19 promising candidates for RA diagnosis. This work provides strategies for citrullinated peptide identification, autoantigen discovery and RA treatment stratification.

Objective To identify autoantibodies in presymptomatic individuals that associate with the onset of rheumatoid arthritis (RA) and to distinguish early RA from osteoarthritis (OA), particularly in individuals lacking classic RA serologic markers. Methods We analyzed serum and plasma from three cohorts: presymptomatic individuals who later developed RA (n = 518), a subset of these at RA diagnosis (n = 241), matched population controls (n = 530), and patients with OA (n = 287). Bead‐based multiplex flow immunoassay detected IgG autoantibodies against joint‐related peptides relevant in arthritis models. Principal component analysis was used to identify subgroups and univariable regression analyses to characterize the performance of autoantibodies with significance for patients with RA negative for anti–cyclic citrullinated peptide (anti‐CCP) and rheumatoid factor (RF), that is, the seronegative RA diagnosis (SeNe) test. Multivariable logistic regression identified autoantibodies with the strongest discriminative power between cases and controls. Results Autoantibody profiles revealed three distinct presymptomatic subgroups, suggesting early immune heterogeneity. The SeNe test was associated with symptom onset within 2.5 years in 13% of anti‐CCP and RF‐negative individuals. Specificity for RA versus OA was 97% (95% confidence interval, 95%–99%). An improved version (SeNe 2.0) identified 16% of anti‐CCP and RF‐negative presymptomatic individuals with 98% specificity versus population controls. Two of five SeNe 2.0 autoantibodies were associated with the presymptomatic state in the multivariable model, including RF and anti‐CCP. Conclusion These novel biomarkers can identify presymptomatic, seronegative individuals at high risk of RA onset and support their recruitment into trials for personalized prevention. Additionally, they distinguish early seronegative RA from OA with high specificity. image

Early initiation of effective treatment is associated with positive long-term prognosis for patients with rheumatoid arthritis (RA). Currently, there are no biomarkers in clinical use to predict treatment response. A predictor of treatment response may be the B-cell compartment, as this is altered in RA patients, making it a potential candidate for predicting treatment response. In this study, we sought to identify B-cell subset(s) at diagnosis that might be associated with Clinical Disease Activity Index (CDAI) remission at 24-week follow-up. Seventy early RA patients from the NORD-STAR trial, recruited from two Swedish sites, and 28 matched healthy controls, were included in this spin-off study. In NORD-STAR, all patients were randomized to methotrexate (MTX) combined with 1) prednisolone, 2) anti-TNF (certolizumab-pegol), 3) CTLA4-Ig (abatacept), or 4) anti-IL-6R (tocilizumab). Circulating B-cell subsets at diagnosis were assessed by flow cytometry. The primary outcome measure was remission according to CDAI ≤ 2.8. A multivariate two-part discriminant analysis was performed to assess whether B-cell subpopulations at diagnosis could predict remission at 24 weeks. Subsequent univariable statistical analyses were performed using t-tests, Mann-Whitney U, or Kruskal-Wallis tests, as appropriate. Correlations were analyzed using Spearman or Pearson tests, depending on data type. The impact of specific B-cell populations on remission at week 24 was assessed using logistic regression models. The logistic regression model was also used to simultaneously visualize the sensitivity and specificity of the model for all possible values of the exposure (B-cell subpopulations) in predicting the outcome. Patients who achieved CDAI remission at 24 weeks had higher proportions of transitional (p < 0.01) and CD21− PD-1+ (p < 0.01) B cells at diagnosis compared to those who did not. When the two B-cell populations were combined, the sensitivity and specificity for remission, including all treatment arms, were 59

Obesity is highly overrepresented in patients with psoriatic arthritis (PsA) and associated with increased disease activity and inferior treatment outcome. We have previously reported in 41 patients with PsA and body mass index (BMI) ≥ 33 kg/m2 that weight loss treatment with Very Low Energy Diet (VLED) resulted in a median weight loss of 18,6

Rheumatoid arthritis (RA) is a systemic inflammatory condition posing challenges in identifying biomarkers for onset, severity and treatment responses. Here we investigate the plasma proteome in a longitudinal cohort of 278 RA patients, alongside 60 at-risk individuals and 99 healthy controls. We observe distinct proteome signatures in at-risk individuals and RA patients, with protein levels alterations correlating with disease activity, notably at DAS28-CRP thresholds of 3.1, 3.8 and 5.0. The combination of methotrexate (MTX) and leflunomide (LEF) modulates proinflammatory pathways, whereas MTX plus hydroxychloroquine (HCQ) impact energy metabolism. A machine-learning model is trained for predicting responses, and achieves average receiver operating characteristic (ROC) scores of 0.88 (MTX + LEF) and 0.82 (MTX + HCQ) in the testing sets. The efficiency of these models is further validated in independent cohorts using enzyme-linked immunosorbent assay data. Overall, our study unveils distinct plasma proteome signatures across various stages and subtypes of RA, providing valuable biomarkers for predicting disease onset and treatment responses.

Rheumatoid arthritis (RA) is a systemic inflammatory joint disease characterized by heterogeneous clinical manifestations, which requires deeper exploration in identifying reliable biomarkers for early diagnosis, monitoring, and treatment assessment. The aim is to discover plasma metabolomic markers to predict RA onset, assess disease activity, and forecast treatment efficacy. The study includes 209 established RA patients who are disease-modifying antirheumatic drugs-free for six months prior to enrollment, with 197 of them followed for 3-6 months to assess treatment response. Additionally, 56 individuals at risk are recruited, with 34 completing a 5-7-year follow-up. Analysis reveals that metabolites related to methylation and redox imbalance, such as S-adenosylmethionine, sarcosine, nicotinamide adenine dinucleotide, glutathione, etc., are associated with RA development and severity, and contribute to its heterogeneity across age, sex, and anti-citrullinated protein autoantibody status. Ridge regression models are constructed using metabolite and clinical features for the response to methotrexate (MTX) plus leflunomide, achieving an average receiver operating characteristic (ROC) score of 0.83, and for the MTX plus hydroxychloroquine, achieving an average ROC score of 0.92. In conclusion, our findings reveal RA metabolomic alterations, aiding early diagnosis and treatment response.

Human bone marrow mesenchymal stromal/stem cells (BM-MSCs) are widely utilized in clinical trials and tissue engineering; however, their native microenvironment remains poorly understood. Here, we introduced a tissue-clearing protocol for human bones and integrated it with simultaneous mRNA and protein detection. Using this protocol, named DeepBone, we spatially mapped BM-MSCs relative to key bone microenvironment components, including human blood capillaries, adipocytes, sinusoids, and bony trabeculae. Quantitative analysis revealed that the native microenvironment of human BM-MSCs in young bone is enriched in vasculature, sinusoids, bone matrix, and adipocytes. In contrast, in aged bone, BM-MSCs showed no preferential association with bone or adipocytes. Proliferative BM-MSCs were predominantly found along blood vessels. Moreover, we identified a specialized microenvironment for BM-MCs in young bone, characterized by sinusoids coiled around trabeculae and enriched by R-type vessels. These findings provide novel insights into the native niches of BM-MSCs, offering a foundation for the development of tissue-engineering strategies that mimic their physiological context. ### Competing Interest Statement The authors have declared no competing interest. Swedish Research Council, 2020-02298 Novo Nordisk Foundation, NNF21OC0070314 IngaBritt och Arne Lundbergs Forskningsstiftelse, LU2021-0069

OBJECTIVES:To determine anticitrullinated protein antibody (ACPA) responses to novel peptides predicting the clinical outcomes of treatment-naïve early rheumatoid arthritis (RA) in the presymptomatic stage. METHODS:We analysed monoclonal ACPAs derived from RA patients, including a characterised protective ACPA (clone E4), along with plasma samples collected from 520 presymptomatic individuals, of whom 244 were also sampled at diagnosis of RA, and 530 population controls in Sweden. The validation cohort (The Nordic Rheumatic Diseases Strategy Trials and Registries, NORD-STAR) consisted of 690 treatment-naïve early RA patients. Responses to citrullinated or native alpha-enolase (ENO1) or peptidylarginine deiminase 4 (PAD4) peptides were analysed by bead-based multiplex flow immunoassay. Clinical outcomes included C-reactive protein (CRP) and the 28-joint disease activity score (DAS28) with its components: tender joint count (TJC), swollen joint count (SJC), and erythrocyte sedimentation rate (ESR). RESULTS:Monoclonal ACPAs displayed distinct binding patterns to ENO1 and PAD4 peptides. A time-dependent increase of ACPA response to citrullinated peptides was observed in the presymptomatic stage towards onset. In the presymptomatic (0.2-5 years before onset) and early RA stage, ACPA responses to several ENO1 and PAD4 peptides were associated with less severe RA, assessed as lower levels of CRP and DAS28 and its components. In early RA, the association was more pronounced in rheumatoid factor (RF)-negative patients based on lower SJC. In presymptomatic individuals, ACPA responses widely predicted lower disease activity in early RA and were more pronounced in 5 selected peptides. CONCLUSIONS:Antibody responses to certain citrullinated epitopes are associated with lower disease activity in treatment-naïve early RA and appear years before symptom onset of RA.

The risk of atherosclerotic cardiovascular disease (ASCVD) is increased in Rheumatoid Arthritis (RA). Previous research has suggested that lipid metabolism is altered in RA, but research under postprandial conditions is scarce. The aim of this study was to investigate whether women with RA have a different lipemic and inflammatory response to a mixed meal containing red meat compared to women without RA. Twenty-two women with RA, with modest disease activity, and 22 women without RA matched for age and body mass index (BMI) at the group level consumed a hamburger meal containing ca. 700 kcal (53 E

Reducing red meat intake in the Western diet is beneficial for health and the environment. However, red meat is nutrient-rich, so understanding the impact of substituting it with other protein sources such as fish or plant-based proteins is essential, especially for vulnerable groups like the elderly and those with chronic diseases. The purpose of this study was to study the postprandial response in serum metabolites in women with Rheumatoid Arthritis (RA) after intake of red meat, fatty fish, and soy protein. Women with RA (n = 24) consumed isocaloric meals that included burgers made from either red meat, fatty fish, or soy protein in a crossover design. Blood samples were taken in fasting state before the meal (0 h) and at intervals up to 5 h after eating. Nuclear Magnetic Resonance (NMR) analysis quantified serum metabolites, and multivariate models and univariate statistics were applied to compare postprandial metabolite changes across protein sources. Postprandial metabolite patterns varied significantly by protein type. The fatty fish meal led to a faster and higher increase in metabolites, including creatinine, isoleucine, valine, and trimethylamine N-oxide, compared to red meat. Unidentified lipids also differed. However, metabolite patterns after soy protein were similar to those after red meat. This postprandial crossover trial found that intake of fatty fish lead to a quicker and more pronounced increase in key blood concentrations of metabolites compared to red meat. However, metabolite profiles in serum based on NMR-analysis were similar after intake of soy protein compared to red meat. The PIRA (Postprandial Inflammation in Rheumatoid Arthritis) trial is Registered at Clinicaltrials.gov (NCT04247009).

OBJECTIVE:To determine whether baseline CD4+ T helper (Th) cell subset proportions in blood may serve as predictive biomarkers for achieving remission 48 weeks after initiating CTLA-4Ig, anti-tumor necrosis factor (TNF), or anti-interleukin 6 receptor (IL6R) treatment in patients with early rheumatoid arthritis (eRA). METHODS:This study included 60 untreated eRA patients from the larger randomized treatment trial NORD-STAR. They were treated with methotrexate (MTX) combined with either CTLA-4Ig (n = 17), anti-TNF (n = 22), or anti-IL6R (n = 21). Disease activity was assessed by clinical disease activity index (CDAI), C-reactive protein, and erythrocyte sedimentation rate. The primary outcome was remission (CDAI ≤ 2.8) at week 48, and the secondary outcomes were time to reach remission or sustained remission during the 48-week follow-up. CD4+ T cell subset proportions were analyzed fresh by flow cytometry at baseline and at 24 and 48 weeks. RESULTS:In CTLA-4Ig + MTX-treated patients, baseline Th2 together with PD1+ T follicular helper (TFh) cell proportions predicted CDAI remission at week 48 (AUC: 0.986, 95% CI 0.94-1.0). Survival analysis revealed that patients with Th2 proportions below 16.8% or PD1+ TFh proportions above 7.6% at baseline were more likely to achieve remission (log-rank p = 0.002 and p = 0.007, respectively), and sustained remission (log-rank p = 0.01 and p = 0.001, respectively), over the 48-week follow-up. CD4+ T cell subset proportions did not predict remission in patients treated with anti-TNF + MTX or anti-IL6R + MTX. Only CTLA-4Ig treatment reduced PD1+ TFh and PD1neg TFh fractions after 48 weeks. CONCLUSION:Circulating Th2 and PD1+ TFh cell proportions at baseline may serve as predictive biomarkers for achieving CDAI remission after 48 weeks of CTLA-4Ig treatment in eRA.

Objective To investigate whether soluble immune checkpoint molecules in blood are associated with the treatment response to disease‐modifying antirheumatic drugs in early rheumatoid arthritis (eRA). Methods This study included 328 Swedish treatment‐naïve patients with eRA from the Nordic Rheumatic Diseases Strategy Trials and Registries (NORD‐STAR) study. Patients were randomized into four treatment groups: methotrexate (MTX) combined with CTLA‐4Ig (n = 90), anti–tumor necrosis factor (n = 83), anti–interleukin‐6 receptor (n = 76), or prednisolone (n = 79). The primary outcome was remission, defined by Clinical Disease Activity Index (CDAI) ≤2.8, assessed at 24 and 48 weeks. Plasma levels of soluble programmed cell death‐1 (sPD1) and soluble 4‐1BB (s4‐1BB) were measured by enzyme‐linked immunosorbent assay at baseline and at weeks 24 and 48 after treatment initiation. Results High baseline levels of sPD1 and s4‐1BB were both associated with CDAI remission at 24 weeks (odds ratio 1.31, 95% confidence interval [CI] 1.04–1.66 and odds ratio 1.50, 95% CI 1.07–2.11, respectively) in patients treated with CTLA‐4Ig with MTX, but not in any other treatment groups. Furthermore, baseline levels of sPD1 or s4‐1BB together with proportions of PD1+ T follicular helper (TFh) cells predicted treatment response to CTLA‐4Ig with MTX after 48 weeks, achieving 90% and 100% positive predictive value, respectively. Conclusion High plasma levels of sPD1 and s4‐1BB are associated with good response to CTLA‐4Ig with MTX therapy in patients with eRA. A combination of sPD1 or 4‐1BB levels and the proportions of PD1+ TFh cells in blood at baseline has potential for predicting remission after CTLA‐4Ig treatment.

Objective Cone beam computed tomography (CBCT) can accurately assess erosive disease in the hands, wrists, and feet in established rheumatoid arthritis (RA). The aim of this study was to compare CBCT with conventional radiography (CR) for the assessment of erosions in patients with early RA. Methods CBCT and CR of the hands, wrists, and feet of 17 patients with treatment-naive early RA were assessed at diagnosis and at the 6-month and 12-month follow-up. Erosions on CBCT scans were scored by the same observer using the modified RA Magnetic Resonance Imaging Score, which evaluates the same joints as the Sharp/van der Heijde score (SHS). Radiographs were scored for erosions using the SHS by the same observer. Results At baseline, there was a significant difference in the erosion score between CBCT and CR, as shown with a percentage of maximum scores. The number of erosions and the number of eroded joints were significantly higher with CBCT compared with CR at 6 and 12 months. The number of detected repair of erosions was higher with CBCT than with CR at both 6 and 12 months. Conclusion CBCT was more sensitive than CR in detecting erosions and repair in patients with early RA. CBCT has the potential to become a sensitive tool for monitoring destructive disease in patients with RA.

OBJECTIVE:For better management of RA, new biomarkers are needed to predict the development of different disease courses. This study aims to identify autoantibodies against epitopes on proteins in the joints and to predict disease outcome in patients with new onset RA. METHODS:Sera from new-onset RA patients from the Swedish BARFOT (Better Anti Rheumatic PharmacOTherapy) and TIRA-2 (Swedish acronym for 'tidiga insatser vid reumatoid artrit') cohorts (n = 1986) were screened for autoantibodies to selected peptides (JointIDs) in a bead-based multiplex flow immunoassay. Disease outcomes included Boolean remission 1.0, swollen joint count and radiographic destruction. Multivariate logistic regression and zero-inflated negative binomial models that accounted for clinical factors were used to identify JointIDs with the strongest potential to predict prognosis. RESULTS:Boolean remission was predicted with 42% sensitivity and 75% specificity in male patients positive for antibodies to a non-modified collagen type II (COL2) peptide at 12 months. When antibodies to a specific citrullinated cartilage oligomeric protein (COMP) peptide were absent and the patient was in Boolean remission at 6 months, the sensitivity was 13% and the specificity 99%. Positivity for the non-modified COL2 peptide also reduced the frequency of swollen joints by 41% and 33% at 6 and 12 months, respectively. Antibodies to CCP predicted joint destruction with low specificity (58%). Positivity for a COL2 and a glucose-6-phosphate dehydrogenase peptide in citrullinated forms increased specificity (86%) at the expense of sensitivity (39%). CONCLUSION:Autoantibodies against joint-related proteins at RA diagnosis predict remission with high specificity and, in combination with clinical factors, may guide future treatment decisions.

ObjectiveSubsets of CD21−/low memory B cells (MBCs), including double‐negative (DN, CD27−IgD−) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21−/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21−/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA).MethodsClinical observations were combined with flow cytometry (n = 36) and single‐cell RNA sequencing (scRNA‐seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA‐seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity.ResultsCD21−/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up‐regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin‐mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor–related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction.ConclusionThis study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization.image