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Objectives: To elucidate the risk and temporal relationship of cardiovascular (CV) comorbidities in rheumatic diseases., Methods: Patients in the FinnGen study diagnosed between 2000 and 2014 with seropositive (n = 2368) or seronegative (n = 916) rheumatoid arthritis (RA), ankylosing spondylitis (AS, n = 715), psoriatic arthritis (PsA, n = 923), systemic lupus erythematosus (SLE, n = 190), primary Sjogren's syndrome (pSS, n = 412) or gout (n = 2034) were identified from healthcare registries. Each patient was matched based on age, sex, and birth region with twenty controls without any rheumatic conditions. Overall risk ratios (RR) were calculated by comparing the prevalence of seven CV diseases between patients and controls. Logistic regression models were used for estimating odds ratios (OR) for CV comorbidities before and after the onset of rheumatic diseases., Results: The RR for 'any CVD' varied from 1.14 (95 % confidence interval [CI] 1.02-1.26) in PsA to 2.05 (95 % CI 1.67-2.52) in SLE. Patients with SLE or gout demonstrated over two-fold risks for several CV comorbidities. Among CV comorbidities, venous thromboembolism (VTE) showed the highest effect sizes in several rheumatic diseases. The ORs for CV comorbidities were highest within one year before and/or after the onset of the rheumatic disease. However, in gout the excess risk of CV disease was especially high before gout diagnosis., Conclusions: The risk of CV comorbidities was elevated in all studied rheumatic diseases, with highest risks observed in SLE and gout. The risk for CV diseases was highest immediately before and/or after rheumatic disease diagnosis, highlighting the increased risk for CV comorbidities across all rheumatic diseases very early on the disease course., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hanna-Kaisa Aaramaa: a lecture fee from Novartis and support for attending rheumatological congresses from UCB Pharma and Medac. Pia Isomäki: honoraria for honoraria for educational events from Abbvie, Galapagos and Pfizer; consultant of Galapagos, Eli Lilly, Pfizer, ViforPharma. Anne M Kerola: speaker fees from Boehringer-Ingelheim and Sanofi; advisory boards of Pfizer, Gilead and Boehringer-Ingelheim; and congress sponsorship from Pfizer, Abbvie and Mylan. Antti Palomäki: consulting fees from Pfizer, Abbvie and Amgen, lecture fees from Boehringer-Ingelheim, Pfizer and Sanofi, and travel expenses from Novartis. Kari K Eklund: lecture fees from Celltrion, Novartis and MSD, and consulting fees from SOBI., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant., Methods: FinnGen is a collection of epidemiological cohorts and hospital biobank samples, integrating genetic data with up to 50 years of follow-up within nationwide registries in Finland. Patients with RA and ILD were identified from the Finnish national hospital discharge, medication reimbursement and cause-of-death registries. We estimated lifetime risks of ILD by age 80 with respect to the common variant rs35705950, a MUC5B promoter variant., Results: Out of 293 972 individuals, 1965 (0.7%) developed ILD by age 80. Among all individuals in the dataset, MUC5B increased the risk of ILD with a HR of 2.44 (95% CI: 2.22 to 2.68). Out of 6869 patients diagnosed with RA, 247 (3.6%) developed ILD. In patients with RA, MUC5B was a strong risk factor of ILD with a HR similar to the full dataset (HR: 2.27, 95% CI: 1.75 to 2.95). In patients with RA, lifetime risks of ILD were 16.8% (95% CI: 13.1% to 20.2%) for MUC5B carriers and 6.1% (95% CI: 5.0% to 7.2%) for MUC5B non-carriers. The difference between risks started to emerge at age 65, with a higher risk among men., Conclusion: Our findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD., Competing Interests: Competing interests: AnttiP has received a consulting fee from Pfizer and Abbvie, a lecture fee from Pfizer and Sanofi, and support for attending a meeting from Bristol-Myers-Squib and Novartis. JK has received a consulting fee and a lecture fee from Pfizer. TL has received consulting fee and lecture fee from Pfizer. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Alterations in the levels and activity of Tfh may lead to impaired immune tolerance and autoimmune diseases. The aim of this study was to investigate the proportion and types of Tfh cells in the peripheral blood (PB) of RA patients. Areas covered: Comprehensive databases were searched for studies evaluating the proportion of Tfh cells in the PB of patients with RA compared to healthy control (HCs).The proportion of Tfh cells in RA patients was significantly higher than in HCs (SMD 0.699, [0.513, 0.884], p < 0.0001). Furthermore, Tfh cells proportion in untreated-RA and early-RA patients was markedly greater than HCs, when comparisons done without considering the definition markers, and also when Tfh cells were defined by the specified definition markers. While the proportion of Tfh cells by all definitions was higher in active-RA compared to HCs, analysis of two definitions, CD4 + CXCR5 + and CD4 + CXCR5 + ICOS + , didn't show significant differences. Furthermore, higher proportion of Tfh cells defined by all definitions and a specified definition (CD4 + CXCR5 + PD-1 high ) was observed when S + RA compared to S - RA patients. Expert opinion: The results demonstrate that circulating Tfh are highly elevated in RA patients highlights its potential use as a biomarker and a target for RA therapy.

Objectives: To study the prevalence of asymptomatic activation of Epstein-Barr virus (EBV) in patients with rheumatoid arthritis (RA) and to analyse the correlation of serum EBV DNA with the disease activity., Methods: The level of EBV DNA was determined by droplet digital PCR assay from the serum of 46 DMARD naive early RA (ERA) and 22 chronic RA (CRA)-patients at study onset. Follow-up samples from 31 ERA and 16 CRA patients were obtained after starting or modifying the anti-rheumatic treatment. EBV DNA was also measured from 33 healthy controls and 9 patients with adult onset Still's disease (AOSD). Disease activity was assessed by the disease activity score (DAS28)., Results: At baseline, EBV DNA was detected in the serum of 7 of the 46 ERA patients all of whom had moderate or high disease activity. In the follow-up samples, 11 of 31 patients were EBV DNA positive. At baseline EBV positive patients had significantly higher disease activity (p=0.036) and the concentration of EBV DNA correlated significantly with DAS28 (rs=0.333, p=0.024). EBV DNA was detected in 3 of 22 CRA patients at study onset and in 8 of 16 in the follow-up samples. At follow-up EBV positive patients had significantly higher DAS28 (p=0.027) and the concentration of EBV DNA correlated significantly with DAS28 (rs=0.724, p=0.002). Only one of the healthy controls and none of the AOSD patients were positive for EBV DNA., Conclusions: Active RA is associated with a lytic EBV infection which may have a role in the pathogenesis of RA.

Rheumatoid arthritis, inflammatory bowel diseases and psoriasis are examples of immune-mediated inflammatory diseases. They involve activation of a partly similar cytokine network that has an essential role in the disease pathogenesis. Biological drugs have been developed for the inhibition of single cytokines, and good therapeutic responses have been achieved by using them. For instance, TNF blockers are used in the treatment of several inflammatory diseases. The use of the blockers of certain other cytokines is more limited. Other important target molecules include certain interleukins. New bispecific antibodies enabling inhibition of the action of two distinct cytokines are currently undergoing clinical studies.

Increasing evidence suggests that mast cells (MCs), in addition to acute allergic reactions, are involved in the pathogenesis of chronic inflammatory diseases and in particular in rheumatoid arthritis (RA). MCs reside in connective tissues and in synovial tissue of joints. They produce an array of proinflammatory mediators, tissue destructive proteases, and cytokines, most prominently tumor necrosis factor-alpha, which is one of the key cytokines in the pathogenesis of RA. MCs may also participate in the development of secondary or amyloid A amyloidosis, as the partial degradation of the serum amyloid A (SAA) protein by MCs leads to the generation of a highly amyloidogenic N-terminal fragment of SAA. MCs may contribute to the pathogenesis of connective tissue diseases, scleroderma, vasculitic syndromes, and systemic lupus erythematosus, although the data available are limited. Inhibition of the most important growth factor receptor of human MCs, c-Kit, by the selective tyrosine kinase inhibitor imatinib mesylate, induces apoptosis of synovial tissue MCs. As MCs are long-lived cells, induction of their apoptosis could be a feasible approach to inhibit their functions. Preliminary findings suggest that a drug that inhibits c-Kit could have anti-rheumatic activity in the treatment of patients with RA and spondyloarthropathies.

Synovial fibroblast is the key cell type in the growth of the pathological synovial tissue in arthritis. Here, we show that platelet-derived growth factor (PDGF) is a potent mitogen for synovial fibroblasts isolated from patients with rheumatoid arthritis. Inhibition of PDGF-receptor signalling by imatinib mesylate (1muM) completely abrogated the PDGF-stimulated proliferation and inhibited approximately 70% of serum-stimulated proliferation of synovial fibroblasts. Similar extent of inhibition was observed when PDGF was neutralized with anti-PDGF antibodies, suggesting that imatinib mesylate does not inhibit pathways other than those mediated by PDGF-receptors. No signs of apoptosis were detected in synovial fibroblasts cultured in the presence of imatinib. These results suggest that imatinib mesylate specifically inhibits PDGF-stimulated proliferation of synovial fibroblasts, and that inhibition of PDGF-receptors could represent a feasible target for novel antirheumatic therapies.

Background: Imatinib mesylate is an inhibitor of a few tyrosine kinases including KIT, which is an important growth factor receptor of mast cells., Aim: To study the efficacy and safety of imatinib in the treatment of rheumatoid arthritis., Method: Three patients with severe rheumatoid were treated with imatinib for 12 weeks. The number of tender and swollen joints, patient-assessed disease activity and pain as assessed by a visual analogue scale, a health assessment questionnaire (HAQ) score, serum C-reactive protein (CRP) and blood erythrocyte sedimentation rate (ESR) were used as the primary outcome measures., Results: All outcome measures improved. The swollen joint count decreased in all patients, and the tender joint count in two of the three patients. The patients reported less pain and disease activity, and the HAQ scores improved. Serum CRP and blood ESR improved in two patients. One patient interrupted therapy due to a rash., Conclusions: Imatinib mesylate may have considerable anti-rheumatic efficacy. The mechanism of action is not known, but one possible target for the action of imatinib is inhibition of the KIT receptor on mast cells.