Immunometabolism and neutrophil extracellular traps (NETs) play pivotal roles in the pathogenesis of coronavirus disease 2019 (COVID-19) and its postacute sequelae. However, the upstream regulators that reprogram neutrophil lipid metabolism and trigger excessive NET formation remain largely undefined. This study identifies a transfer RNA-derived fragment, tRF-His-GTG-1, enriched in platelet-derived extracellular vesicles, as a key driver of neutrophil lipophagy dysfunction and inflammation in COVID-19. The use on neutrophils from 60 patients and 20 healthy controls, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected hamster model, and multiple in vitro assays shows that severe COVID-19 and long COVID are characterized by increased lipid droplet (LD) accumulation and NET release. Mechanistically, tRF-His-GTG-1 activates Toll-like receptor 8 (TLR8)-mammalian target of rapamycin (mTOR) signaling and suppresses RAB7A expression, changes that impair lipophagic flux. This dual pathway impairs lipophagy and promotes NET formation and proinflammatory cytokine secretion. Importantly, ex vivo treatment with a tRF-His-GTG-1 inhibitor restores lipophagy, reduces LD and NET levels, and suppresses interleukin 1beta (IL-1β)/IL-8 production in patient-derived neutrophils. These findings reveal a novel EV-mediated immunometabolic axis linking platelets to neutrophil dysfunction, and position tRF-His-GTG-1 as a promising RNA-based therapeutic target for COVID-19-associated hyperinflammation.

Although pulmonary hypertension (PH) and interstitial lung disease (ILD) are major contributors to mortality in patients with connective tissue disease (CTD), data on concomitant PH specifically in those with CTD-associated ILD (CTD-ILD) remain limited. We aimed to identify predictors for PH development in CTD-ILD patients, and assess their impact on survival in this population. This retrospective observational study included 224 patients with CTD-ILD, confirmed through multidisciplinary discussion, including patients with inflammatory myopathy-associated ILD (IIM-ILD, n = 88), systemic sclerosis-associated ILD (SSc-ILD, n = 57), rheumatoid arthritis-associated ILD (RA-ILD, n = 55), and primary Sjögren’s syndrome-associated ILD (pSS-ILD, n = 24). PH was diagnosed using right heart catheterization (RHC) or, in patients unable to undergo RHC, by transthoracic echocardiography. Autoantibodies related to IIM and SSc were assessed using Euroimmun immunoblot assays. Among CTD-ILD patients, 28 (12.5

Systemic lupus erythematosus (SLE) exhibits diverse clinical presentations and requires regionally specific management strategies. Building upon established international guidelines, the Taiwan College of Rheumatology developed the first set of recommendations for SLE management to focus on the unmet needs of clinical practice in Taiwan. This consensus aims to empower healthcare professionals and optimize patient outcomes in Taiwan. Rheumatologists from various practicing institutions formed a 15-member panel and, through a modified Delphi process, developed consensus statements that encompass various aspects of SLE care in Taiwan, including screening and diagnosis, disease monitoring, treatment strategies, and pregnancy. The expert panel reviewed and refined statements through two meetings with anonymous voting based on a 5-point Likert scale. Consensus is defined as ≥ 75% agreement to the proposed statements. In total, 32 statements achieved consensus. These statements incorporate the latest scientific evidence with insights from Taiwanese experts to address the unique disease characteristics and challenges faced by patients in the region, and could serve as a guide to specialists, family physicians, specialty nurses, and other healthcare professionals in Taiwan for the management of SLE.

Mutations or reduced expression in glycine N-methyltransferase (GNMT) has been linked to liver diseases. Methotrexate (MTX) is commonly prescribed for the treatment of human rheumatic diseases. We previously demonstrated that MTX selectively inhibits the partitioning of mitochondria derived formate pathways, including glycine cleavage system (GCS). We also demonstrated that GNMT expression is essential for methyl group supply, intracellular folate homeostasis and MTX toxicity. We tested the hypothesis that GNMT regulates the metabolic response to low-dose methotrexate by altering mitochondrial one-carbon metabolism, thereby influencing glycine-derived one-carbon partitioning, DNA methylation, and central carbon metabolism. Metabolic alterations of mitochondrial one carbon metabolism and TCA cycle were investigated in liver derived cell-lines with/without human GNMT expression, as well as in wild-type (WT, Gnmt+/+) and GNMT knockout (KO, Gnmt-/-) mouse models treated with MTX using stable isotopic tracers and GC/MS. MTX inhibited deoxythymidylate (dTMP) synthesis from mitochondria derived formate in both WT and Gnmt-/- mice bone marrow. Deletion of Gnmt in mice decreased enrichment in 5-methyl-2′-deoxycytidine (5-mdC) but not dTMP synthesis from GCS using [2-13 C] glycine tracer. Interestingly, MTX inhibited 5-mdC enrichments in Gnmt+/+ but promoted that in Gnmt-/- in the bone marrow, indicating gene-drug interactions in GCS activity. MTX decreased liver pyruvate concentrations in both Gnmt+/+ and Gnmt-/-, whereas MTX increased plasma citrate concentration in Gnmt+/+ but not in Gnmt-/-. MTX suppressed liver alpha-ketoglutarate but increased malate concentrations in Gnmt+/+ but not Gnmt-/-. The present study provides evidence on the interactions between MTX and GNMT function and provides new insights on how this essential gene may affect mitochondria derived formate dependent pathways and central carbon metabolism during MTX therapy. In patients taking long-term MTX therapy, genetic factors such as hepatic GNMT function should be taken into consideration.

Rheumatoid arthritis (RA) is associated with increased risks of osteoporosis and fracture. Amorphous calcium carbonate (ACC) may enhance osteogenic differentiation and increase bone mineral density (BMD). The effects of ACC supplementation on BMD and bone turnover markers (BTMs) in RA have not been explored. This study investigated the influence of ACC supplementation on BMD, BTMs, and the risk of osteoporotic fractures in RA patients. We enrolled 67 RA patients with osteopenia or osteoporosis. BMD was measured by dual-energy X-ray absorptiometry before and after 1 year of ACC supplementation, providing elemental calcium 800 mg/day combined with vitamin D3 400 IU/day. Serum levels of N-terminal propeptide of type I collagen and C-terminal cross-linking telopeptide were measured at baseline and every 3 months following ACC supplementation. The 10-year fracture probability was calculated using the Fracture Risk Assessment Tool (FRAX®), and RA activity was assessed using the 28-joint disease activity score. Multivariate regression analysis revealed that age and corticosteroid dosage ≥5 mg were significant risk factors for major osteoporotic fracture. The 28-joint disease activity scores were inversely correlated with BMD of the right femoral neck (r = -0.426, P < .001) and left femoral neck (r = -0.383, P < .005). After 12 months of ACC supplementation, bilateral femoral neck BMD increased significantly (from 0.61 to 0.63 g/cm2, both P < .001), accompanied by improvement in T-scores. Serum levels of N-terminal propeptide of type I collagen and C-terminal cross-linking telopeptide were significantly decreased (mean 53.42 vs 41.24 ng/mL, P < .001; 0.29 vs 0.25 ng/mL, P < .05, respectively). Twelve-month ACC supplementation increased bilateral femoral neck BMD and reduced BTM levels in RA patients, particularly in anti-citrullinated peptide antibody-positive patients.

INTRODUCTION:Accumulative evidence indicates that both innate and adaptive immunity are involved in pathogenesis of Still's disease, an autoinflammatory disease. With Increasing insights into the pathogenesis of Still's disease coupled with the availability of emerging targeted therapeutics, it may be the unmet need for personalizing therapy and achieving a treat-to-target goal. We aim to summarize the available evidence regarding immunopathogenesis of Still's disease and therapeutic strategies based on immunologic endotypes. AREAS COVERED:We searched MEDLINE database using the PubMed interface and reviewed relevant English-language literature from 1971 to 2024. This review focuses on the existing evidence on pathophysiology and immunological endotypes of Still's disease and their implications for personalized strategies for patients with this disease. EXPERT OPINION:Targeting the complex immunopathogenesis of Still's disease, emerging new agents are available for treatment, including biologic disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) such as Janus kinase inhibitors (JAKi). According to the updated evidence, meta-analyses, and recommendations, we propose a flow chart emphasizing personalized therapeutic strategies based on immunological endotypes. Hopefully, the therapeutic strategy might help guide the optimal selection of b/tsDMARDs to achieve a 'treat-to-target' goal in Still's disease. This proposed flow chart will be updated as newer evidence emerges.

Interstitial lung diseases (ILDs) include various lung parenchymal disorders characterized by inflammation and fibrosis of the lung tissue, leading to progressive dyspnea and respiratory failure. Clinical evidence has suggested an association between human parvovirus B19 (B19V) infection and the progression of ILD and pulmonary fibrosis, but the mechanisms involved remain unclear. The present study screened 86 patients with connective tissue disease (CTD) and reported that B19V infection was significantly more prevalent among those with ILD than among those without (P<0.001). To investigate the potential underlying mechanisms, a bleomycin (BLM)‑treated mouse model was employed to assess the effect of B19V nonstructural protein 1 (NS1) on pulmonary fibrosis. Mice treated with BLM or BLM + NS1 exhibited markedly higher fibrosis scores, hydroxyproline content, and higher levels of transforming growth factor‑β and collagen I. Treatment with nintedanib attenuated fibrosis in both groups; however, lung fibrosis remained more pronounced in the BLM + NS1 group than in the BLM group. Furthermore, the levels of neutrophil‑associated markers, including citrullinated histone H3 and myeloperoxidase, as well as inflammasome‑related factors, such as IL‑18 and IL‑17A, were markedly elevated in lung tissues from both groups, with the highest levels observed in the BLM + NS1 group. These findings suggested that B19‑NS1 may exacerbate fibrosis in patients with ILD by increasing neutrophil‑driven responses and inflammasome activation, highlighting a need for nintedanib therapies to more effectively address B19V‑associated pulmonary fibrosis.

Background/Aims: Fibromyalgia (FM) is a chronic disease characterized by widespread pain. An increased cardiovascular risk has been suggested in these patients. The aim was to investigate the cardiovascular risk factors in these patients. Materials and Methods: Patients with primary FM consecutively were prospectively recruited from a tertiary medical center in Taiwan. As the control group, individuals without FM who had undergone a health checkup examination were recruited. Their traditional cardiovascular risk factors, carotid intima-media thickness (IMT), and the presence of metabolic syndrome were then determined. Metabolic dysfunction–associated steatotic liver disease (MASLD) and the severity of hepatic steatosis (the Saverymuttu and Hamaguchi scores) were both determined by sonography. Multivariate logistic and linear regression were used to compare groups of subjects. Results: A total of 66 FM patients and 116 controls were recruited. Between FM patients and controls, comparable cardiovascular risk factors were found, including carotid IMT and metabolic syndrome. FM patients had a higher proportion of central adiposity when compared with the controls, with an odds ratio of 6.1 (95% CI: 2.9, 13.1). Fibromyalgia patients had a more severe hepatic steatosis, if present, as determined by the Hamaguchi score. In female subjects, FM patients had a higher proportion of MASLD when compared with the controls, with an odds ratio of 2.8 (95% CI: 1.3, 6.1). The disease severity was associated with left IMT value and lipid blood levels in FM patients. Conclusion: Fibromyalgia patients had a higher proportion of central adiposity and more severe hepatic steatosis when compared with the controls. Those patients with more severe FM symptoms likely had a higher cardiovascular risk. Metabolic dysfunction–associated steatotic liver disease merits more attention in FM patients.Cite this article as: Chen C, Chen Y, Chen D, Yang S, Tang K. Metabolic syndrome and metabolic dysfunction-associated steatotic liver disease in fibromyalgia. Arch Rheumatol. 2025;40(4):452-458.

The APLAR has published a set of recommendations on the management of systemic lupus erythematosus (SLE) in 2021. The current consensus paper supplements and updates specifically the treatment of lupus nephritis (LN) according to two rounds of Delphi exercise from members of the APLAR SLE special interest group, invited nephrologists, histopathologists, and lupus nephritis patients. For initial treatment of LN, we recommend a combination of glucocorticoids (GCs) with cyclophosphamide (CYC), mycophenolate mofetil (MMF), or the calcineurin inhibitors (CNIs) as first-line options. An upfront combination of immunosuppressive drugs and the biological agents may be considered in patients at significant risk of disease progression and renal function deterioration. Switching or "add-on" among different immunosuppressive agents, including biological agents, may be considered for refractory disease. Subsequent/maintenance therapy of LN should continue for at least 3 years to reduce the risk of renal flares. Lower dose MMF and azathioprine are options, but MMF maintenance should follow induction by the same drug. Prednisolone or equivalent should be maintained at a dose of 5 mg/day or less. The APLAR consensus for the management of LN includes recommendations for adjunctive therapies, monitoring and treatment of LN-related co-morbidities, and renal replacement therapies. It is hoped that this consensus paper can provide an evidence-based and pragmatic approach to the management of LN, taking into account the evidence level of therapies in Asian patients, cost-effectiveness, and differences in health care resources and reimbursement policies in the Asia-Pacific region.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced serum immunoglobulin (Ig) levels and is typically caused by immunosuppressive therapy or certain diseases. Patients with systemic autoimmune rheumatic diseases (SARDs) and hematological malignancies are particularly susceptible to developing SHG due to underlying diseases and the use of immunosuppressive medications, such as B-cell-targeted agents. Consequently, SHG significantly contributes to increased risks of severe infections and mortality in SARDs patients. Considering the lack of a unified strategy for managing SHG, the Taiwan College of Rheumatology (TCR) aimed to formulate consensus recommendations for the screening, diagnosis, and management of SHG. These recommendations were developed based on emerging evidence during a face-to-face meeting of the TCR committee (nine immunologists and rheumatologists), and utilizing the modified Delphi process. This meeting involved a comprehensive review of the current evidence, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Thirteen consensus recommendations were developed to emphasize the importance of early detection and optimal treatment of SHG. Furthermore, effective prevention of infections through risk assessment alongside timely and regular monitoring of IgG levels was highlighted. The recommendations also included anti-infective therapies and intravenous Ig replacement, offering valuable guidance to rheumatologists in managing SHG. This consensus will be regularly updated as newer evidence emerges.

Current serological markers for rheumatoid arthritis (RA) lack sensitivity in early or seronegative disease. We evaluated anti-BR1 antibodies, targeting a Porphyromonas gingivalis RgpA-derived peptide, as a novel biomarker. From 15 peptides screened in a training cohort, BR1 showed the highest diagnostic potential (AUC = 0.9553). In an independent validation cohort, anti-BR1 demonstrated an AUC of 0.7668, with 58.6 % sensitivity and 97.0 % specificity based on a ROC-derived cutoff. Anti-BR1 antibodies were detected in 82 of 140 (58.6 %) RA cases, including 35 of 58 (60.3 %) seronegative patients, and in 16 of 38 (42.1 %) early arthritis (EA) cases, outperforming RF and ACPA. Combining anti-BR1 with RF and ACPA increased the diagnostic yield from 58.6 % to 83.6 % in RA, and from 26.3 % to 55.3 % in EA.

OBJECTIVES:To maximize the cost-effectiveness of tofacitinib, one of the Janus kinase inhibitors, there is an unmet need to identify predictors of therapeutic response. Utilizing phage immunoprecipitation sequencing (PhIP-Seq), we aim to identify peptide biomarkers for predicting good response to tofacitinib in rheumatoid arthritis (RA) patients. METHODS:We enrolled 106 patients who had received 24-week tofacitinib therapy, including 12 patients undergoing PhIP-Seq analysis in the discovery stage and 94 patients validated with enzyme-linked immunosorbent assay (ELISA) in the replication stage. Disease activity was assessed using the 28-joint disease activity score-erythrocyte sedimentation rate, and therapeutic response was evaluated using EULAR response criteria. Plasma levels of caspase-1 and IL-18 were determined using ELISA. RESULTS:PhIP-Seq analysis identified antibodies to sucrose non-fermenting-related kinase (SNRK) and HUWE1 (ubiquitin E3 ligase) as peptide biomarkers for discriminating good responders from the non-good responders. Using ELISA for validation on another cohort, an optimal cut-off value of anti-SNRK antibody for predicting good response was 0.381, with AUC 0.823, specificity 80.6% and sensitivity 78.1% (P = 3.01E-07), and anti-HUWE1 antibody at 0.362, with AUC 0.740, specificity 74.2% and sensitivity 62.5% (P < 0.001). Plasma levels of anti-SNRK and anti-HUWE1 antibodies were positively correlated with levels of caspase-1 and IL-18 (both P < 0.05). Multivariate logistic regression analysis revealed anti-SNRK antibody as a significant predictor of good therapeutic response. After tofacitinib therapy, anti-SNRK antibody levels significantly declined in good responders, but not in non-good responders. CONCLUSION:We identify two peptide antibodies, anti-SNRK and anti-HUWE1 antibodies, as pretreatment predictors of good therapeutic response to tofacitinib in RA patients.

PV260 / #333 Poster Topic:AS24 - SLE-Treatment Systemic lupus erythematosus (SLE) exhibits diverse clinical presentations and requires regionally-specific management strategies. Building upon established international guidelines, The Taiwan College of Rheumatology developed the first set of recommendations for SLE management to focus on the unmet needs in clinical practice in Taiwan. This consensus aims to empower healthcare professionals and optimize patient outcomes in Taiwan. Rheumatologists from various practicing institutions formed a 15-member panel, through a modified Delphi process, developed consensus statements, which encompasses various aspects of SLE care in Taiwan, including screening and diagnosis; disease monitoring; treatment strategies; and pregnancy. The expert panel reviewed and refined statements through 2 meetings with anonymous voting based on a 5-point Likert scale. Consensus is defined as ≥75% agreement to the proposed statements. In total, 32 statements achieved consensus. These statements incorporate the latest scientific evidence with insights from Taiwanese experts to address the unique disease characteristics and challenges faced by patients in the region. These could serve as a guide to specialists, family physicians, specialty nurses, and other healthcare professionals in Taiwan in the management of SLE.

Background: We aimed to investigate the risk for a serious infection in rheumatoid arthritis (RA) patients after tapering the dose of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Methods: This nested case–control study investigated the risk for a serious infection in RA patients who underwent mandatory b/tsDMARDs dose reduction 2.5 years after starting therapy with a single b/tsDMARD in the National Health Insurance Research Database (NHIRD). Cases were those patients who developed a serious infection afterwards. Matched controls were selected from those patients who did not develop a serious infection. We used unconditional logistic regression to analyze the odds ratios (ORs) of b/tsDMARDs dose reduction and discontinuation between cases and controls. Results: RA patients underwent an average dose reduction of 60%. Among a total of 268 cases and 1072 controls, we did not observe a lower risk for a serious infection in those patients who tapered or discontinued b/tsDMARDs. However, those patients who had discontinued b/tsDMARDs had a higher risk for a serious infection when compared with those who had not and had reduced their b/stDMARDs dose reduction below the average (i.e., ≤60%), with an adjusted OR of 1.48 (95%CI: 1.05, 2.09). Conclusions: Dose reduction in b/tsDMARDs in RA patients might not be associated with a lower risk for serious infection. Discontinuation of b/tsDMARDs, however, was likely associated with a higher risk for serious infection.