A percutaneous conchotome muscle biopsy, which is a semi-open technique, provides significant diagnostic yield, especially for inflammatory myopathies. In patients with small vessel vasculitis, muscle involvement could sometimes be the sole or most prominent organ involvement. While open muscle biopsy has been reported to be useful for the diagnosis of vasculitis, the diagnostic utility with conchotome muscle biopsy for vasculitis remains unclear. Here, we report four cases in which a conchotome muscle biopsy made a significant contribution to their diagnosis of small vessel vasculitis. All cases presented with myalgia and weakness at the onset of their diseases, and with an elevation of myeloperoxidase antineutrophil cytoplasmic antibodies. Pathological examination of muscle tissues revealed significant inflammatory infiltration with fibrinoid necrosis in perimysial arterioles, measuring 50-100 mm in diameter, in all of four cases. Disruption of the elastic plates of the arterioles was found with Elastica van Gieson staining in three cases. Low levels of patients' pain, evaluated with a visual analogue scale (0-100), ranging from 0 to 30, and no occurrence of adverse events in our cases indicated the safety of this technique. All patients were treated successfully with glucocorticoids, with or without immunosuppressants. The conchotome muscle biopsy could yield the pathological features of small vessel vasculitis with minimal invasiveness.

Multidisciplinary genomic evaluation is increasingly recognized for its diagnostic and therapeutic implications in adults with suspected inborn errors of immunity (IEI) presenting with rheumatic and musculoskeletal disease (RMD) phenotypes. We retrospectively analyzed 50 adults with suspected IEI who underwent genetic testing and were pre-classified into immunodeficiency (ID), autoinflammatory disorders (AID), and non-ID/AID groups. Genetic findings, clinical classification, treatment modifications, and exploratory machine learning analyses were evaluated. A final genetic diagnosis consistent with IEI was identified in 15 patients (30.0%), with the highest yield in the non-ID/AID group (44.4%). Variants were most frequently associated with autoinflammatory diseases (40.0%). Four patients, all initially classified as non-ID/AID, were reclassified based on genetic findings and IUIS classification. Treatment was modified in 12 patients, including eight genetically diagnosed patients and three genotype-driven interventions. Two patients died from disease-related complications. Machine learning analyses provided heterogeneous feature contributions across groups. These findings highlight the utility of multidisciplinary genomic evaluation for refining diagnoses in challenging adult patients.

OBJECTIVES:To investigate the achievement of complete remission (CR) and the management for relapsed cases in the treatment of idiopathic inflammatory myopathies (IIM). METHODS:A total of 132 patients were retrospectively analysed. CR was defined as no evidence of disease activity in all involved organs for a continuous period of six months. Relapse was defined as a dose increase of glucocorticoid (GC) more than 50% and an increase in prednisolone (PSL) equivalent to more than 0.4 mg/kg/day. Clinical data were collected by electrical chart review. RESULTS:Eighty-eight (66.7%) patients achieved CR with an initial treatment. Forty-three patients experienced at least one relapse. Anti-ARS antibody was positively and achieving CR was negatively associated with relapse (HR 3.02 and OR 0.17, respectively). Re-induction therapies were classified into three groups: high-dose GC plus one immunosuppressant (IS)/biologics (H+1IS, n=12), moderate-dose GC plus two IS/biologics (M+2IS, n=12), and moderate-dose GC plus one IS/biologics (M+1IS, n=19). The frequency of second relapse was least in M+2IS regimen. Concomitant use of two IS/biologics did not increase the incidence of severe adverse events. CONCLUSIONS:CR was achieved in two-thirds of IIM patients. Achieving CR was protective for relapse. Combination therapy with two IS/biologics might be preferable in relapsed cases.

Objectives To quantify the clinical burden and healthcare resource use (HCRU) associated with difficult-to-treat (D2T) rheumatoid arthritis (RA) compared with non-D2T RA and evaluate clinical characteristics and factors associated with D2T RA as well as treatment patterns in Japan. Design Longitudinal, retrospective observational study using electronic medical record data from 1992 to 2024 and a physician survey administered between November 2022 and November 2025. Setting A single academic medical centre real-world clinical practice setting in Japan. Participants A total of 1581 patients with RA were included. Primary and secondary outcome measures The primary outcome measures were the comparisons of clinical burden and HCRU in the D2T RA group compared with the non-D2T RA group. D2T RA status was defined according to the European Alliance of Associations for Rheumatology definition. Clinical burden included disease activity, physical function, patient-reported outcomes, serological markers and renal function. HCRU included outpatient visits and hospitalisations evaluated over 12-month, 24-month and 36 month windows pre-index using overlap weighting and regression models. Factors associated with D2T RA status were evaluated using logistic regression. Treatment patterns were reconstructed longitudinally as lines of therapy across biologic and targeted synthetic disease-modifying antirheumatic drugs. Results Among 1581 patients with RA, 102 (6.5%) met the D2T criteria. Treatment trajectories showed earlier escalation and frequent switching across biologic and targeted synthetic disease-modifying antirheumatic drugs in the D2T RA group. The D2T RA group had modestly elevated outpatient visit rates (rate ratio 1.08–1.09) and were more likely to be hospitalised (OR 4.35–6.12) than the non-D2T RA group. Factors associated with D2T RA included RA onset at age <50 (adjusted OR versus ≥50 years: 2.01, 95% CI 1.19 to 3.39), female sex (2.38, 95% CI 0.95 to 5.94) and pulmonary comorbidities (2.82, 95% CI 1.38 to 5.74). Conclusions In this real-world Japanese cohort, D2T RA was associated with higher disease burden and HCRU, particularly hospital-based care. Earlier identification and targeted management of D2T RA may help reduce the overall clinical and healthcare burden in RA.

ObjectiveTo evaluate the effectiveness of a lower initial glucocorticoid (GC) dose (0.4-0.6 mg/kg/day) compared to the conventional dose (0.8-1.2 mg/kg/day) in achieving complete renal response (CRR) at 12 months in Japanese patients with proliferative lupus nephritis (LN).MethodsThis multicentre, retrospective observational study analyzed data from 344 Japanese patients diagnosed with LN (class III or IV ± V) via renal biopsy. Patients were divided into two groups based on their initial dose of GC. 1:1 propensity score matching (PSM) based on key baseline variables, 23 patients were included in each group. The primary endpoint was CRR at 12 months, defined according to the BLISS-LN trial criteria. A non-inferiority margin of -10% was prespecified.ResultsAfter PSM, the CRR rate at 12 months was 87.0% in the low-dose group and 73.9% in the conventional-dose group (risk difference: 13.1%; 95% confidence interval [CI]: -9.4% to 35.6%), confirming statistical non-inferiority. While GC doses differed significantly during the initial 3 months, they became comparable between the groups after 6 months.ConclusionA reduced initial GC dose of 0.4-0.6 mg/kg/day achieved renal outcomes comparable to conventional dosing in Japanese patients with LN. Given the risks of GC toxicity, these findings may support the potential for lower-dose GC strategies in LN treatment.

OBJECTIVE:We investigated the role of GLI3, a transcription factor highly expressed in the pathogenic THY1+CD34- sublining subset of rheumatoid arthritis synovial fibroblasts (RASFs), in regulating their pathogenic behavior. METHODS:GLI3 protein levels were quantified in freshly isolated RASF subsets by Western blotting. Bulk RASFs were subjected to siRNA-mediated knockdown (KD) of GLI3 or GLI1, followed by RNA sequencing. The effects of GANT61 on RASF proliferation, cell-cycle progression, migration, viability, and apoptosis were assessed using EdU/PI analysis, scratch assays, CCK-8 assays, and Annexin V/PI flow cytometry. RESULTS:GLI3 expression was enriched in THY1+CD34- RASFs at both mRNA and protein levels. GLI3 KD increased GLI1 expression and upregulated genes involved in inflammation, matrix remodeling, and cell cycle regulation, including IL6, IL11, IL24, IL33, MMP3, PLAU, CCNA2, and E2F1. Pathway enrichment analysis revealed activation of ECM-receptor interaction, PI3K-Akt, and TNF signaling. Co-silencing GLI1 with GLI3 blunted the induction of IL11, IL24, IL33, CCNA2, E2F1, and PLAU observed with GLI3 KD alone, indicating that GLI1 mediates a subset of the transcriptional effects induced by GLI3 loss. GANT61 suppressed CCNA2 and E2F1 expression, inhibited RASF proliferation and migration, and did not markedly increase apoptosis. CONCLUSION:GLI3 functions as a negative regulator of GLI1 and its downstream targets that drive the pathogenic behavior of RASFs. Targeting the GLI1-GLI3 axis may represent a promising therapeutic strategy to modulate fibroblast-driven inflammation and joint destruction in RA.

Objectives:While recent guidelines recommend early glucocorticoid (GC) tapering for LN, supporting evidence for pure membranous LN remains limited. The present study investigated the impact of rapid GC tapering on renal outcomes in this population. Methods:We performed a multicentre retrospective study across 16 centres in Japan, including 67 patients with biopsy-proven pure membranous LN who initiated GC therapy between 2003 and 2023. Patients were classified into rapid tapering (GC dose ≤7.5 mg/day at 6 months) and conventional tapering (>7.5 mg/day at 6 months) groups. The primary endpoint was the partial renal response (PRR) at 12 months. Secondary endpoints included the complete renal response (CRR), relapse and severe adverse events (SAEs). Adjusted risk ratios (aRRs) were estimated using modified Poisson regression models for failure to achieve PRR/CRR. Results:Fifteen patients underwent rapid tapering and 52 conventional tapering. Baseline characteristics were generally comparable. At 12 months, PRR was achieved in 85.7% of the rapid group and 84.3% of the conventional group (aRR for failure 1.04; 95% CI 0.17-6.39). CRR rates at 12 months were 64.3% and 56.9%, respectively (aRR for failure 0.90; 95% CI 0.40-2.02). At 24 months, PRR and CRR did not differ statistically between groups. Relapse occurred in 20.0% versus 7.7% (P = 0.185). No SAEs were reported in the rapid group, while three occurred in the conventional group. Conclusions:Rapid GC tapering to ≤7.5 mg/day at 6 months appeared feasible in a subset of patients with pure membranous LN, but the findings are preliminary and should be interpreted cautiously because of the small rapid-taper group and imprecise estimates.

To investigate clinical features and physical function in rheumatoid arthritis (RA) in remission with and without glucocorticoid (GC). Data from 2078 RA patients aged 55–84 years in remission (simplified disease activity index (SDAI) ≤ 3.3) and at stage I/II according to the Steinbrocker classification were extracted from the National Database of Rheumatic Diseases in Japan (NinJa) which includes 11,036 patients from 2017 to 2018 before the coronavirus pandemic. Patients were stratified into six groups: RA aged 55–64, aged 65–74, and aged 75–84 with or without GCs. The primary outcome was the health assessment questionnaire disability index (HAQ-DI) > 0.5, and interactions of age and GC use on the HAQ-DI > 0.5 were examined by multivariable logistic regression. GC use in patients in remission increased with age. Methotrexate and biological disease-modifying antirheumatic drug prescriptions were similar in patients aged 75–84 with and without GC. Significantly more GC users aged 75–84, but not aged 65–74 and 55–64, had a HAQ-DI > 0.5 than GC non-users (23.9

Background: Long COVID is a condition that may arise following SARS-CoV-2 infection and is associated with a range of systemic complications. Autoantibodies are implicated in the pathogenesis of long COVID. However, the details of the pathogenic mechanisms undergone by these autoantibodies remain unclear. Neural cell adhesion molecule 1 (NCAM1) is the human protein with the highest sequence homology to the SARS-CoV-2 proteins. Previous in silico studies indicate that SARS-CoV-2 infection may induce the production of anti-NCAM1 autoantibodies. Thus, this study investigated the presence of anti-NCAM1 autoantibodies in individuals affected by COVID-19, including those with long COVID. Methods: Serum samples were obtained from 173 individuals 3 months after SARS-CoV-2 infection. Among them, 63 were diagnosed with long COVID. A cell-based assay was used to assess all 173 serum samples for the presence of anti-NCAM1 autoantibodies. We also analyzed the clinical profiles of patients with and without long COVID to identify potential risk factors associated with long COVID. Results: Anti-NCAM1 autoantibodies were not detected in any serum sample. The proportion of female patients in the long COVID group was significantly higher than that in the non-long COVID group. Conclusion: The results indicate that the production of anti-NCAM1 autoantibodies following COVID-19 is unlikely. Female sex is associated with higher risk of long COVID.

Familial Mediterranean fever (FMF) is an autoinflammatory disease associated with mutations in MEFV, which encodes pyrin. Patients with FMF present intermittent high fever with elevated inflammatory markers during periodic attacks. While some forms of vasculitis, including immunoglobulin A (IgA) vasculitis and polyarteritis nodosa have been reported in some patients with FMF, Takayasu arteritis (TAK) rarely associated with FMF. In addition, little has been known about the clinical features and pathogenesis of vasculitis with FMF. Here we report a case of FMF with TAK. Our case is remarkable on his clinical course of neck pain with low-grade elevation of serum C-reactive protein during interictal periods of fever attacks. He possessed the dual genetic background of a pathogenic variant of p.M694V in MEFV and HLA-B*52:01, which is susceptible to TAK. Although he was refractory to the combination therapy with colchicine, corticosteroids, and methotrexate, tocilizumab was effective for both recurrent fever attacks and vasculitis. Previous four reports of FMF with TAK as well as our case suggest the pathogenic MEFV mutation could be a predisposing or additional factor that modify the development of TAK. Since both the activity of FMF and TAK responded to tocilizumab in our case, the pathogenesis shared between FMF and TAK was indicated.

The EORTC/MSGERC definition lacks sufficient sensitivity for diagnosing invasive pulmonary aspergillosis (IPA) in patients with autoimmune inflammatory rheumatic diseases (AIIRDs). We hypothesized that the partial fulfillment of the EORTC/MSGERC definition can improve its diagnostic sensitivity. This retrospective observational study included patients with AIIRDs on immunosuppressive therapy who underwent serum galactomannan antigen testing for suspected IPA. Patients who fulfilled the clinical features or mycological evidence as per the EORTC/MSGERC definition were considered as having "potential IPA." We compared the clinical characteristics of 364 patients who were categorized into 3 groups-potential IPA (n = 29), proven/probable IPA (n = 24), and non-IPA (n = 311; not meeting any definition). The potential and proven/probable IPA groups had significantly lower survival rates than the non-IPA group (p < 0.001). The potential IPA (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.1-3.8) and proven/probable IPA (aHR, 2.6; 95% CI, 1.4-4.9) were independent risk factors for mortality. Compared with the EORTC/MSGERC definition, our proposed criteria improved sensitivity based on the diagnosis at the end of observation (50.0%, 100.0%, respectively). The characteristics and mortality rates of patients were similar between the potential and proven/probable IPA groups. Using these criteria for clinical diagnosis may provide high sensitivity.

Background: Post-acute COVID-19 Syndrome (PACS) occurs in some COVID-19 patients long after acute infection and significantly affects patients' health. However, the mechanism by which PACS develops is unknown. Myosin light chain 9 (Myl9), produced by activated platelets, plays a role in immune dysregulation and microthrombi formation during acute COVID-19. However, in the PACS phase, the association between Myl9 and residual symptoms remains unclear, and further investigation is needed. Methods: In this prospective cohort study, serum Myl9 concentrations were measured in 195 COVID-19 patients during hospitalization and at 3- and 6-month follow-up visits. Gaussian mixture modeling was used to identify groups on the basis of Myl9 levels. Relationships between Myl9 levels and residual symptoms were evaluated. Clinical characteristics influencing Myl9 levels were analyzed via logistic regression. Results: A total of 304 serum samples from 195 patients were collected. Two distinct groups were identified in the Myl9 distribution with a cutoff of 386 ng/mL by Gaussian mixture modeling in this cohort. The high-Myl9 group presented significant residual respiratory symptoms at 6 months post-infection (p < 0.05). Elevated Myl9 levels at 6 months were correlated with increased neutrophil counts (p < 0.01) and respiratory comorbidities at diagnosis (p < 0.05) according to univariate regression analysis. Multivariate regression analysis confirmed the relationship between the neutrophil count and high Myl9 levels. Conclusion: Prolonged high Myl9 levels are associated with respiratory symptoms, suggesting the potential involvement of prolonged inflammation or endothelial damage in PACS.

OBJECTIVES:Recent guidelines and recommendations for LN suggest rapid glucocorticoid (GC) reduction; however, robust supporting evidence remains limited. This study aimed to evaluate the impact of rapid GC reduction on renal outcomes in patients with proliferative LN. METHODS:We conducted a multicentre retrospective chart review of patients with GC-naïve, biopsy-proven proliferative LN with available urinary protein-to-creatinine ratio (UPCR) data before and 52 weeks after GC treatment. Patients who reduced their prednisolone-equivalent dose to ≤7.5 mg/day within 6 months (rapid GC reducers) were compared with those who did not (conventional GC reducers) regarding partial renal response (PRR) at 12 months. Modified Poisson regression analysis was used to adjust for confounding factors. RESULTS:A total of 344 patients from 17 centres were included: 50 rapid GC reducers and 294 conventional GC reducers. PRR at 12 months was achieved by 43/50 (86%) in the rapid GC group and 248/294 (84.4%) in the conventional group. After adjusting for age, initial UPCR, initial estimated glomerular filtration rate, the presence of a concomitant membranous lesion in the glomerulus, initial GC dose, use of methylprednisolone pulse therapy, strong immunosuppressants (mycophenolate mofetil, cyclophosphamide or rituximab) and hydroxychloroquine, no significant difference was observed in PRR at 12 months (adjusted risk ratio: 0.92, P = 0.758). Relapse rates and serious adverse events over 2 years of follow-up were also comparable between the groups. CONCLUSION:Rapid GC reduction to ≤7.5 mg/day within 6 months did not compromise renal outcomes or increase relapse in proliferative LN.

In severe COVID-19 patients, excessive inflammation can lead to multiorgan dysfunction. Current anti-inflammatory treatments like glucocorticoids partially improve the outcomes, while immune systems are compromised. We have identified that SARS-CoV-2-infected obese mice were a good model of the cytokine storm seen in COVID-19. Here, we revealed that iguratimod (IGU), an approved agent for rheumatoid arthritis, improved survival by attenuating inflammation with minimal immune suppression. In this study, C57BL/6 mice were fed a high-fat diet (HFD) or a normal-fat diet (NFD) for ten weeks before being infected with a mouse-adapted SARS-CoV-2. IGU significantly improved survival rates and reduced lung inflammation in HFD-fed mice, with minimal impact on interferon-induced genes and viral load. Meanwhile, dexamethasone (DEX) did not improve survival, while it suppressed various immune reactions with different mechanisms to IGU. Interestingly, IGU-treated mice had fewer SARS-CoV-2 positive cells in the lung, although viral replication was comparable to the control mice. Neither IGU nor DEX inhibited the SARS-CoV-2 infection in Vero-E6 cells, unlike the antiviral agent, remdesivir. Of note, IGU was effective prophylactically and therapeutically in HFD mice, and showed beneficial effects in NFD-fed mice with a lethal dose exposure of SARS-CoV-2. We demonstrated that IGU could be a promising treatment for severe COVID-19, especially in obese patients, by fine-tuning inflammation without compromising antiviral immunity. This study supports the possibility of drug repositioning for IGU COVID-19 beyond autoimmune diseases.

OBJECTIVE:To identify the factors that inhibit human papilloma virus (HPV) vaccination to improve the high HPV infection rate and cervical cancer incidence among SLE patients. METHODS:We conducted a questionnaire survey of female SLE patients aged 18-45 years attending our hospital to analyze factors related to HPV vaccination. RESULTS:We obtained responses of 88 participants. Only 5 (5.7%) were received HPV vaccination, 15 (17.0%) were uncertain of their vaccine history, and 27 (30.7%) had never even heard of HPV vaccination. The reasons for unvaccinated against HPV were "don't know" with 24 participants, "missed opportunity" with 15, and "troublesome, somehow" with 8. The most trusted source of medical information for the unvaccinated was their physician (69, 60.2%). Among the unvaccinated, those who wished to be vaccinated in the future were positively correlated with "trust of vaccine benefit" (r = 0.561, p = 0.005) and "general knowledge about HPV vaccine" (r = 0.512, p = 0.013), and negatively correlated with "negative attitudes toward vaccination and vaccine policy" (r = -0.547, p = 0.007). CONCLUSION:HPV vaccination rate among SLE patients in Japan was extremely low. The main reason was lack of knowledge. The most effective solution is considered to provide accurate information and adequate recommendations of HPV vaccination by attending physicians.

T cell receptor rearrangement excision circles (TRECs) and immunoglobulin κ-deleting recombination excision circles (KRECs) represent the lymphopoiesis capacity, widely used for newborn screening of inborn errors of immunity. To clarify the significance of TRECs and KRECs as immune indicators in patients with systemic autoimmune diseases, we prospectively evaluated TREC and KREC levels with qPCR, lymphocyte phenotypes with flow cytometry, along with lymphocyte counts and serum immunoglobulin levels in peripheral blood samples from newly diagnosed patients. Each variable was assessed before immunosuppressive treatments (baseline), 3-, 6-, and 12-months after the treatment. Severe infections were recorded until 6 months after treatment. Among 35 patients, TREC and KREC levels were associated positively with the proportion of recent thymic emigrants, naïve T and B cells at all the timepoints. TREC and KREC levels decreased after treatment. The ratios of TREC and KREC levels under treatment to baseline were significantly lower in patients with severe infection than those without. In conclusion, TREC and KREC levels reflect peripheral blood immunophenotypes, specifically recent-emigrated T and B cells, in patients under treatment-naïve and immunosuppressive conditions. The longitudinal changes in TREC and KREC levels were beneficial markers for predicting the risk of severe infection during immunosuppressive treatments.