Yuya Kondo

Objectives: Eosinophilic granulomatosis with polyangiitis (EGPA) is classified as a subtype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A recent genome-wide association study (GWAS) of EGPA in populations of European ancestry reported several susceptibility loci. In view of population differences in genetic factors of AAV, we made an attempt to examine the contribution of these loci to EGPA in a Japanese population. Methods: The EGPA-associated variants in LPP , TSLP , IRF1 / IL5 , HLA , CDK6 , 10p14 and 12q21 in European populations (EUR) were analysed in a total of 103 Japanese patients with EGPA, including 48 myeloperoxidase (MPO)-ANCA-positive and 45 ANCA-negative patients. Allele frequency data on approximately 60 000 Japanese individuals from the Japanese Multi Omics Reference Panel served as the controls. Results: An increasing tendency in TSLP rs1837253 C allele was observed in total EGPA, MPO-ANCA-positive EGPA and ANCA-negative EGPA. In addition, association of HLA-DRB1*07:01 was observed in total EGPA and MPO-ANCA-positive EGPA. These findings supported the previous findings in the EUR. On the other hand, unlike in the EUR, association of DRB1*09:01 was observed in Japanese EGPA. With respect to amino acid residues in HLA-DRβ1, Val 78 encoded by DRB1*07:01 and * 09:01 was associated with total EGPA and MPO-ANCA-positive EGPA with genome-wide significance (pTSLP was suggested to be associated with EGPA both in the European and Japanese populations regardless of the ANCA status. In HLA-DRB1 , both shared and population-specific susceptibility alleles were observed.

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.

Temporal arteritis with marked eosinophilic infiltration is uncommon and can present as either a localized arteritis or a manifestation of systemic eosinophilic disease. We report a 48-year-old woman who presented with fatigue, intermittent fever, and bilateral painful cord-like swelling in the frontal region. Laboratory tests showed marked eosinophilia and elevated total IgE with mild inflammation, while anti-neutrophil cytoplasmic antibodies were negative. Biopsies of both superficial temporal arteries demonstrated transmural eosinophilic infiltration with disruption of the internal elastic lamina and intraluminal thrombosis without giant cells or granulomas. During follow-up, the patient developed hepatobiliary enzyme elevation, and biopsies of the esophagus, liver, and a breast mass confirmed eosinophilic infiltration. Bone marrow examination showed eosinophilic hyperplasia without evidence of a myeloproliferative neoplasm and no FIP1L1-PDGFRA fusion was detected. These findings supported a diagnosis of hypereosinophilic syndrome (HES) with temporal artery involvement. Prednisolone improved systemic symptoms, but temporal arteritis relapsed during tapering and was refractory to methotrexate. The addition of mepolizumab achieved sustained remission and enabled further glucocorticoid (GC) reduction. This case highlights that bilateral or GC-dependent eosinophilic temporal arteritis warrants evaluation for systemic eosinophilic disorders, and suggests that IL-5 blockade can be an effective GC-sparing strategy in HES.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement. It is known that cytokines produced from activated CD4+ T cells play a pivotal role in the development of SLE; however, the details of pathological processes remain unclear. The purpose of this study is to elucidate the role of activated CD4+ T cells on the pathogenesis of lupus using SLE murine models induced by toll like receptor 7 agonist imiquimod (IMQ). Lupus was induced in wild-type (WT) and interferon γ (IFNγ)-deficient (IFNγ−/−) mice by topical IMQ treatment. Splenic T and B cell subsets were analyzed by flow cytometry. CD4+ T cells and B cells were isolated for co-culture to assess B cell differentiation and IgG production. Comprehensive lupus-like phenotypes were evaluated. Single-cell RNA sequencing (scRNA-seq) was performed to characterize IFNγ-associated cellular and molecular pathways. IMQ treatment increased IFNγ-producing CD4+ T cells, along with Tfh cells, Tph cells, age-associated B cells, and plasma cells in WT mice. CD4+ T cells from IMQ-treated WT mice promoted B-cell differentiation and IgG production in co-culture assays. In IFNγ−/− mice, lupus-like phenotypes were significantly attenuated, and co-cultured B cells showed reduced differentiation and IgG production. Single-cell RNA sequencing revealed that IFNγ plays a critical role in promoting B cell differentiation and autoantibody production. IFNγ derived from activated CD4+ T cells plays a critical role in driving B-cell differentiation and promoting autoantibody production in IMQ-induced lupus.

Objectives: Rituximab (RTX) is a key treatment for ANCA-associated vasculitis (AAV), but RTX-induced acute thrombocytopenia (RIAT) remains a concern. We aimed to evaluate the risk and risk factors of RIAT in patients with AAV undergoing RTX induction therapy. Methods: Patients with new-onset microscopic polyangiitis or granulomatosis with polyangiitis who received RTX in a nationwide multicentre registry in Japan were included. RIAT was defined by platelet count reductions within 28 days post-RTX. Risk factors for RIAT were identified by using logistic regression with stepwise selection, and prediction models were developed. Model performance was assessed using C-statistics. Results: Among 175 patients with AAV receiving RTX, RIAT occurred in 35.4% of them. Diabetes mellitus (odds ratio [OR] = 4.96), cardiac disease (OR = 3.57), low platelet count (OR = 1.04 per 104/μl decrease), increased serum creatinine (OR = 1.44 per 1 mg/dl increase), low albumin (OR = 2.33 per 1 g/dl decrease), and high KL-6 (OR = 1.09 per 100 U/ml increase) were identified as significant predictors. A predictive model incorporating these factors achieved a C-statistic of 0.817. Conclusion: RIAT is a frequent complication of RTX induction in patients with AAV, with diabetes mellitus and cardiac disease being strong risk factors. Our predictive model enables risk assessment for RIAT, allowing clinicians to optimize treatment strategies.

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.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody positive clinically amyopathic dermatomyositis (CADM) is a subtype of inflammatory myopathy associated with a distinct clinical phenotype, characterized by rapidly progressing interstitial lung disease and limited muscle involvement. Although cases with onset of anti-MDA5 antibody positive CADM during pregnancy or the postpartum period are rare, they present unique challenges due to a potential pregnancy complications and the possible severity of the disease course. We present a case of anti-MDA5 antibody positive CADM that developed during the postpartum period following childbirth without any pregnancy complication. Additionally, we conducted a comprehensive review of case reports and series of similar cases to elucidate the clinical characteristics and outcomes. Our analysis revealed considerable variability in disease presentation, ranging from severe cases requiring multi-targeted therapy to well-controlled cases with less demanding treatments. The scarcity of evidence in this population underscores the importance of accumulating evidence from case series to inform treatment strategies. More precise prediction tools are needed to effectively manage this rare subset of patients.