Isao Matsumoto

Aim: To investigate seasonal patterns in new‐onset antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) during the coronavirus disease 2019 (COVID‐19) pandemic in Japan. Methods: We conducted a retrospective cohort study using data from the nationwide multicenter registry of patients with AAV. Patients newly diagnosed with AAV between 2017 and 2022 were included, comprising microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). We compared the seasonal distribution of AAV onset between the pre‐COVID‐19 (2017–2019) and COVID‐19 (2020–2022) periods. Results: A total of 871 patients were included (499 before and 372 during the COVID‐19 period). Poisson regression analysis revealed a seasonal variation in AAV onset in the pre‐COVID‐19 period ( p < 0.001), with lower onset in autumn [incidence rate ratio (IRR) 0.64, p < 0.001] and higher onset in spring and summer (IRR 1.16, p = 0.048 and IRR 1.23, p = 0.005) compared to winter. Importantly, a significant interaction between season and period ( p for interaction = 0.032) indicated that the seasonal pattern differed between periods, with a relative increase in spring (IRR 1.16, p = 0.010). In the subanalyses, seasonal variation was consistently observed in MPA, but not in GPA and EGPA. The interaction between season and period was not statistically significant in each disease group. Conclusion: AAV exhibited a clear seasonal pattern, which differed during the COVID‐19 period. However, these differences were not consistently observed across individual disease subtypes, and the factors underlying them remain unclear.

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.

Objective: To compare clinicopathological phenotype-based, anti-neutrophil cytoplasmic antibody (ANCA) serotype-based, and unsupervised data-driven classifications in relation to clinical outcomes and patient heterogeneity in a large Japanese cohort with ANCA-associated vasculitis (AAV). Methods: This multicentre, retrospective cohort study analysed data from a nationwide Japanese registry of 729 newly diagnosed patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), all positive for myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA. Patients were classified by phenotype, serotype, combined phenotype-serotype groupings, and data-driven clustering based on baseline clinical and laboratory features. Associations with clinical outcomes—including mortality, relapse, and response to rituximab (RTX) versus cyclophosphamide (IVCY)—were evaluated using inverse probability of treatment weighting (IPW). Results: Phenotype-based classification more accurately distinguished all-cause mortality risk (MPA vs. GPA: hazard ratio [HR] 2.53, 95% CI 1.34–4.76). Combined phenotype-serotype analysis identified MPO-MPA patients with the highest mortality (HR 3.45, 95% CI 1.09-11.0, vs. PR3-GPA) and PR3-GPA with the highest severe relapse. Discordant groups, such as MPO-GPA, demonstrated unique clinical characteristics. After IPW adjustment, no significant difference in 24-week remission rates was observed between RTX and IVCY across classifications, both overall (RR 1.02, 95% CI 0.95–1.09) and within subgroups. Unsupervised clustering identified four distinct clinical subgroups, with limited concordance with conventional phenotype or serotype classifications. Conclusion: Phenotype and serotype classifications provide complementary, not competing, prognostic insights in Japanese patients with AAV. Data-driven clustering revealed additional clinical heterogeneity not captured by traditional systems, underscoring the need for integrated, multi-dimensional stratification approaches to improve personalised risk assessment and treatment strategies.

To evaluate the relationship between anti-neutrophil cytoplasmic antibody (ANCA) positivity and the disease characteristics, treatment, and prognosis of eosinophilic granulomatosis with polyangiitis (EGPA). We conducted a retrospective cohort study of patients with new-onset or severely relapsing ANCA-associated vasculitis, enrolled in the J-CANVAS registry. The clinical characteristics at baseline, treatments, and prognoses of ANCA-positive and ANCA-negative patients were assessed. Three patients with positive proteinase-3 ANCA were excluded, and 166 patients with EGPA (new onset, 159; severe relapse, seven) were included. Sixty-two patients were myeloperoxidase (MPO)-ANCA positive and 104 patients were negative. No differences in age or sex were observed between the two groups. The MPO-ANCA-positive group had significantly more frequent mucous membrane and eye involvement, more frequent renal involvement, higher total Birmingham Vasculitis Activity Score, higher neutrophil counts, and higher C-reactive protein levels at baseline. Although rituximab was administered more frequently in the MPO-ANCA-positive group, no other differences in treatment were found. Both groups had comparable estimated glomerular filtration rates and prednisolone doses at weeks 24 and 48. The incidence rates of severe relapse, minor relapse, and serious infectious diseases were comparable. Cox regression analysis revealed that MPO-ANCA positivity was not a significant factor in serious infectious diseases and relapse. Patients with MPO-ANCA-positive EGPA demonstrated different baseline clinical characteristics from MPO-ANCA-negative patients. However, subsequent relapses and serious infectious diseases were comparable.

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.

Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) is a major protein in serum and reported to be upregulated at the onset of rheumatoid arthritis (RA). Its citrullinated form, cit-ITIH4, is specifically found in the serum and synovial fluid of patients with RA. However, the detailed function of ITIH4 in arthritis remains unknown. The aim of this study was to clarify the role of ITIH4 and cit-ITIH4 using experimental arthritis models. ITIH4 and cit-ITIH4 expression was examined in steady-state mice and two different arthritis models, and their pathological effects were examined in Itih4-deficient mice. In naïve C57BL/6 (WT) mice, ITIH4 was expressed as mRNA in the liver and the lung and was expressed as protein in serum and hepatocytes. In K/BxN serum transferred arthritis (K/BxN-STA) and collagen-induced arthritis (CIA), ITIH4 and cit-ITIH4 in sera were increased before the onset of arthritis, and cit-ITIH4 was further increased at the peak of arthritis. In Itih4-deficient mice, citrullinated proteins in serum and joints, especially 120 kDa protein, were clearly diminished; however, there was no significant difference in arthritis severity between WT and itih^−/− mice either in the K/BxN-STA or CIA model. CIA mice also exhibited pulmonary lesions and itih4^−/− mice tended to show enhanced inflammatory cell aggregation compared to WT mice. Neutrophils in the lungs of itih4^−/− mice were significantly increased compared to WT mice. In summary, ITIH4 itself did not alter the severity of arthritis but may inhibit autoimmune inflammation via suppression of neutrophil recruitment.

IgG4-related disease (IgG4-RD) is a systemic condition in which IgG4⁺ plasma cell infiltration and fibrosis cause organ swelling and lead to diverse clinical manifestations. Although IgG4-RD typically responds to glucocorticoids (GCs), relapse during tapering occurs and an early GC-sparing approach might therefore be beneficial. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with multiple symptoms that is also treated with GCs as a first-line therapy. Recently, belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor, was approved, but reports of use for IgG4-RD are scarce. Here, we present a rare case of IgG4-RD complicated with SLE which was successfully treated with belimumab. A 67-year-old man was diagnosed with IgG4-RD based on a high serum IgG4 level and histopathological findings. Furthermore, he had pericardial effusion on echocardiography, and laboratory tests revealed thrombocytopenia, autoimmune hemolysis, positive anti-nuclear antibodies, positive anti-DNA antibodies, and hypocomplementemia. These data led to an SLE diagnosis. Treatment was started with prednisolone at 40 mg/day, plus hydroxychloroquine, which initially improved both the SLE and IgG4-RD symptoms. During the GC tapering, belimumab was added and clinical symptoms resolved completely. Our case and the literature review summarize reported rare overlapping cases of IgG4-RD and SLE and suggest that belimumab is a promising candidate for the treatment of IgG4-RD.

Objective: Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of DRB1*03:01 . With respect to DRB1*15:01 , strong linkage disequilibrium (LD) with a variant rs2105898T in the XL9 region, located between DRB1 and DQA1 and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, where DRB1*15:01 and DRB1*15:02 are commonly present and only DRB1*15:01 is associated with SLE, this study aimed to distinguish the genetic contribution of DRB1*15:01 and XL9 variants. Methods: Among the XL9 variants, two (rs2105898 and rs9271593) previously associated variants in the European populations and two (rs9271375 and rs9271378) which showed a trend towards association in a Japanese genome-wide association study were selected. Associations of the XL9 variants and HLA-DRB1 were examined in 442 Japanese SLE patients and 779 controls. Genotyping of the XL9 variants were performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by polymerase chain reaction-reverse sequence-specific oligonucleotide probes. Results: Among the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned on DRB1*15:01 . In contrast, the association of DRB1*15:01 remained significant after conditioning on the XL9 variants. Conclusion: In the Japanese population, HLA-DRB1*15:01 was found to be primarily associated with SLE, and to account for the apparent association of XL9 region. WHAT IS ALREADY KNOWN ON THIS TOPIC: The association of HLA-DRB1*03:01 with susceptibility to systemic lupus erythematosus (SLE) was reported to be secondarily caused by linkage disequilibrium (LD) with copy number reduction of C4 , which has the primary role. A possibility has been hypothesized that the association of HLA-DRB1*15:01 with SLE may possibly be caused by LD with XL9 region variants, associated with expression levels of HLA-class II; however, due to strong LD between DRB1*15:01 and XL9 variants, this hypothesis could not be addressed in the European populations. WHAT THIS STUDY ADDS: In the Japanese population, two common DRB1*15 alleles, DRB1*15:01 and DRB1*15:02 , are present, both in LD with XL9 variants. However, only DRB1*15:01 is associated with SLE. Leveraging the population difference in the genetic background, we demonstrated that DRB1*15:01 , rather than XL9 region variants, is primarily associated with SLE in the Japanese population. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY: This study provides us with critical information in understanding the respective roles of HLA genes and their regulatory regions in the development of SLE. This study also shows the usefulness of association studies in multiple populations with different genetic backgrounds in the identification of causative variants.

Recent studies have suggested that the clinical features of elderly-onset adult-onset Still’s disease (AOSD) differ from those of young and middle-aged-onset patients, whereas the details remain unclear, and cytokine profiles of elderly-onset AOSD have not been reported. To clarify the clinical features and cytokine profiles of elderly-onset AOSD, we examined patients with AOSD who developed the disease between January 2006 and September 2021. We divided the patients into the young and middle-aged-onset group (aged < 65 years) and the elderly-onset group (aged ≥ 65 years) and compared the groups in terms of patient characteristics, clinical symptoms, laboratory findings including serum interleukin (IL)-6 and IL-18, treatment, and prognosis. A total of 48 patients were examined (10 in the elderly-onset group). In the elderly-onset group, atypical rash was significantly more frequent, typical rash and splenomegaly were significantly less frequent, white blood cell count and neutrophil ratio were significantly higher and serum IL-6 levels were significantly lower. Serum IL-6 showed a significantly negative correlation with age at onset. Treatment and relapse were comparable between the 2 groups, whereas infections were significantly more frequent in the elderly-onset group. The clinical features and cytokine profiles of elderly-onset AOSD might differ from those of young and middle-aged-onset AOSD.