Masataka Umeda

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.

We investigated the diagnostic challenges of TAFRO syndrome and idiopathic multicentric Castleman disease (iMCD), focusing on the usefulness of anterior mediastinal lesions for distinguishing the disease subtypes. A comparative analysis using computed tomography (CT) imaging was performed for three patient groups: TAFRO without iMCD/iMCD-TAFRO (n=13), iMCD-idiopathic plasmacytic lymphadenopathy (IPL)- not otherwise specified (NOS) (n=16), and IgG4-related disease (IgG4-RD) (n=59). Lesions were categorized into increased fat density, micronodular opacity, and mass. The lesions’ CT attenuation values were compared, and receiver operating characteristic (ROC) curve analyses assessed their diagnostic relevance. Anterior mediastinal lesions were most frequent in the TAFRO without iMCD/iMCD-TAFRO group (85%) compared to the iMCD-IPL/NOS group (31%) and IgG4-RD group (6.8%). Distinct patterns such as increased fat density were predominantly observed in the TAFRO without iMCD/iMCD-TAFRO group. The CT values showed significant intergroup differences, with ROC analyses confirming high diagnostic accuracy for distinguishing the TAFRO without iMCD/iMCD-TAFRO group from the other groups. Post-treatment, all patients with TAFRO without iMCD/iMCD-TAFRO showed improvement in CT readings, whereas only half of the patients with iMCD-NOS group showed changes. These findings emphasize the importance of CT-detected anterior mediastinal lesions in the diagnosis of TAFRO without iMCD/iMCD-TAFRO and warrant further research to validate these results.

Objective: Interleukin‐17–producing CD4 ⁺ Th17 cells contribute to the pathogenesis of autoimmune diseases, including crescentic glomerulonephritis. Although ADAM9 has been reported to contribute to organ inflammation, the mechanism remains poorly understood. The goal of the current study was to investigate how ADAM9 alters T cell metabolism to promote the generation of Th17 cell differentiation. Methods: We induced antiglomerular basement membrane (anti‐GBM) glomerulonephritis in Adam9 ^+/+ and Adam9 ^−/− mice using sheep anti‐GBM IgG and compared disease severity. Glycolysis in Th17 cells was measured using a Seahorse XFp Extracellular Flux Analyzer (Agilent Technologies, Inc), and metabolomic analysis was conducted on Th17 cells from both Adam9 ^+/+ and Adam9 ^−/− mice. We measured the GLUT1 expression in Th17 cells from Adam9 ^+/+ and Adam9 ^−/− mice and insulin‐like growth factor 1 (IGF‐1)–treated Th17 cells. Finally, we assessed the protease activity of ADAM9 on IGF‐binding protein 4 (IGFBP4). Results: Mice deficient in ADAM9 had limited numbers of kidney‐infiltrating CD4 ⁺ T cells and suffered reduced kidney damage and inflammation following the injection of sheep anti‐GBM IgG. ADAM9 deficiency led to decreased GLUT1 expression and glycolysis in Th17 cells. Mechanistically, we found that ADAM9 cleaved IGFBP4 and enabled the release of IGF‐1, which enhanced the expression of GLUT1 and promoted glycolysis. Conclusion: By cleaving IGFBP4, ADAM9 releases IGF‐1, which in turn upregulates GLUT1 expression and promotes glycolysis in Th17 cells. These findings suggest that targeting ADAM9 or blocking IGF‐1 should provide a therapeutic strategy for autoimmune diseases.

The human monoclonal antibody belimumab (BEL) has emerged as a promising treatment for systemic lupus erythematosus (SLE), particularly for reducing the need for glucocorticoids and minimizing organ damage. The optimal timing of BEL initiation has been unclear; emerging evidence suggests that early intervention with BEL, particularly within the first 5 years of diagnosis, may yield better outcomes by modulating disease progression and reducing flare frequency. Understanding the relationship between disease duration and BEL efficacy is essential for the development of tailored strategies. We analyzed patients with SLE treated at our hospital and associated facilities who were diagnosed according to the 1997 ACR or 2012 SLICC criteria and who began BEL treatment between December 2017 and August 2021. Patients who were followed for ≥ 12 months after BEL initiation were included. We investigated the changes in the patients' Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores at 3, 6, 9, and 12 months after the introduction of BEL, comparing patients with disease durations ≤ 5 years to those with > 5 years. A mixed-effects model was adjusted for the patients' ages, prednisolone dosages, initial SELENA-SLEDAI scores, Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI), hydroxychloroquine use, and lupus nephritis. Clinical manifestations including arthritis, skin lesions, and hematological abnormalities were monitored to assess the broader impacts of BEL. One hundred eleven patients were initially registered; among them, 97 patients were included in the final analysis. The study population (mean age, 41 years; mean SELENA-SLEDAI, 7 points; 51% using hydroxychloroquine) included 19 patients with a ≤ 5-year SLE duration and 78 with SLE durations > 5 years. The baseline SELENA-SLEDAI scores were higher in the ≤ 5-year group (p = 0.047), indicating more active disease. Patients with ≤ 5 years of disease had significantly greater improvements in SELENA-SLEDAI scores at 6, 9, and 12 months (p < 0.05). These results highlight the importance of early BEL initiation in SLE, demonstrating that patients with shorter disease durations achieve more substantial improvements in disease activity with early BEL treatment. Our findings also reveal the potential benefits of early BEL intervention and suggest that incorporating the disease duration into treatment decisions may optimize patient outcomes.

Objective: Enhanced expression of transforming growth factor (TGF) β in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end‐organ damage. ADAM9 activates TGFβ1 by cleaving the latency‐associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGFβ1.Methods: We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up‐regulation of ADAM9 and the subsequent activation of TGFβ1. To assess the role of ADAM9 in the development of tubular‐intestinal fibrosis in individuals with LN, we generated MRL/lpr mice who were Adam9 deficient.Results: ADAM9 was highly expressed in tubules from MRL/lpr mice. The transcription factor hypoxia‐inducible factor–1α was found to promote the transcription of ADAM9 in TECs. TECs from mice who were Adam9 deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGFβ1 from latent TGFβ1. Coculture of TECs from mice who were Adam9 deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGFβ1 produced decreased amounts of type I collagen and α–smooth muscle actin (SMA) by fibroblasts. MRL/lpr mice who were Adam9 deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase.Conclusion: Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGFβ1 activation, which promotes fibroblasts to produce collagen and α‐SMA. image

Rationale: Behçet’s disease (BD) is characterized by recurrent oral ulcers, skin lesions, genital ulcers, and ocular inflammation, with uncontrolled gastrointestinal manifestations potentially leading to fatal complications. Human leukocyte antigen (HLA) class I alleles such as HLA-B51 and HLA-A26 are genetic risk factors for BD, and interleukin-1β activation plays a key role in BD pathogenesis. Familial Mediterranean fever, another autoinflammatory disease caused by MEFV gene mutations, shares similarities with BD, including enhanced interleukin-1β production. Patient concerns: We present a case of BD with severe gastrointestinal ulcers and MEFV variants treated with canakinumab. Diagnoses: A 69-year-old Japanese woman with a history of malignant lymphomas and nontuberculous mycobacterial arthritis developed BD symptoms, including oral and gastrointestinal ulcers. Interventions: Despite after treatments with 2 tumor necrosis factor inhibitors, her oral and gastrointestinal ulcers persisted. Genetic analysis revealed L110P/E148Q MEFV variants, prompting the administration of canakinumab and granulocyte and monocyte adsorption apheresis. Outcomes: Continuous treatment with canakinumab improved the oral and gastrointestinal ulcers. Lessons: This case highlights the potential efficacy of canakinumab in treating severe gastrointestinal ulcers in BD patients with MEFV variants.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by reduction of tolerance to nuclear antigens and dysfunction of various immune players, leading to inflammation in multiple organs. The overproduction of type 1 interferons, including interferon alpha (IFNα), along with its enhanced signalling and the activation of auto-reactive B cells are believed to play the central roles in the pathogenesis of SLE [ 1]. Numerous clinical trials in SLE have been completed without reaching their primary end-points, possibly due to the intricate nature of the disease, but two approved biologics, belimumab (BEL) targeting B-cell activating factor and anifrolumab (ANI) targeting IFNα receptor signalling, are now in clinical use [ 2]. Since BEL and ANI have different target molecules, their responder populations may also be different; however, there is limited available information concerning the utilization of these two biological agents, particularly in the context of switching. We conducted a retrospective study to assess the efficacy and safety of a treatment switch from BEL to ANI in daily clinical practice for patients with SLE.

Sjögren’s syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS potentially affects the prognosis of patients, especially in cases of complicated extraglandular symptoms; however, only symptomatic therapies against xerophthalmia and xerostomia are currently included in the practice guidelines as recommended therapies for SS. Considering that SS is presumed to be a multifactorial entity caused by genetic and environmental factors, a multidisciplinary approach is necessary to clarify the whole picture of its pathogenesis and to develop disease-specific therapies for SS. This review discusses past achievements and future prospects for pursuing the pathophysiology and therapeutic targets for SS, especially from the perspectives of viral infections, toll-like receptors (TLRs), long-noncoding RNAs (lncRNAs), and related signals. Based on the emerging roles of viral infections, TLRs, long-noncoding RNAs and related signals, antiviral therapy, hydroxychloroquine, and vitamin D may lower the risk of or mitigate SS. Janus-kinase (JAK) inhibitors are also potential novel therapeutic options for several rheumatic diseases involving the JAK-signal transducer and activator of transcription pathways, which are yet to be ascertained in a randomized controlled study targeting SS.