Tomoaki Higuchi

Objectives: Clinical heterogeneity in ANCA-associated vasculitis (AAV) is not fully captured by conventional disease subtypes or ANCA serotypes. We aimed to identify data-driven, clinically meaningful disease phenotypes based on patterns of organ involvement in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), and to evaluate their prognostic and therapeutic implications. Methods: We conducted a multicentre retrospective cohort study using two nationwide Japanese registries (J-CANVAS as derivation; JPVAS as validation). Ensemble clustering was applied to high-dimensional organ involvement data derived from the Birmingham Vasculitis Activity Score and additional clinically relevant manifestations. The resulting clusters were replicated using classification and regression tree (CART) across the derivation and validation cohorts, and associations between cluster memberships and clinical outcomes (overall survival and relapse), as well as response to induction therapy, were evaluated. Results: Among 726 patients with newly diagnosed MPA or GPA, ensemble clustering identified four reproducible clinical phenotypes: (a) renal-dominant without interstitial lung disease (ILD); (b) renal-dominant with ILD; (c) systemic multi-organ and (d) ear, nose and throat (ENT)-dominant. CART reproduced these clusters with good concordance. Overall survival and relapse incidence differed across clusters. The ENT-dominant cluster demonstrated favourable survival but a higher relapse risk and showed a trend towards improved relapse-free survival with rituximab compared with CYC, even among MPO-ANCA-positive patients. Conclusion: Organ involvement-based ensemble clustering identifies clinically meaningful and reproducible AAV phenotypes with distinct prognostic and therapeutic profiles. Integrating phenotypic patterns with ANCA serotype may enhance risk stratification and support more individualized management strategies in AAV.

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.

Introduction: To compare the retention rate, hazard ratio of treatment discontinuation, and effectiveness of tumor necrosis factor inhibitor (TNFi), interleukin‐6 inhibitor (IL‐6i), and cytotoxic T lymphocyte‐associated antigen‐4‐Ig (CTLA4‐Ig) in patients with rheumatoid arthritis (RA) and reduced kidney function. Methods: We analyzed data from patients with RA and reduced kidney function included in the large‐scale, real‐world observational cohort study in Japan. Patients who initiated treatment with biological disease‐modifying antirheumatic drugs (bDMARDs) between 2003 and 2018 were selected. Reduced kidney function was defined as an estimated glomerular filtration rate of < 60 mL/min/1.73 m ² . Drug retention, disease activity, and physical function were compared during the observational period using inverse probability of treatment weighting (IPTW). Results: The study included 154 patients with 237 treatment courses. The overall drug retention rate was 54.6% at 3 years, while the individual rates of TNFi, IL‐6i, and CTLA4‐Ig were 54.9%, 61.1%, and 44.3%, respectively. Retention rates due to ineffectiveness were 72.4%, 67.7%, and 49.3%, and due to adverse drug reactions were 76.2%, 90.3%, and 89.9%, respectively. Adjusted hazard ratios of discontinuation were 0.85 (95% confidence interval [CI], 0.37–1.96) for IL‐6i and 1.31 (95% CI, 0.63–2.73) for CTLA4‐Ig compared to TNFi. After IPTW, mean scores for the clinical disease activity index and the Japanese version of the health assessment questionnaire at 3 years were similar across the three groups. Conclusion: The drug retention rates and effectiveness of bDMARDs with different modes of action were comparable in patients with RA and reduced kidney function.

To investigate longitudinal trends in the proportion of seronegative rheumatoid arthritis (RA) and to compare clinical outcomes between seronegative and seropositive patients in a Japanese single-centre cohort. We included 4,354 RA patients with a disease duration < 4 years from the Institute of Rheumatology, Rheumatoid Arthritis cohort. Seronegativity was defined as the absence of both rheumatoid factor (RF) and anti-citrullinated peptide (CCP) antibody. We assessed the association between enrolment period and seronegativity using multivariable logistic regression. A mixed-effects model was used to compare 3-year trends in Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), clinical disease activity index (CDAI), and the Japanese version of the Health Assessment Questionnaire (J-HAQ) scores between serostatus groups. The proportion of seronegative RA increased from 14.4% in 2000-2010 to 17.9% in 2011-2021. The later period was associated with seronegativity (adjusted odds ratio [95% confidence interval]: 1.32 [1.08-1.61]), negative RF (1.23 [1.05-1.45]), and negative anti-CCP antibody (1.31 [1.11-1.56]). At 3 years, seronegative patients had better mean (95% confidence interval) CDAI (4.50 [3.48-5.53] vs. 5.57 [4.66-6.48]), DAS28-ESR (2.13 [1.93-2.32] vs. 2.54 [2.37-2.71]), and J-HAQ (0.43 [0.33-0.54] vs. 0.52 [0.42-0.61]) compared with seropositive patients. The proportions of patients achieving J-HAQ remission were comparable between the groups. The proportion of seronegative RA has increased significantly over time. Seronegative patients demonstrate a favourable disease course with a higher rate of remission compared with seropositive patients, thus identifying them as a distinct RA subgroup. Key Points • The proportion of seronegative rheumatoid arthritis increased over time in a large Japanese cohort. • Patients with seronegative rheumatoid arthritis had significantly higher rates of clinical remission over 3 years. • The increasing proportion and distinct prognosis of seronegative rheumatoid arthritis may require specific management strategies.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) develop in patients with rheumatoid arthritis (RA) during treatment with disease-modifying antirheumatic drugs (DMARDs). Periarticular OIIA-LPDs are rare and poorly understood. An 81-year-old woman with RA presented with knee swelling, a fever, and weight loss. Imaging studies revealed bone erosion and a 18F-fluorodeoxyglucose uptake around the knees. A histopathological analysis was consistent with diffuse large B-cell lymphoma, confirming the diagnosis of OIIA-LPD. Discontinuation of DMARDs resolved the knee swelling and prevented further bone erosion. This report highlights the importance of considering OIIA-LPDs in patients with RA, atypical joint swelling, and systemic symptoms.

Aim: To evaluate whether seasonal changes influence fluctuations in serum Krebs von den Lungen‐6 (KL‐6) levels in systemic sclerosis‐related interstitial lung disease (SSc‐ILD).Methods: Summer was defined as the period between July and September, and winter as between December and February. The study was conducted between 2015 and 2016, with a focus on these two seasons. A diagnosis of ILD and ILD progression overtime were evaluated using chest computed tomography. Among patients with SSc‐ILD, those with data on serum KL‐6 and lactate dehydrogenase (LDH) levels in the 2015 winter, 2015 summer, and 2016 winter seasons were included. Patients with comorbidities that could affect serum KL‐6 levels were excluded.Results: Of 60 patients with SSc‐ILD, 52 (86.7%) had stable ILD, 5 (8.3%) had worsened ILD, and 3 (5.0%) had improved ILD. Serum KL‐6 levels were significantly higher during the winter than those during the summer (2015 winter vs. 2015 summer: 649 U/mL vs. 585 U/mL, p < .0001; 2016 winter vs. 2015 summer: 690 U/mL vs. 585 U/mL, p < .0001). No significant differences were observed between the winters of 2015 and 2016 (649 U/mL vs. 690 U/mL, p = .78). However, serum LDH levels did not exhibit seasonal fluctuations (2015 winter vs. 2015 summer: 203 U/L vs. 199 U/L, p = .3; 2016 winter vs. 2015 summer: 201 U/L vs. 199 U/L, p = .6; 2015 winter vs. 2016 winter: 203 U/L vs. 201 U/L, p = .24).Conclusion: Seasonal fluctuations in serum KL‐6 levels were observed in patients with SSc‐ILD.

Aim: To assess the usefulness of carbohydrate antigen 19‐9 (CA19‐9) as a biomarker for systemic sclerosis‐associated interstitial lung disease (SSc‐ILD), using serum samples and clinical parameters of patients with SSc.Methods: Patients with SSc admitted to Tokyo Women's Medical University Hospital between 2010 and 2021 and those who underwent chest computed tomography (CT) were included. Patients were diagnosed with ILD based on chest CT findings, and SSc‐ILD was categorized as either a limited or extensive disease based on chest CT and pulmonary function test findings. Serum CA19‐9 levels were measured in 56 patients with SSc and in 32 healthy individuals. Additionally, we evaluated the difference in serum CA19‐9 levels between the groups, the correlation with ILD area and pulmonary function, and discriminative performance to diagnose extensive ILD.Results: Of the 56 patients with SSc, 40 (71.4%) had ILD, and 17 (30.4%) were classified as having extensive disease. Serum CA19‐9 levels were significantly elevated in patients with extensive disease compared to those with limited disease (median [interquartile range]: 25.7 U/mL [10.1–50.8] vs. 8.8 U/mL [4.5–17.6], p = .02) and correlated with ILD area (r = .30, p = .02). There was no significant correlation between serum CA19‐9 level and pulmonary function. The cutoff of CA19‐9 for the diagnosis of the extensive disease was determined to be 19.8 U/mL, with a sensitivity of 64% and specificity of 82% and an area under the curve of 0.74 (95% confidence interval 0.58–0.90).Conclusion: The serum CA19‐9 level may be a useful marker for identifying patients with SSc‐ILD with extensive disease.

Phosphodiesterase (PDE) 4 inhibitors have been reported to suppress the progression of dermal fibrosis in patients with systemic sclerosis (SSc); however, the precise mechanisms remain to be elucidated. Therefore, we conducted experiments focusing on the antifibrotic and anti-inflammatory effects of apremilast using dermal fibroblasts derived from patients with SSc and an SSc mouse model. Dermal fibroblasts derived from healthy controls and patients with SSc were incubated with apremilast in the presence or absence of 10 ng/ml transforming growth factor (TGF)-β1 for the measurement of intracellular cAMP levels and evaluation of mRNA and protein expression. A bleomycin-induced dermal fibrosis mouse model was used to evaluate the inhibitory effects of apremilast on the progression of dermal fibrosis. Intracellular cAMP levels were significantly reduced in dermal fibroblasts derived from patients with SSc compared with those derived from healthy controls. Apremilast reduced the mRNA expression of profibrotic markers and the protein expression of type I collagen and Cellular Communication Network Factor 2 (CCN2) in dermal fibroblasts. Additionally, apremilast inhibited the progression of dermal fibrosis in mice, partly by acting on T cells. These results suggest that apremilast may be a potential candidate for treating dermal fibrosis in SSc.

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare type of idiopathic interstitial pneumonia, which is characterised by pleural fibrosis and subjacent parenchymal fibroelastosis of the upper lobes. Herein, we present a case of microscopic polyangiitis (MPA) following PPFE. The patient had abnormal shadows on chest radiographs 15 years before the onset of MPA, and the patient was diagnosed with PPFE. Four years after the PPFE diagnosis, the patient was diagnosed with MPA based on persistent fever, purpura, mononeuritis multiplex, myeloperoxidase–antineutrophil cytoplasmic antibody positivity, and pathological findings of peritubular capillaritis on kidney biopsy. The patient was treated with glucocorticoids, including methylprednisolone pulse therapy and rituximab, followed by maintenance therapy with rituximab. One year after treatment, the PPFE had not worsened. PPFE occasionally occurs secondary to connective tissue disease, including MPA; however, to the best of our knowledge, this is the first report of PPFE preceding MPA. Our case suggests that PPFE, as other interstitial lung diseases, may be associated with MPA and precede the onset of MPA. The accumulation of more cases is needed to clarify the characteristics of MPA-associated PPFE.