Effectiveness and safety of rituximab in severely relapsed antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective analysis of a Japanese multicentre cohort from the J-CANVAS.

We aimed to clarify the long-term safety and efficacy of rituximab (RTX) as a remission induction therapy following severe relapse in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We retrospectively collected the data of patients with severely relapsed AAV from a Japanese multicentre cohort. The primary exposure was RTX use; the primary outcome was complete remission (CR) proportions at week 24. Baseline characteristics were compared between the RTX and non-RTX groups. We performed multivariate logistic regression analysis and one-to-one propensity score matching analysis as a sensitivity analysis. Totally, 100 patients were enrolled: 52 in the RTX group and 48 in the non-RTX group. Baseline characteristics were comparable between the two groups, except for age, AAV subtype and ANCA serotype. The median age was 71 vs. 75 years, and the PR3-ANCA positivity rate was 44.2% vs. 18.8% in the RTX and non-RTX groups, respectively. No significant difference was observed in CR proportions at week 24 between the two groups (79.2% vs. 68.1%, p = 0.321), with an adjusted odds ratio of 1.27 (95% confidence interval [CI] 0.47-3.51). At week 48, CR proportions were significantly higher in the RTX group (91.7% vs. 64.9%, p = 0.005), with an adjusted odds ratio of 2.95 (95% CI 0.97-9.91). Serious infection rates were lower in the RTX group than in the non-RTX group, with no statistically significant difference. RTX was not superior to conventional immunosuppressive therapies at week 24 but showed significantly favourable results at week 48 for severely relapsed AAV.

Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSIONS: This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management.

Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. CONCLUSION: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Seasonal Influence on Development of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort Study Conducted at Multiple Institutions in Japan (J-CANVAS).

OBJECTIVE: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season. RESULTS: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA (P < 0.001), but not in those with PR3-ANCA (P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis. CONCLUSION: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study.

OBJECTIVES: To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. METHODS: We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. RESULTS: Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. CONCLUSION: Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Association between early immunophenotypic changes and therapeutic response of belimumab in patients with systemic lupus erythematosus.

Belimumab is a therapeutic medication that inhibits the B-cell-activating factor (BAFF) used for systemic lupus erythematosus (SLE); however, the response sometimes varies among individuals, even when patients are stratified based on general clinical characteristics. Therefore, we focused on immunological phenotypic changes with belimumab, investigated their association with subsequent clinical courses, and sought to identify relevant immunological indicators to stratify patients who would benefit from belimumab. We assessed changes in B and T cell phenotypes, as well as BAFF-related factors, such as levels of BAFF and a proliferation-inducing ligand, and expression of three BAFF receptors: BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA), transmembrane activator and cyclophilin ligand interactor (TACI), in 19 patients with SLE who were treated with belimumab before and 3 months after treatment. First, to visualize patterns in complex and diverse data, we summarized B cell changes such as subsets and BAFF receptor expressions into two axes, the first and second principal components (PC1 and PC2), and characterized broad phenotypic changes by cluster analysis. Next, we evaluated whether the B cell changes represented by PC1 and PC2 were associated with other concurrent phenotypic changes, baseline factors, and treatment response at 6 months. We found that lower PC2, indicating increased BAFF-R expression and decreased percentage of naïve B cells, was associated with a subsequent therapeutic response at 6 months (odds ratio 5.3, 95% confidence interval 1.2-24, p = .031). Furthermore, higher percentages of effector memory CD3+CD4+ T cells at baseline were associated with lower PC2 and therapeutic response. Further analysis revealed that increased PC1, as reflected by increased BCMA and TACI expression and an increase in the percentage of class-switched memory B cells, was associated with both T and B cell activation. Although belimumab is a B-cell targeted therapy, it can also influence T-cell phenotypes. Thus, early B cell changes could be used to predict treatment response, and their changes could be predicted from baseline T cell phenotypes, indicating the importance of B and T cell interactions.

Systematic review and meta-analysis for 2023 clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVES: The objective of this study is to provide evidence for the revision of clinical practice guidelines for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society databases were searched for articles published between 2015 and 2020 to update the systematic review for existing clinical questions, while PubMed, CENTRAL, EMBASE, and the Japan Medical Abstracts Society were searched for articles published between 2000 and 2020 to conduct a systematic review for newly developed clinical questions. The certainty of evidence was assessed with the GRADE approach. RESULTS: For remission induction, when used in conjunction with cyclophosphamide or rituximab, reduced-dose glucocorticoid lowered the risk of serious adverse events compared to standard-dose glucocorticoid. Avacopan improved sustained remission at 12 months compared to high-dose glucocorticoid. Addition of plasma exchange to remission induction therapy did not reduce the risk of death, end-stage kidney disease, or relapse. For remission maintenance, rituximab reduced the risk of relapse compared to azathioprine. Long-term rituximab or azathioprine reduced the risk of relapse compared to short-term rituximab or azathioprine, respectively. CONCLUSIONS: This systematic review provided evidence required to develop the 2023 clinical practice guideline for the management of ANCA-associated vasculitis.

Hypertrophic pachymeningitis in ANCA-associated vasculitis: a cross-sectional and multi-institutional study in Japan (J-CANVAS).

BACKGROUND: This study investigated the characteristics of hypertrophic pachymeningitis (HP) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), using information from a multicenter study in Japan. METHODS: We analyzed the clinical information of 663 Asian patients with AAV (total AAV), including 558 patients with newly diagnosed AAV and 105 with relapsed AAV. Clinical findings were compared between patients with and without HP. To elucidate the relevant manifestations for HP development, multivariable logistic regression analyses were additionally performed. RESULTS: Of the patients with AAV (mean age, 70.2 ± 13.5 years), HP was noted in 30 (4.52%), including 20 (3.58%) with newly diagnosed AAV and 10 (9.52%) with relapsed AAV. Granulomatosis with polyangiitis (GPA) was classified in 50% of patients with HP. A higher prevalence of GPA was significantly observed in patients with HP than in those without HP in total AAV and newly diagnosed AAV (p < 0.001). In newly diagnosed AAV, serum proteinase 3 (PR3)-ANCA positivity was significantly higher in patients with HP than in those without HP (p = 0.030). Patients with HP significantly had ear, nose, and throat (ENT) (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.03-2.14, p = 0.033) and mucous membrane/eye manifestations (OR 5.99, 95% CI 2.59-13.86, p < 0.0001) in total AAV. Moreover, they significantly had conductive hearing loss (OR 11.6, 95% CI 4.51-29.57, p < 0.0001) and sudden visual loss (OR 20.9, 95% CI 5.24-85.03, p < 0.0001). CONCLUSION: GPA was predominantly observed in patients with HP. Furthermore, in newly diagnosed AAV, patients with HP showed significantly higher PR3-ANCA positivity than those without HP. The ear and eye manifestations may be implicated in HP development.

Exposure to particulate matter upregulates ACE2 and TMPRSS2 expression in the murine lung.

Coronavirus disease (COVID-19) is currently a serious global issue. Epidemiological studies have identified air pollutants, including particulate matter (PM), as a risk factor for COVID-19 infection and severity of illness, in addition to numerous factors such as pre-existing conditions, aging and smoking. However, the mechanisms by which air pollution is involved in the manifestation and/or progression of COVID-19 is still unknown. In this study, we used a mouse model exposed to crude PM, collected by the cyclone method, to evaluate the pulmonary expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2), the two molecules required for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. Multiplex immunohistochemical analysis revealed that exposure to PM increased the expression of these two molecules at the same site. Furthermore, image cytometry analysis revealed increased expression of these proteins, particularly, in the alveolar type 2 cells and macrophages, which are potential targets for SARS-CoV-2. Our findings provide an experimental evidence that exposure to PM may adversely affect the manifestation and progression of COVID-19, mediated by the impact of SARS-CoV-2 on the site of entry. The study results suggest that examining these effects might help to advance our understanding of COVID-19 and aid the development of appropriate social interventions.

Upregulation of sphingosine-1-phosphate receptor 3 on fibroblast-like synoviocytes is associated with the development of collagen-induced arthritis via increased interleukin-6 production.

BACKGROUND: Sphingosine-1-phosphate receptor 3 (S1P3) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P3 signaling is involved in numerous physiological and pathological processes including bone metabolism, sepsis, cancer, and immunity. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) are activated by several factors and promote abundant proinflammatory cytokine production and bone destruction. The aim of this study was to investigate whether S1P3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs. METHODS: Wild-type (WT) and S1P3 knockout (S1P3-KO) collagen-induced arthritis (CIA) mice were evaluated with respect to clinical and histological disease severity, along with the levels of anti-collagen antibodies and expression of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). S1P3 expression in the synovium was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. FLSs isolated from CIA mice were activated with TNFα and S1P3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P3 signaling in activated and non-activated FLSs was investigated by measuring cell proliferation and cyto/chemokine production by real-time RT-PCR and/or enzyme-linked immunosorbent assay. RESULTS: Clinical and histological scores, and synovial IL-6 expression were significantly lower in S1P3-KO mice with CIA than in WT mice. Arthritic synovia had higher S1P3 expression than intact synovia and FLSs in arthritic joints expressed S1P3 in vivo. Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P3 expression after activation with TNFα. S1P3-induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα. CONCLUSION: In this study, we demonstrated that S1P3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P3 signaling could open the door to the development of new therapies for RA.

Roles of high-mobility group box 1 and thrombin in murine pulmonary fibrosis and the therapeutic potential of thrombomodulin.

Cross talk between inflammation and coagulation plays important roles in acute or subacute progressive pulmonary fibrosis characterized by diffuse alveolar damage. Thrombomodulin is a physiological inhibitor of high-mobility group box 1 (HMGB1), and thrombin and may be effective for this condition. This study investigated the roles of HMGB1 and thrombin in the pathophysiology of bleomycin-induced pulmonary fibrosis and the efficacy of recombinant human soluble thrombomodulin (rhTM). Pulmonary fibrosis was induced in wild-type C57BL/6 mice by intratracheal instillation of bleomycin. We first assessed HMGB1, thrombin, transforming growth factor (TGF)-ß1, and α-smooth muscle actin (SMA) levels in bronchoalveolar lavage fluid and lung tissue sections over time. Expression of HMGB1 and thrombin was elevated before that of TGF-ß1 and α-SMA and remained high during the fibrotic phase after bleomycin instillation. We next examined whether in vitro stimulation with HMGB1 and thrombin induced expression of TGF-ß1 and α-SMA in cultured alveolar macrophages and lung fibroblasts, respectively, by performing quantitative PCR, enzyme-linked immunosorbent assay, Western blot, and immunofluorescence analyses. HMGB1 and thrombin stimulation induced TGF-ß1 production by alveolar macrophages, and thrombin stimulation also induced α-SMA expression in lung fibroblasts. Finally, we evaluated the effect of rhTM on bleomycin-induced pulmonary fibrosis. Compared with the vehicle control, both early and late-phase administration of rhTM suppressed the fibrotic process. Our results suggest that HMGB1 and thrombin were involved in the pathophysiology of pulmonary fibrosis via production of profibrotic proteins and that rhTM attenuated bleomycin-induced pulmonary fibrosis. rhTM may be a therapeutic option for acute or subacute pulmonary fibrosis.

Role of allograft inflammatory factor-1 in bleomycin-induced lung fibrosis.

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries in a rat ectopic cardiac allograft model. We previously reported that AIF-1 is associated with the pathogenesis of rheumatoid arthritis and skin fibrosis in sclerodermatous graft-versus-host disease mice. Here, we used an animal model of bleomycin-induced lung fibrosis to analyze the expression of AIF-1 and examine its function in lung fibrosis. The results showed that AIF-1 was expressed on lung tissues, specifically macrophages, from mice with bleomycin-induced lung fibrosis. Recombinant AIF-1 increased the production of TGF-ß which plays crucial roles in the mechanism of fibrosis by mouse macrophage cell line RAW264.7. Recombinant AIF-1 also increased both the proliferation and migration of lung fibroblasts compared with control group. These results suggest that AIF-1 plays an important role in the mechanism underlying lung fibrosis, and may provide an attractive new therapeutic target.

Allograft inflammatory factor-1 in the pathogenesis of bleomycin-induced acute lung injury.

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries of rats with an ectopic cardiac allograft. Some studies have shown that expression of AIF-1 increased in a mouse model of trinitrobenzene sulfonic acid-induced acute colitis and in acute cellular rejection of human cardiac allografts. These results suggest that AIF-1 is related to acute inflammation. The current study used bleomycin-induced acute lung injury to analyze the expression of AIF-1 and to examine its function in acute lung injury. Results showed that AIF-1 was significantly expressed in lung macrophages and increased in bronchoalveolar lavage fluid from mice with bleomycin-induced acute lung injury in comparison to control mice. Recombinant AIF-1 increased the production of IL-6 and TNF-α from RAW264.7 (a mouse macrophage cell line) and primary lung fibroblasts, and it also increased the production of KC (CXCL1) from lung fibroblasts. These results suggest that AIF-1 plays an important role in the mechanism underlying acute lung injury.

The rapid efficacy of abatacept in a patient with rheumatoid vasculitis.

We report a case of rheumatoid vasculitis (RV) that responded well to abatacept, a cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-immunoglobulin fusion protein. A 38-year-old woman developed RV despite treatment with methotrexate and tumor necrosis factor (TNF) inhibitors. The effects of steroid therapy, immunoabsorption plasmapheresis, and interleukin-6 inhibitor were insufficient, however, administration of abatacept rapidly improved her clinical symptoms with almost normalization of the immunological findings. This is the first published case report of the successful treatment of RV with abatacept.