Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of microscopic polyangiitis and granulomatosis with polyangiitis: The 2023 update - secondary publication.

OBJECTIVE: To revise the 2017 clinical practice guidelines (CPG) for the management of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) to reflect advancements in the field. METHODS: Similar to the 2017 CPG, the Grading of Recommendations, Assessment, Development, and Evaluation system was adopted for this revision. The intended users of this CPG include patients diagnosed with MPA or GPA in Japan and their families and healthcare professionals, including specialists and non-specialists. Based on a scoping review, four clinical questions (CQs) of the 2017 guidelines were modified, and six new CQs were added. RESULTS: We suggest a combination of glucocorticoid and cyclophosphamide or rituximab for remission induction therapy. In cases where cyclophosphamide or rituximab is used, we suggest the use of avacopan over high-dose glucocorticoid. Furthermore, we suggest against the use of plasma exchange in addition to the standard treatment in severe cases of MPA/GPA. Finally, we suggest the use of glucocorticoid and rituximab over glucocorticoid and azathioprine for remission maintenance therapy. CONCLUSIONS: The recommendations have been updated based on patient preference, certainty of evidence, benefit and risk balance, and cost.

Evaluation of Ministry of Health, Labour and Welfare diagnostic criteria for antineutrophil cytoplasmic antibody-associated vasculitis compared to ACR/EULAR 2022 classification criteria.

OBJECTIVE: This study aimed to evaluate the Ministry of Health, Labour and Welfare (MHLW) diagnostic criteria for antineutrophil cytoplasmic antibody-associated vasculitis compared to the new American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria. METHODS: Two nationwide cohort studies were used, and participants were categorised as having eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) according to the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 and MHLW criteria. RESULTS: Of the entire patient population, only 10 (2.1%) were unclassifiable according to the MHLW probable criteria, while a significant number of patients (71.3%) met at least two criteria. The MHLW probable criteria for MPA had some challenges in differentiating between MPA and eosinophilic granulomatosis with polyangiitis, and the same was true for MHLW probable criteria for GPA in differentiating MPA from GPA. Nevertheless, improved classification results were obtained when the MHLW probable criteria were applied in the order of eosinophilic granulomatosis with polyangiitis, MPA, and GPA. CONCLUSIONS: The application of MHLW criteria could categorise a substantial number of patients with antineutrophil cytoplasmic antibody-associated vasculitis into one of the three antineutrophil cytoplasmic antibody-associated vasculitis diseases. The classification was in accordance with the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria when considering the order of application.

Validation of new ACR/EULAR 2022 classification criteria for anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: The objective of this study was to compare the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria with the previous classification algorithm for anti-neutrophil cytoplasmic antibody-associated vasculitis. METHODS: We used data from two nationwide, prospective, inception cohort studies. The enrolled patients were classified as having eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) according to the new criteria; these criteria were compared with Watts' algorithm. RESULTS: Among 477 patients, 10.7%, 9.9%, and 75.6% were classified as having EGPA, GPA, and MPA, respectively; 6.1% were unclassifiable. Three patients met both the EGPA and MPA criteria, and eight patients met both the GPA and MPA criteria. Of 78 patients with GPA classified using Watts' algorithm, 27 (34.6%) patients were reclassified as having MPA. Ear, nose, and throat involvement was significantly less frequent in patients reclassified as having MPA than in those reclassified as having GPA. Of 73 patients unclassifiable using Watts' algorithm, 62 were reclassified as having MPA. All patients reclassified as having MPA were myeloperoxidase-anti-neutrophil cytoplasmic antibody positive, and 46 had interstitial lung disease. CONCLUSION: Although the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria cause overlapping multiple criteria fulfilments in some patients, those items contribute to classifying unclassifiable patients using Watts' algorithm into MPA.

Concordance between practice and published evidence in the management of ANCA-associated vasculitis in Japan: A cross-sectional web-questionnaire survey.

OBJECTIVES: We conducted a descriptive study of the physicians' evidence-practice gap for adults covered by the 2017 clinical practice guidelines for the management of antineutrophil cytoplasmic antibody-associated vasculitis in Japan. METHODS: This web-based survey, conducted between January and February 2021, involved physicians who had treated at least five patients in the preceding year at a regional core hospital. The outcome was the physicians' experience in treating patients with microscopic polyangiitis or granulomatosis with polyangiitis [prevalence with 95% confidence intervals (CIs)], defined as treating at least 60% of their patients with the recommended therapy during the year. A modified Poisson regression analysis was performed to explore the factors associated with concordance. RESULTS: The 202 participants included 49 pulmonologists, 65 nephrologists, 61 rheumatologists, and other physicians. The concordance was 31.5% (95% CI, 25.1-38.5) of physicians who used cyclophosphamide or rituximab for the induction of remission. Rheumatology showed the highest concordance with published evidence (risk ratio = 2.4; 95% CI, 1.10-5.22, p = .03). CONCLUSIONS: These results suggest an evidence-practice gap, which varies substantially among subspecialties. Further studies and a new promotional initiative are necessary to close this gap in clinical practice.

Nation-wide cohort study of remission induction therapy using rituximab in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: Effectiveness and safety in the first 6 months.

OBJECTIVES: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan. METHODS: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome. RESULTS: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months. CONCLUSIONS: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated.

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.

Nation-wide survey of the treatment trend of microscopic polyangiitis and granulomatosis with polyangiitis in Japan using the Japanese Ministry of Health, Labour and Welfare Database.

OBJECTIVES: In Japan, clinical records of patients with intractable diseases, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), are compiled into a database. This study aimed to understand the current treatment status and changes in treatment regimens from our previous survey. METHODS: Using data from 2012 and 2013, patients with new-onset MPA and GPA were extracted and analysed. RESULTS: We analysed 1278 MPA and 215 GPA patients. The average age was 71.7 and 62.7 years, respectively. Methylprednisolone pulse therapy was used in 51.2% of MPA patients and 40.5% of GPA patients; the initial prednisolone-equivalent glucocorticoid dose was 39.5 mg/day in MPA and 46.6 mg/day in GPA. Concomitant intravenous or oral cyclophosphamide (CY) was administered to 22.6% of MPA and 56.3% of GPA. Young age, bloody sputum, low serum creatinine, and high C-reactive protein levels were independently associated with CY use in MPA. Compliance with treatment protocol for Japanese patients with myeloperoxidase (MPO)-anti-neutrophilic cytoplasmic antibody-associated vasculitis study criteria or the 2011 clinical practice guidelines for rapidly progressive glomerulonephritis was 42.7% and 49.7%, respectively. CONCLUSIONS: MPA was more prevalent than GPA in the registry. Compared to patients with GPA, MPA patients were older and used CY less frequently. No apparent changes in treatment trends were observed from the previous survey.

Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.

BACKGROUND: Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation. CASE PRESENTATION: A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid. CONCLUSIONS: We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.

Systematic review and meta-analysis for 2017 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: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach. RESULTS: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3. CONCLUSION: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.

2017 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.

OBJECTIVE: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan. METHODS: The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements. RESULTS: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy. CONCLUSION: The revised CPG has demonstrated evidence-based treatment recommendations for AAV.

Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population.

ETS proto-oncogene 1, transcription factor (ETS1) is involved in various immune responses. Genome-wide association studies on systemic lupus erythematosus in Chinese populations identified the association of ETS1 polymorphism in 3' untranslated region, rs1128334A, which was associated with lower ETS1 expression. In view of substantial sharing of susceptibility genes across multiple autoimmune diseases, we examined whether ETS1 is associated with a rare autoimmune rheumatic disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Association of rs1128334 was tested in 466 Japanese patients with AAV and 1099 healthy controls by logistic regression analysis under the additive model. AAV patients were classified into 285 microscopic polyangiitis (MPA), 92 granulomatosis with polyangiitis (GPA), 56 eosinophilic GPA, and 33 unclassifiable AAV, according to the European Medicines Agency (EMEA) algorithm. Among the patients, 376 were positive for MPO-ANCA and 62 for PR3-ANCA. When the patients were classified according to the EMEA classification, rs1128334A allele was significantly increased in GPA (P = 0.0060, P c = 0.030, odds ratio (OR), 1.54; 95% confidence interval (CI), 1.13-2.10). With respect to the ANCA specificity, significant association was observed in PR3-ANCA positive AAV (P = 0.0042, P c = 0.021, OR, 1.72; 95% CI, 1.19-2.49). In conclusion, ETS1 polymorphism was suggested to be associated with GPA and PR3-ANCA positive AAV in a Japanese population.

Simplified Disease Activity Index remission at month 6 is an independent predictor of functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis: A multi-center, prospective cohort study in Japan.

OBJECTIVE: To evaluate association of clinical remission at month 6 with functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis (RA). METHODS: This 12-month prospective, multicenter cohort study enrolled 168 patients with RA who started abatacept. Outcomes were assessed using composite measures, quality of life indices, and the van der Heijde-modified total Sharp score (mTSS). The logistic regression analysis was applied to identify factors associated with outcomes and their odds ratios (OR) with 95% confidence interval (95% CI). RESULTS: At month 6 and 12, 21.4% and 26.2% of the patients achieved Simplified Disease Activity Index (SDAI) remission (SDAI <3.3), and 40.6% and 41.7% achieved Health Assessment Questionnaire-Disability Index (HAQ-DI <0.5) remission. Among 129 patients whose mTSS progression was evaluated at month 12, 83 (64.3%) achieved structural remission (ΔmTSS ≤0.5 for 12 months). SDAI remission at month 6 was identified as a significant predictor of both functional (OR, 3.732; 95% CI, 1.328-10.489) and structural remissions (OR, 4.301; 95% CI, 1.298-14.243) at month 12 after adjusting for covariates. CONCLUSIONS: Aiming for SDAI remission at month 6 is an appropriate strategy to obtain good functional and structural outcomes at month 12.

Poncet's disease with high titers of rheumatoid factor and anti-citrullinated peptide antibodies mimicking rheumatoid arthritis.

Reactive arthritis accompanying tuberculosis (TB), also known as Poncet's disease, is a rare condition. In the present report, we describe the case of a patient with Poncet's disease, who presented with high titers of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), which mimicked rheumatoid arthritis (RA). A 69-year-old man with a childhood history of chronic left gonitis suffered from right knee arthritis for 3 years. Chronic monoarthritis in his right knee and positive results obtained on interferon-gamma release assay were suggestive of tuberculous arthritis. However, there was no evidence of TB infection. Moreover, the high titers of RF and ACPA suggested a diagnosis of RA. Surprisingly, the culture of a small sample from his bony ankylosed left knee that had no focal signs of infection, exhibited a positive result for TB infection. Thus, based on these findings, the patient was diagnosed with Poncet's disease. His symptoms improved after initiation of anti-TB therapy, which supported the accuracy of the diagnosis. In addition, we analyzed the characteristics of Poncet's disease by conducting a literature review, and identified that the presence of extra-articular manifestation and negative results for RF and ACPA tests were the features that facilitated distinguishing between typical Poncet's disease and RA; however, since tuberculous patients occasionally exhibit positive results for ACPA tests, the differential diagnosis is essential in ACPA-positive arthritic patients.

A dose-escalation regimen of trimethoprim-sulfamethoxazole is tolerable for prophylaxis against Pneumocystis jiroveci pneumonia in rheumatic diseases.

OBJECTIVE: To investigate the safety and efficacy of a dose-escalation regimen of trimethoprim-sulfamethoxazole (TMP/SMX) for prophylaxis against Pneumocystis jiroveci pneumonia (PCP) in rheumatic diseases. METHODS: Data from 41 patients, who received glucocorticoids with or without immunosuppressive agents and prophylactic use of TMP/SMX, were retrospectively analyzed. Thirteen patients were started on a daily dose of 10% of single-strength (SS) TMP/SMX, which was increased gradually (dose-escalation group), while 28 patients were started on 1 SS tablet daily (routine group). RESULTS: In the dose-escalation group, the retention rate was 100% at 6 months. In the routine group, 5 patients discontinued TMP/SMX; the retention rate was 82.1%. Moreover, the retention rate when taking a daily dose of 50% or more of SS TMP/SMX, or 1 SS tablet thrice-weekly, was significantly higher in the dose-escalation group (100 versus 71.4%, P = 0.032). No PCP was observed in the dose-escalation group; however, 1 patient in the routine group, who had discontinued TMP/SMX, developed PCP. The rate of adverse effects was less, although nonsignificant, in the dose-escalation group (30.8 versus 46.4%, P = 0.344). CONCLUSIONS: In rheumatic diseases, a dose-escalation regimen of TMP/SMX resulted in a higher retention rate and was safer than the routine regimen.

Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population.

Background: Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV. Methods: First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method. Results: The association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34-2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRß1 (HLA-DRß1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRß1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02). Conclusion: HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.

Successful treatment of steroid-resistant methotrexate-induced interstitial pneumonia with peripherally administered ulinastatin.

A 76-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for 9 months was admitted because of acute respiratory failure. A chest radiograph revealed diffuse ground-glass attenuation. MTX-induced interstitial pneumonia (IP) was strongly suspected. Her respiratory failure worsened in spite of steroid pulse therapy. Intravenous administration of ulinastatin, however, dramatically improved her clinical condition. The second ulinastatin treatment was also effective. This case suggests that peripherally administered ulinastatin may be effective for steroid-resistant MTX-induced IP.

Successful treatment of cyclosporine-A-resistant cytophagic histiocytic panniculitis with tacrolimus.

A 34-year-old woman with discoid lupus erythematosus and lupus profundus was admitted to our hospital showing signs of a fever, malaise, and abdominal swelling. Diagnosis of cytophagic histiocytic panniculitis (CHP) was made based on lobular panniculitis with a hemophagocytosis. Treatment with high doses of prednisolone combined with cyclosporine A (CsA) was not effective enough. However, after changing CsA to tacrolimus (TAC), CHP improved. Our case demonstrates that TAC may be a novel therapy for CHP.