Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study.

OBJECTIVES: The LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance glucocorticoid requirements and long-term outcomes are unknown. METHODS: A total of 140 patients with new-onset ANCA-associated vasculitis without severe glomerulonephritis or alveolar haemorrhage were randomised to receive reduced-dose prednisolone (0.5 mg/kg/day) plus rituximab (375 mg/m2/week×4) or high-dose prednisolone (1 mg/kg/day) plus rituximab. After achieving remission, patients received the rituximab maintenance therapy (1 g/6 months). RESULTS: A total of 134 patients were analysed. Among patients who achieved remission with the protocolised treatments, the majority of patients in the reduced-dose group (89.7%) and 15.5% in the high-dose group discontinued prednisolone (median time to withdrawal, 150 and 375 days, respectively). During 24-month trial period, two patients in the reduced-dose group (2.8%) died, while five patients in the high-dose group (7.6%) died (p=0.225). Relapse occurred in nine patients in the reduced-dose group (13.0%) (two major and seven minor) and five in the high-dose group (7.6%) (two major and three minor) (p=0.311). Serious adverse events (SAEs) were less frequent in the reduced-dose group (36 events in 19 patients, 27.5%) than in the high-dose group (54 events in 30 patients, 46.2%) (p=0.025). CONCLUSION: At 24 months, frequencies of relapse did not differ between the groups, and SAEs were less frequent in the reduced-dose group due to the lower event rate in the 6-month induction phase. The bias to myeloperoxidase-ANCA positivity (85.8%) in the trial population should be noted. TRIAL REGISTRATION NUMBER: NCT02198248.

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.

Predictors of damage accrual in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A nationwide prospective study.

OBJECTIVES: This study elucidated the prognosis and risk factors associated with damage accrual during long-term remission maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We obtained data from 120 patients registered in a nationwide prospective cohort study on remission induction therapy in Japanese patients with AAV and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), who achieved remission at 24 months after treatment initiation and were followed up for additional 24 months. The primary outcome was the vasculitis damage index (VDI) score at Month 48, and the secondary outcome included risk factors associated with increased total VDI at Month 48. RESULTS: The understudied patients comprised 52 men and 68 women aged 68 ± 13 years. Between Months 25 and 48, the patients' survival rate was 95% (114/120). End-stage renal disease developed in seven patients by Month 48, and 64 cases had increased VDI. The multivariable analysis results revealed that oral prednisolone (PSL) doses at Month 24 were associated with damage accrual between Months 24 and 48. CONCLUSIONS: VDI accrual was observed in more than half of patients with AAV during maintenance therapy, and increased VDI scores were associated with oral PSL doses 24 months after initiating remission induction therapy in Japan.

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.

Chemoprophylaxis against Pneumocystis jirovecii pneumonia in Japanese patients with ANCA-associated vasculitis: An observational study.

OBJECTIVES: This study investigated the current practice of prophylactic treatment against Pneumocystis jirovecii pneumonia (PCP) and its effectiveness in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: This study included 319 patients registered from 53 institutions in Japan and newly diagnosed with AAV. During the 2-year observation period, we examined the frequency of usage, effectiveness and safety of prophylactic drugs against PCP. RESULTS: Most patients received prophylactic drugs against PCP with the initiation of immunosuppressive agents, and >50% of them remained on chemoprophylaxis against PCP at 2 years after. The initial daily dose of oral prednisolone and the proportion of cyclophosphamide administration were higher in patients who received chemoprophylaxis against PCP than in those who did not. PCP occurred in nine patients (3%) and resulted in the death of four. The incidence rate of PCP in patients who received chemoprophylaxis was 1.13/100 patient-years (95% confidence interval, 0.38-2.68) and that in those who did not was 2.74 (1.04-6.02). The incidence rate ratio was 0.41 (0.11-1.53). CONCLUSIONS: The markedly low incidence of PCP may be attributed to the continuous chemoprophylaxis against PCP received by >50% of Japanese patients with AAV, although the effectiveness of chemoprophylaxis against PCP was not statistically confirmed.

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.

Safety and efficacy of filgotinib for Japanese patients with RA and inadequate response to MTX: FINCH 1 52-week results and FINCH 4 48-week results.

OBJECTIVES: To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020. METHODS: The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement; safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX. RESULTS: In all, 114/147 Japanese patients completed the PS, 115 enrolled in LTE, and 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients. CONCLUSIONS: Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS.

Long-term safety and efficacy of filgotinib treatment for rheumatoid arthritis in Japanese patients naïve to MTX treatment (FINCH 3).

OBJECTIVES: To evaluate the long-term safety and efficacy of filgotinib (FIL) for Japanese patients with rheumatoid arthritis (RA) and limited/no prior methotrexate (MTX) exposure. We present a Japanese population subanalysis of a global randomised-controlled trial at Week 52 and interim long-term extension (LTE) to Week 48 through June 2020. METHODS: Patients were randomised to FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, or MTX for 52 weeks. At completion, eligible patients could enrol in the LTE. Those receiving FIL continued; those receiving MTX were rerandomised (blinded) to FIL 200 or 100 mg upon discontinuation of MTX. After a 4-week washout period, MTX could be re-added. RESULTS: Adverse event rates at Week 52 and in the LTE to Week 48 were comparable across treatment groups. Week 52 American College of Rheumatology 20% improvement (ACR20) rates were 83% (19/23), 82% (9/11), 75% (9/12), and 76% (19/25) for FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, and MTX, respectively. Through LTE Week 48, ACR20 rates were maintained. CONCLUSIONS: In the 56 Japanese patients treated with FIL, efficacy was maintained through Week 52 and beyond, with no increases in the incidence of adverse events.

Integrated safety analysis of filgotinib treatment for rheumatoid arthritis in patients from Japan over a median of 1.5 years.

OBJECTIVE: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA). METHODS: Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest. RESULTS: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE). CONCLUSION: Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA.

Selection of treatment regimens based on shared decision-making in patients with rheumatoid arthritis on remission in the FREE-J study.

OBJECTIVE: To compare the outcome of various treatment de-escalation regimens in patients with RA who achieved sustained remission. METHODS: At period 1, 436 RA patients who were treated with MTX and bDMARDs and had maintained DAS28(ESR) at <2.6 were divided into five groups based on shared patient/physician decision-making; continuation, dose reduction and discontinuation of MTX or bDMARDs. At end of year 1, patients who achieved DAS28(ESR) <3.2 were allowed to enrol in period 2 for treatment using the de-escalation regimens for another year. The primary and secondary endpoints were the proportion of patients with DAS28(ESR) <2.6 at year 1 and 2, respectively. RESULTS: Based on shared decision-making, 81.4% elected de-escalation of treatment and 48.4% selected de-escalation of MTX. At end of period 1, similar proportions of patients maintained DAS28(ESR) <2.6 (continuation, 85.2%; MTX dose reduction, 79.0%; MTX-discontinuation, 80.0%; bDMARD dose reduction, 73.9%), although the rate was significantly different between the continuation and bDMARD-discontinuation. At end of period 2, similar proportions of patients of the MTX groups maintained DAS28(ESR) <2.6 (continuation or de-escalation), but the rates were significantly lower in the bDMARD-discontinuation group. However, half of the latter group satisfactorily discontinued bDMARDs. Adverse events were numerically lower in MTX and bDMARD-de-escalation groups during period 1 and 2, compared with the continuation group. CONCLUSIONS: After achieving sustained remission by combination treatment of MTX/bDMARDs, disease control was achieved comparably by continuation, dose reduction or discontinuation of MTX and dose reduction of bDMARDs at end of year 1. Subsequent de-escalation of MTX had no impacts on disease control but decreased adverse events in year 2.

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.

Efficacy and safety of filgotinib in combination with methotrexate in Japanese patients with active rheumatoid arthritis who have an inadequate response to methotrexate: Subpopulation analyses of 24-week data of a global phase 3 study (FINCH 1).

OBJECTIVES: Evaluate the efficacy and safety of the Janus kinase-1 inhibitor filgotinib in Japanese patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). METHODS: Data from 147 Japanese patients in FINCH 1, a 52-week global Phase 3 study, were analysed up to 24 weeks. Patients received once-daily filgotinib 200 or 100 mg, biweekly adalimumab, or placebo, all with stable background MTX. RESULTS: In the Japanese population, American College of Rheumatology 20% response rates at Week 12 (primary endpoint) were 77.5%, 65.9%, 53.6%, and 36.8% for filgotinib 200 mg, filgotinib 100 mg, adalimumab, and placebo. Proportions of patients achieving Disease Activity Score with 28 joints <2.6 at Week 24: filgotinib 200 mg, 65.0%; filgotinib 100 mg, 51.2%; adalimumab, 42.9%; and placebo, 5.3%. Incidence rates of serious infections: filgotinib 200 mg, 2.5%; filgotinib 100 mg, 0%; adalimumab, 10.7%; and placebo, 5.3%. Treatment-emergent laboratory abnormalities Grade ≥3 occurred in five (12.5%) filgotinib 200 mg, three (7.3%) filgotinib 100 mg, one (3.6%) adalimumab, and no placebo patients. No deaths were reported among Japanese patients. CONCLUSIONS: Filgotinib once daily combined with MTX was effective and generally safe and well tolerated up to Week 24 in Japanese patients with RA and inadequate response to MTX.

Efficacy and safety of filgotinib alone and in combination with methotrexate in Japanese patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: Subpopulation analyses of 24-week data of a global phase 3 study (FINCH 3).

OBJECTIVES: To evaluate the efficacy and safety of filgotinib for Japanese patients with rheumatoid arthritis (RA) and limited or no prior methotrexate (MTX) exposure. METHODS: Data up to 24 weeks were analysed for 71 Japanese patients from a 52-week global Phase 3 study. Patients with RA and limited or no prior MTX exposure were randomised in a 2:1:1:2 ratio to filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, or MTX. Maximum MTX dose was 15 mg/week. Primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24. RESULTS: Week 24 ACR20 rates in Japanese patients were 82.6%, 90.9%, 83.3%, and 80.0% for filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, and MTX, respectively. Greater ACR20 rates with filgotinib vs MTX occurred at Week 2. Greater proportions receiving filgotinib vs MTX achieved DAS28-CRP <2.6 at Weeks 12 and 24. Adverse event rates were comparable across treatments and between the Japanese and overall populations. CONCLUSIONS: While Week 24 ACR20 rates were similar, filgotinib provided faster responses and higher remission rates vs MTX. In Japanese patients with RA and limited or no prior MTX exposure, filgotinib was generally well tolerated.

Efficacy and safety of filgotinib in Japanese patients with refractory rheumatoid arthritis: Subgroup analyses of a global phase 3 study (FINCH 2).

OBJECTIVES: To evaluate efficacy and safety of filgotinib in Japanese RA patients who have failed or were intolerant to one or more biologic disease-modifying antirheumatic drugs (bDMARD) from the global FINCH 2 study (NCT02873936). METHODS: This subgroup analysis was performed using the predefined statistical analyses. The FINCH 2 study is a randomized, double-blind, placebo-controlled, Phase 3 study in adult RA patients with inadequate response to bDMARDs. The randomized patients were treated with once-daily filgotinib 200 mg, filgotinib 100 mg or placebo on a background of csDMARDs for 24 weeks. RESULTS: Of 449 patients enrolled in the overall population, 40 patients were enrolled from Japan. In the Japanese population, the American College of Rheumatology 20% response rates at week 12 (primary endpoint) were 83.3% and 53.3% for filgotinib, 200 mg and 100 mg, respectively, vs 30.8% for placebo. Filgotinib was well tolerated, similar to the overall population. CONCLUSIONS: Both doses of once-daily filgotinib 200 mg and filgotinib 100 mg were effective, and generally well-tolerated in Japanese patients with active refractory RA.

Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. METHODS: U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. RESULTS: U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. CONCLUSIONS: Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial.

Importance: The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. Objective: To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. Design, Setting, and Participants: This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Interventions: Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). Main Outcomes and Measures: The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Results: Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Conclusions and Relevance: Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT02198248.

Rationale of concomitant cyclophosphamide for remission-induction in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A propensity score-matched analysis of two nationwide prospective cohort studies.

OBJECTIVES: We evaluated the effectiveness of cyclophosphamide for patients with microscopic polyangiitis and granulomatosis with polyangiitis. METHODS: Patients treated with cyclophosphamide and glucocorticoid (cyclophosphamide group) or glucocorticoid alone (non-cyclophosphamide group) for remission-induction were enrolled from two Japanese nationwide prospective inception cohort studies. The effectiveness and safety outcomes were compared before and after propensity score (PS)- matching. RESULTS: Proportion of patients achieving Birmingham Vasculitis Activity Score (BVAS)-remission and BVAS-remission plus a daily prednisolone dosage of ≤10 mg (GC-remission) by Month 6 were not significantly different between cyclophosphamide and non-cyclophosphamide groups before (n = 144 and 155) and after (n = 94 for each group) PS-matching. In myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive PS-matched patients, GC-remission by Month 6 was superior in CYC group (n = 82) than in non-CYC group (n = 91) (49 vs. 31%, p = .020). Overall, end-stage renal disease-free and relapse-free survival rates, Vasculitis Damage Index score, and proportions of serious infection were comparable between the two groups both in the unmatched and PS-matched patients. Prednisolone doses at any point after treatment initiation in the PS-matched patients were lower in the cyclophosphamide group than in a non-cyclophosphamide group. CONCLUSIONS: Concomitant cyclophosphamide use may improve GC-remission by Month 6 in MPO-ANCA-positive patients and could exert glucocorticoid sparing effect.

Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial.

OBJECTIVES: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. METHODS: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. RESULTS: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. CONCLUSION: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.