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Objective: B‐cell depletion using the anti‐CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B‐cell depletion is associated with a higher risk for severe infections, and the time span of B‐cell repopulation differs greatly between individuals. Data on factors influencing B‐cell repopulation kinetics are limited. This study aims to identify patient‐specific and therapy‐associated covariates that modulate B‐cell repopulation. Methods: This single‐center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient‐specific factors (sex, age, kidney function, and underlying disease) and co‐immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B‐cell repopulation (≥5/μl). The secondary end point is the time to B‐cell reconstitution (≥50/μl). Multivariate time‐to‐event analysis and logistic regression models were applied to estimate the influence of covariates. Results: Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody‐associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co‐immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B‐cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent. Conclusion: Prolonged rituximab dosing intervals may be effective to achieve B‐cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co‐medication with corticosteroids or azathioprine prolongs B‐cell recovery, which may increase therapeutic effects but also the rate of adverse events. [ABSTRACT FROM AUTHOR]

Objective: To compare rituximab‐ versus cyclophosphamide‐based remission induction strategies for the long‐term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) in a real‐world cohort. Methods: We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3–ANCA+ and myeloperoxidase (MPO)‐ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score–matched analyses to assess the association of rituximab‐ versus cyclophosphamide‐based treatment strategies with the composite outcome of kidney failure or death. Results: Of 595 included patients, 352 patients (~60%) received rituximab‐based and 243 patients (~40%) received cyclophosphamide‐based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO‐ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2). There were 133 events at 5 years, and the incidence rates in rituximab‐ and cyclophosphamide‐based regimens were 6.8 and 6.1 per 100 person‐years, respectively. The risk of kidney failure or death was similar in both groups in multivariable‐adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55–1.93]) and in propensity score–matched analyses (HR 1.05 [95% CI 0.55–1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. Conclusion: Rituximab‐ and cyclophosphamide‐based remission induction strategies for AAV are associated with similar risks of kidney failure and death. [ABSTRACT FROM AUTHOR]

Objective: Patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. Methods: Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA‐Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t‐tests and multivariable linear regression were used to assess changes in lipid levels. Results: Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)–ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low‐density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3‐ANCA–positive patients but not among those with relapsing disease or myeloperoxidase‐ANCA–positive patients. There was no difference in change in lipid levels between rituximab‐treated patients and cyclophosphamide‐treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. Conclusion: Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3‐ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: In this multicenter, double‐blind, placebo‐controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low‐dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol‐specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results: The intent‐to‐treat population totaled 105 patients with AAV, of whom 52 (40 with PR3‐ANCAs, 12 with MPO‐ANCAs) received placebo and 53 (41 with PR3‐ANCAs, 12 with MPO‐ANCAs) received belimumab; 27 of the patients were in rituximab‐induced disease remission, while 78 were in cyclophosphamide‐induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3‐ANCA–associated vasculitis with cyclophosphamide‐induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse. [ABSTRACT FROM AUTHOR]

Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group ( P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 ( P = 0.0043) and baseline and month 6 ( P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse ( P = 0.028). Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. [ABSTRACT FROM AUTHOR]

Objective The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. Methods Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. Results No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission ( P = 0.01). The 519AA genotype predicted complete remission ( P = 0.006) and a shorter time to complete remission ( P < 0.001). Conclusion The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy. [ABSTRACT FROM AUTHOR]

Objective To identify predictors of respiratory failure and to evaluate the therapeutic efficacy of plasma exchange (PE) and of rituximab versus cyclophosphamide in a cohort of patients with diffuse alveolar hemorrhage (DAH) secondary to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with or without respiratory failure. Methods We performed a single-center historical cohort study of all consecutive patients with AAV-associated DAH who were evaluated over a 16-year period. Logistic regression models were developed to examine the predictive role of the baseline clinical characteristics for the development of respiratory failure, and for the effect of PE and remission induction therapy on the main outcome (complete remission at 6 months). Results Seventy-three patients with DAH were identified, and 34 of them experienced respiratory failure. The degree of hypoxemia upon initial presentation, a higher percentage of neutrophils in the bronchoalveolar lavage fluid cell count, and higher C-reactive protein levels were independently associated with the development of respiratory failure. PE was not associated with achieving complete remission at 6 months, with an odds ratio (OR) of 0.49 (95% confidence interval [95% CI] 0.12-1.95) ( P = 0.32). Rituximab treatment was independently associated with achieving complete remission at 6 months (OR 6.45 [95% CI 1.78-29], P = 0.003). Conclusion Our findings indicate that the most important predictor of respiratory failure in patients with DAH secondary to AAV is the degree of hypoxemia upon presentation. No clear benefit of the addition of PE to standard remission induction therapy was demonstrated. Complete remission by 6 months was achieved at a higher rate with rituximab than with cyclophosphamide in patients with DAH secondary to AAV, including those needing mechanical ventilation. [ABSTRACT FROM AUTHOR]

Objective Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. Methods RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. Results Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). Conclusion Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients. [ABSTRACT FROM AUTHOR]

Objective Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. Results Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). Conclusion Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment. [ABSTRACT FROM AUTHOR]

A reply from the author of the article "Diffuse alveolar hemorrhage secondary to antineutrophil cytoplasmic antibody–associated vasculitis: predictors of respiratory failure and clinical outcomes" in the 2016 issue is presented.