Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial.

OBJECTIVE: To compare two long-term remission maintenance strategies for antineutrophil cytoplasmic antibody (ANCA) vasculitis. METHODS: We conducted a prospective, single-centre, open-label, randomised controlled trial of patients with ANCA vasculitis in remission after completing at least 2 years of fixed-schedule rituximab. In the B cell arm, rituximab was reinfused upon B cell repopulation; in the ANCA arm, rituximab was reinfused upon significant rise in ANCA level. Evaluations were conducted every 3 months. The primary endpoint was clinical relapse, defined as a modified BVAS/WG >0 by 36 months. Secondary endpoints included serious adverse events (SAEs) and rituximab exposure. RESULTS: 115 patients were enrolled. Median follow-up time was 4.1 years (IQR 2.5-5.0). By Kaplan-Meier analysis, 4.1% (95% CI 1.0 to 15.6) of patients had a clinical relapse in the B cell arm, compared with 20.5% (95% CI 11.9 to 34.1) in the ANCA arm, at 3 years after study entry (log-rank p=0.045). Total SAEs, including infectious SAEs, and deaths did not differ. The number of SAEs due to COVID-19 was higher in the B cell arm (p=0.049). In the B cell arm, patients received a mean of 3.6 (SD 2.4) infusions (3.6 g) per person over the median study follow-up time of 4.1 years, compared with 0.5 (SD 1.4) infusions (0.5 g) per patient in the ANCA arm (p<0.001). CONCLUSIONS: Rituximab dosed for B cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level in maintenance of remission for ANCA vasculitis. Overall safety was equivalent; SAEs due to COVID-19 and rituximab exposure were higher with the B cell strategy. TRIAL REGISTRATION NUMBER: NCT02749292.

Combination of Rituximab, Low-Dose Cyclophosphamide, and Prednisone for Primary Membranous Nephropathy: A Case Series With Extended Follow Up.

RATIONALE & OBJECTIVE: B-cell depletion with rituximab has emerged as a first-line therapy for primary membranous nephropathy (MN). However, most patients do not achieve complete remission with rituximab monotherapy. In this case series, we report longer-term remission and relapse rates, anti-phospholipase A2 receptor (PLA2R) antibody levels, B-cell levels, and serious adverse events in patients with primary MN who received rituximab combined with an initial short course of low-dose oral cyclophosphamide and a course of rapidly tapered prednisone. STUDY DESIGN: Single-center retrospective case series. SETTING & PARTICIPANTS: 60 consecutive patients with primary MN treated with the combination of rituximab, low-dose cyclophosphamide, and prednisone at the Vasculitis and Glomerulonephritis Center at the Massachusetts General Hospital. FINDINGS: After treatment initiation, median follow-up was 38 (interquartile range [IQR], 25-62) months; 100% of patients achieved partial remission, defined as a urinary protein-creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline, at a median of 3.4 months. By 2 years after treatment initiation, 83% achieved complete remission, defined as a UPCR < 0.3 g/g. The median time to complete remission was 12.4 months. Immunologic remission (defined by an anti-PLA2R titer < 14 RU/mL) was achieved by 86% and 100% of anti-PLA2R seropositive patients (n = 29) at 3 and 6 months, respectively, after treatment initiation. After 1 year, the median UPCR fell from 8.4 (IQR, 5.0-10.7) to 0.3 (IQR, 0.2-0.8) g/g (P < 0.001). No patient relapsed throughout the duration of B-cell depletion. Relapse occurred in 10% of patients at 2 years after the onset of B-cell reconstitution following the last rituximab dose. Over a combined follow-up time of 228 patient-years, 18 serious adverse events occurred. One death occurred unrelated to treatment or primary MN, and 1 patient progressed to kidney failure requiring kidney replacement therapy. LIMITATIONS: Absence of a comparison group. CONCLUSIONS: All patients with primary MN treated with combination therapy achieved partial remission and most achieved a durable complete remission with an acceptable safety profile.

Inflammatory vaginitis in women on long-term rituximab treatment for autoimmune disorders.

BACKGROUND: Consequences of long-term B cell depletion with rituximab are not well understood. We describe inflammatory vaginitis as a potential side effect of long-term rituximab treatment, distinct from previously described vulvovaginal pyoderma gangrenosum. METHODS: We performed a retrospective analysis of women treated with rituximab for more than 1 year to determine the prevalence and clinical characteristics of vaginitis cases. We conducted a case-control analysis with up to 3 controls for each vaginitis case. RESULTS: We identified sixteen inflammatory vaginitis cases. Women with vaginitis were age 23-68 (median 42), primarily being treated for ANCA-associated vasculitis (11/16; 69%). Most reported copious vaginal discharge (100%) and pain with sex (75%). All women with return of circulating B-cells to > 10 cells/mL had complete (5/9) or significant (4/9) improvement in symptoms. In case-control analysis there was no significant difference in length of B-cell depletion, immune parameters, creatinine levels, and history of neutropenia. CONCLUSION: Inflammatory vaginitis is a potential side effect of prolonged continuous B cell depletion with rituximab. More studies are needed to characterize the incidence and etiology of vaginitis among women on long term rituximab therapy and establish a causal relationship.

Improved survival with renal transplantation for end-stage renal disease due to granulomatosis with polyangiitis: data from the United States Renal Data System.

BACKGROUND: Renal transplantation is the optimal treatment for selected patients with end-stage renal disease (ESRD). However, the survival benefit of renal transplantation among patients with ESRD attributed to granulomatosis with polyangiitis (GPA) is unknown. METHODS: We identified patients from the United States Renal Data System with ESRD due to GPA (ESRD-GPA) between 1995 and 2014. We restricted our analysis to waitlisted subjects to evaluate the impact of transplantation on mortality. We followed patients until death or the end of follow-up. We compared the relative risk (RR) of all-cause and cause-specific mortality in patients who received a transplant versus non-transplanted patients using a pooled logistic regression model with transplantation as a time-varying exposure. RESULTS: During the study period, 1525 patients were waitlisted and 946 received a renal transplant. Receiving a renal transplant was associated with a 70% reduction in the risk of all-cause mortality in multivariable-adjusted analyses (RR=0.30, 95% CI 0.25 to 0.37), largely attributed to a 90% reduction in the risk of death due to cardiovascular disease (CVD) (RR=0.10, 95% 0.06-0.16). DISCUSSION: Renal transplantation is associated with a significant decrease in all-cause mortality among patients with ESRD attributed to GPA, largely due to a decrease in the risk of death to CVD. Prompt referral for transplantation is critical to optimise outcomes for this patient population.

Combination therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic membranous nephropathy: a case series.

BACKGROUND: Membranous nephropathy is a common cause of the nephrotic syndrome. Treatment with standard regimens fails to induce complete remission in most patients. We evaluated the efficacy of combination therapy with rituximab, low-dose, oral cyclophosphamide, and an accelerated prednisone taper (RCP) for the treatment of idiopathic membranous nephropathy. METHODS: We analyzed 15 consecutive patients with idiopathic membranous nephropathy treated with RCP at Massachusetts General Hospital. Seven patients (47%) received RCP as initial therapy, and the other eight patients (53%) received RCP for relapsing or refractory disease. All patients had at least 1 year of follow-up. The co-primary outcomes were attainment of partial and complete remission. Partial remission was defined as a urinary protein to creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline. Complete remission was defined as a UPCR < 0.3 g/g. Secondary outcomes were serious adverse events and the change in proteinuria, serum creatinine, serum albumin, cholesterol, triglycerides, and immunoglobulin G levels after 1 year of treatment. RESULTS: Over a median follow-up time of 37 (IQR, 34-44) months, 100% of patients achieved partial remission and 93% of patients achieved complete remission at a median time of 2 and 13 months, respectively. After 1 year of treatment, median (IQR) UPCR declined from 8.2 (6.6-11.1) to 0.3 (0.2-0.7) g/g (P < 0.001). Three serious adverse events occurred over 51 patient years. No patients died or progressed to ESKD. CONCLUSIONS: Treatment of idiopathic membranous nephropathy with RCP resulted in high rates of complete remission. Larger studies evaluating this regimen are warranted.

Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis.

PURPOSE OF REVIEW: Antineutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease resulting in small-vessel inflammation caused by pathogenic autoantibodies directed against proteinase 3 or myeloperoxidase. Legal drug culprits have been implicated as causative agents in secondary forms of disease, and a recent burst of reports also implicate levamisole-adulterated cocaine as a culprit. RECENT FINDINGS: Here, we briefly discuss all drug culprits associated with ANCA vasculitis and then focus on clinical, serologic, therapeutic and mechanistic aspects of four main drug culprits receiving attention of late, namely hydralazine, minocycline, propylthiouracil (PTU) and levamisole-adulterated cocaine. SUMMARY: Hydralazine, minocycline, propylthiouracil and levamisole-adulterated cocaine use should be closely considered in any patient where ANCA vasculitis is entertained given the wide use of these drugs in the community. Furthermore, medical practitioners should test urine for the presence of cocaine in any patient with presumed ANCA vasculitis, and if positive, then urine should also be tested for levamisole. Clinical features can be severe requiring not only drug cessation and supportive care, but also immunosuppression, plasma exchange in severe cases and dialysis as needed. Clinical trial investigators should strongly consider excluding patients with drug-induced forms of disease and mechanistic inroads are greatly needed in these secondary forms of disease to help elucidate the underlying cause and pathogenesis of ANCA vasculitis.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Continuous renal replacement therapy outcomes in acute kidney injury and end-stage renal disease: a cohort study.

INTRODUCTION: Continuous renal replacement therapy (CRRT) is a widely used but resource-intensive treatment. Despite its broad adoption in intensive care units (ICUs), it remains challenging to identify patients who would be most likely to achieve positive outcomes with this therapy and to provide realistic prognostic information to patients and families. METHODS: We analyzed a prospective cohort of all 863 ICU patients initiated on CRRT at an academic medical center from 2008 to 2011 with either new-onset acute kidney injury (AKI) or pre-admission end-stage renal disease (ESRD). We examined in-hospital and post-discharge mortality (for all patients), as well as renal recovery (for AKI patients). We identified prognostic factors for both in-hospital and post-discharge mortality separately in patients with AKI or ESRD. RESULTS: In-hospital mortality was 61% for AKI and 54% for ESRD. In patients with AKI (n=725), independent risk factors for mortality included age over 60 (OR 1.9, 95% CI 1.3, 2.7), serum lactate over 4 mmol/L (OR 2.2, 95% CI 1.5, 3.1), serum creatinine over 3 mg/dL at time of CRRT initiation (OR 0.63, 95% CI 0.43, 0.92) and comorbid liver disease (OR 1.75, 95% CI 1.1, 2.9). Among patients with ESRD (n=138), liver disease was associated with increased mortality (OR 3.4, 95% CI 1.1, 11.1) as was admission to a medical (vs surgical) ICU (OR 2.2, 95% CI 1.1, 4.7). Following discharge, advanced age became a predictor of mortality in both groups (AKI: HR 1.9, 95% CI 1.2, 3.0; ESRD: HR 4.1, 95% CI 1.5, 10.9). At the end of the study period, only 25% (n=183) of patients with AKI achieved dialysis-free survival. CONCLUSIONS: Among patients initiating CRRT, risk factors for mortality differ between patients with underlying ESRD or newly acquired AKI. Long-term dialysis-free survival in AKI is low. Providers should consider these factors when assessing prognosis or appropriateness of CRRT.

Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan.

Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m2 in the avacopan group and 4.1 ml/min per 1.73 m2 in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m2. Methods: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. Results: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m2. At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m2 in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m2, respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. Conclusion: Among patients with baseline eGFR ≤20 ml/min per 1.73 m2 in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

T cell responses to SARS-CoV-2 infection and vaccination are elevated in B cell deficiency and reduce risk of severe COVID-19.

Individuals with primary and pharmacologic B cell deficiencies have high rates of severe disease and mortality from coronavirus disease 2019 (COVID-19), but the immune responses and clinical outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination have yet to be fully defined. Here, we evaluate the cellular immune responses after both SARS-CoV-2 infection and vaccination in patients receiving the anti-CD20 therapy rituximab (RTX) and those with low B cell counts due to common variable immune deficiency (CVID) disease. Assessment of effector and memory CD4+ and CD8+ T cell responses to SARS-CoV-2 revealed elevated reactivity and proliferative capacity after both infection and vaccination in B cell-deficient individuals, particularly within the CD8+ T cell compartment, in comparison with healthy controls. Evaluation of clinical outcomes demonstrates that vaccination of RTX-treated individuals was associated with about 4.8-fold reduced odds of moderate or severe COVID-19 in the absence of vaccine-induced antibodies. Analysis of T cell differentiation demonstrates that RTX administration increases the relative frequency of naïve CD8+ T cells, potentially by depletion of CD8+CD20dim T cells, which are primarily of an effector memory or terminal effector memory (TEMRA) phenotype. However, this also leads to a reduction in preexisting antiviral T cell immunity. Collectively, these data indicate that individuals with B cell deficiencies have enhanced T cell immunity after both SARS-CoV-2 infection and vaccination that potentially accounts for reduced hospitalization and severe disease from subsequent SARS-CoV-2 infection.

COVID-19 Recovery Without B Cells or Antibodies in Patients Receiving Rituximab for Autoimmune Disease.

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Incidence, Clinical Features, and Outcomes of Late-Onset Neutropenia From Rituximab for Autoimmune Disease.

OBJECTIVE: Late-onset neutropenia (LON) is an underrecognized complication of rituximab treatment. We undertook this study to describe its incidence, risk factors, clinical features, management, and recurrence. METHODS: We conducted a single-center retrospective cohort study of 738 adult patients with autoimmune disease who were treated with rituximab to induce continuous B cell depletion. The primary outcome measure was LON, defined as an unexplained absolute neutrophil count of <1,000 cells/µl during B cell depletion. Secondary outcome measures included incidental diagnosis, fever, sepsis, filgrastim use, and recurrent LON. We assessed predictors of LON using Cox proportional hazards regression models. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We identified 107 episodes of LON in 71 patients. The cumulative incidence at 1 year of B cell depletion therapy was 6.6% (95% CI 5.0-8.7). The incidence rate during the first year was higher compared to thereafter (7.2 cases per 100 person-years [95% CI 5.4-9.6] versus 1.5 cases per 100 person-years [95% CI 1.0-2.3]). Systemic lupus erythematosus and combination therapy with cyclophosphamide were each independently associated with an increased risk of LON (adjusted HR 2.96 [95% CI 1.10-8.01] and 1.98 [95% CI 1.06-3.71], respectively). LON was not observed in minimal change disease or focal segmental glomerulosclerosis. The majority of episodes (59.4%) were asymptomatic. Fever and sepsis complicated 31.3% and 8.5% of episodes, respectively. Most patients (69%) were treated with filgrastim. Rituximab rechallenge occurred in 87% of patients, of whom 21% developed recurrent LON. CONCLUSION: LON is common and often incidental. Most cases are reversible and respond well to filgrastim. However, LON can be associated with serious infections and thus warrants vigilant monitoring.

Long-Term Safety of Rituximab in Granulomatosis With Polyangiitis and in Microscopic Polyangiitis.

OBJECTIVE: The present study was undertaken to conduct a phase IV, open-label, prospective study to characterize the long-term safety of rituximab in a 4-year observational registry of adult patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) within the US. METHODS: Patients initiating treatment with rituximab were evaluated every 6 months for up to 4 years. Outcomes included the incidence of serious adverse events (SAEs), infusion-related reactions (IRRs), and SAEs of specific interest, including serious infections, serious cardiac events, serious vascular events, and malignancies. RESULTS: Overall, 97 patients (72 with GPA and 25 with MPA) received rituximab through a median of 8 (range 1-28) infusions and were followed up for a median of 3.94 years (range 0.05-4.32 years). The estimated incidence rates (95% confidence interval [95% CI]) of serious infections, serious cardiac events, and serious vascular events were 7.11 (4.55-10.58), 5.03 (2.93-8.06), and 2.37 (1.02-4.67) per 100 patient-years (PYs), respectively. No IRRs or SAEs occurred within 24 hours of an infusion of rituximab. None of the 9 deaths reported (crude mortality rate 2.67 [95% CI 1.22-5.06] per 100 PYs) were considered to be related to use of rituximab. CONCLUSION: The safety profile of long-term treatment with rituximab in patients with GPA or MPA was consistent with that of rituximab administered for shorter durations and with rituximab's known safety profile in other autoimmune diseases for which it has received regulatory approval. These findings provide clinicians with long-term, practice-level safety data for rituximab in the treatment of GPA or MPA.

Continuous B-cell depletion in frequently relapsing, steroid-dependent and steroid-resistant nephrotic syndrome.

BACKGROUND: Patients with frequently relapsing (FR), steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome are a therapeutic challenge with limited treatment options. Here, we retrospectively analyze the efficacy and safety of rituximab-induced continuous B-cell depletion in these populations. METHODS: Patients were included if they were at least 18 years of age and had FR, SD or SR minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and were treated with a strategy of continuous B-cell depletion. Partial remission (PR) was defined as a urinary protein:creatinine ratio (UPCR) of ≤3.5 g/g and a 50% reduction in the UPCR from baseline. Complete remission (CR) was defined as a UPCR ≤0.3 g/g. RESULTS: We identified 20 patients with MCD (n = 13) or FSGS (n = 7) who fulfilled the inclusion criteria. All patients had either SD (n = 12), SR (n = 7) or FR (n = 1) disease. Patients received a median of nine rituximab doses [interquartile range (IQR) 7.5, 11] and were treated for a median time of 28 months (IQR 23, 41). Prednisone was weaned from a median of 60 mg daily (IQR 40, 60) at rituximab initiation to 4.5 mg daily (IQR 0, 5.5) by 12 months. All patients achieved PR. CR occurred in 11 of 13 patients with FR or SD disease, but only 1 of 7 patients with SR disease (logrank P = 0.01). Four relapses occurred, all in patients with SR disease. Three serious infections occurred over 70.3 patient-years. CONCLUSION: Continuous B-cell depletion is a therapeutic option in the management of complicated nephrotic syndrome. Additional studies are needed to clarify the utility of this strategy.

Phospholipase A2 receptor-associated membranous nephropathy in a patient with IgG4-related disease: A case report.

RATIONALE: IgG4-related disease (IgG4-RD) is a multiorgan disease of unestablished prevalence that is characterized histopathologically by a dense lymphoplasmacytic infiltrate enriched with IgG4-expressing plasma cells and associated with storiform fibrosis. Tubulointerstitial nephritis (TIN) is the most common renal manifestation of IgG4-RD, but membranous nephropathy (MN) has also been described and often occurs in the context of concurrent TIN. Patients with IgG4-related MN have been characteristically negative for autoantibodies to the phospholipase A2 receptor (PLA2R). PATIENT CONCERNS: A 45-year-old man presented with abdominal pain and lower extremity edema. DIAGNOSIS: Histopathological evaluation of pancreas and liver biopsies established a diagnosis of IgG4-RD. Renal biopsy confirmed a diagnosis of PLA2R-associated MN without evidence of concurrent TIN. INTERVENTIONS: The patient was treated with rituximab, a short course of low-dose, oral cyclophosphamide, and a rapid glucocorticoid taper. OUTCOMES: The patient achieved remission of MN after 8 months of therapy and maintained remission of IgG4-RD. LESSONS: PLA2R-associated MN may be a rare manifestation of IgG4-RD. Systematic evaluation of larger cohorts of IgG4-RD patients for the presence of PLA2R autoantibodies and the investigation of PLA2R-associated MN cohorts for evidence of IgG4-RD would facilitate the understanding of the nature of the relationship between these observations.