ANCA-Associated Vasculitis.

ANCA-associated vasculitis (AAV) is a necrotizing, small-to-medium vessel vasculitis associated with significant morbidity and mortality. AAV is a systemic autoimmune disease affecting kidneys, eyes, sinuses, peripheral nerves, skin, and upper and lower respiratory tracts. AAV tends to present in characteristic phenotypes categorized clinically as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA). Kidney involvement is a common feature of AAV, and has important implications on disease prognosis and management. Existing therapies have been refined and improvements in our understanding of the pathophysiology of AAV has led to approval of novel therapies. In this review, we provide an overview of epidemiology, disease mechanisms, clinical presentation and review therapeutic strategies for induction and maintenance of remission.

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.

Oxalate nephropathy and chronic turmeric supplementation: a case report.

We present a case of a 69-year-old man who presented for routine check-up and was incidentally found to have kidney failure with an initially unrevealing history and bland urinary sediment. He was diagnosed with oxalate nephropathy in the setting of chronic turmeric supplementation and chronic antibiotic therapy with associated diarrhea. Our case provides several key insights into oxalate nephropathy. First, the diagnosis requires a high index of clinical suspicion. It is uncommonly suspected clinically unless there is an obvious clue in the history such as Roux-en-Y gastric bypass or ethylene glycol poisoning. Diagnosis can be confirmed by histopathologic findings and corroborated by serum levels of oxalate and 24-hour urinary excretion. Second, the diagnosis can often be missed by the pathologist because of the characteristics of the crystals unless the renal pathologist has made it a rule to examine routinely all H&E sections under polarized light. This must be done on H&E, as the other stains dissolve the crystals. Third, one oxalate crystal in a routine needle biopsy is considered pathologic and potentially contributing to the AKI or to the CKD in an important way. Fourth, secondary oxalosis can be largely mitigated or prevented in many cases, especially iatrogenic cases. This can come through the surgeon or the gastroenterologist providing proper instructions to patients on an oxalate-restricted diet or other specific dietary measures. Lastly, this case highlights the success that results from cooperation and communication between the pathologist and the treating physician.

Oxalate nephropathy and chronic turmeric supplementation: a case report / Nefropatia por oxalato e suplementação crônica de cúrcuma: relato de caso

ABSTRACT We present a case of a 69-year-old man who presented for routine check-up and was incidentally found to have kidney failure with an initially unrevealing history and bland urinary sediment. He was diagnosed with oxalate nephropathy in the setting of chronic turmeric supplementation and chronic antibiotic therapy with associated diarrhea. Our case provides several key insights into oxalate nephropathy. First, the diagnosis requires a high index of clinical suspicion. It is uncommonly suspected clinically unless there is an obvious clue in the history such as Roux-en-Y gastric bypass or ethylene glycol poisoning. Diagnosis can be confirmed by histopathologic findings and corroborated by serum levels of oxalate and 24-hour urinary excretion. Second, the diagnosis can often be missed by the pathologist because of the characteristics of the crystals unless the renal pathologist has made it a rule to examine routinely all H&E sections under polarized light. This must be done on H&E, as the other stains dissolve the crystals. Third, one oxalate crystal in a routine needle biopsy is considered pathologic and potentially contributing to the AKI or to the CKD in an important way. Fourth, secondary oxalosis can be largely mitigated or prevented in many cases, especially iatrogenic cases. This can come through the surgeon or the gastroenterologist providing proper instructions to patients on an oxalate-restricted diet or other specific dietary measures. Lastly, this case highlights the success that results from cooperation and communication between the pathologist and the treating physician.

RESUMO Relatamos o caso de um homem de 69 anos que se apresentou para exame de rotina e descobriu-se incidentalmente que ele tinha insuficiência renal, com histórico inicialmente não revelador e sedimento urinário brando. Ele foi diagnosticado com nefropatia por oxalato no contexto de suplementação crônica de cúrcuma e antibioticoterapia crônica com diarreia associada. Nosso caso fornece diversas sugestões importantes sobre nefropatia por oxalato. Primeiro, o diagnóstico requer elevado índice de suspeita clínica. A suspeita clínica é incomum, a menos que haja evidência óbvia no histórico, como bypass gástrico em Y de Roux ou envenenamento por etilenoglicol. O diagnóstico pode ser confirmado por achados histopatológicos e corroborado por níveis séricos de oxalato e excreção urinária de 24 horas. Segundo, o diagnóstico pode passar despercebido pelo patologista devido às características dos cristais, a menos que o patologista renal estabeleça como regra examinar rotineiramente todas as seções coradas com H&E sob luz polarizada. Isso deve ser feito com H&E, pois, outras colorações dissolvem os cristais. Em terceiro lugar, um cristal de oxalato em biópsia por agulha de rotina é considerado patológico, contribuindo potencialmente para LRA ou para DRC de maneira significativa. Em quarto lugar, a oxalose secundária pode ser amplamente mitigada ou prevenida em muitos casos, especialmente casos iatrogênicos. Isso pode ser feito pelo cirurgião ou pelo gastroenterologista, fornecendo instruções adequadas aos pacientes sobre uma dieta restrita em oxalato ou outras medidas dietéticas específicas. Por fim, esse caso destaca o sucesso que resulta da cooperação e comunicação entre o patologista e o médico assistente.

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.

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.

Small fiber neuropathy associated with ANCA positivity: a case series and brief literature review.

INTRODUCTION: Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN. METHODS: This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA. RESULTS: Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients. DISCUSSION: This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association.

Association of renal transplantation with reduced risk of myocardial infarction and ischemic stroke in ANCA-associated vasculitis: An observational cohort study.

OBJECTIVE: Myocardial infarction and ischemic stroke are leading causes of cardiovascular (CV) morbidity and mortality in ANCA-associated vasculitis (AAV), especially for the 20% with end-stage renal disease (ESRD). We assessed the impact of renal transplantation on the risk of myocardial infarction and stroke among patients with ESRD due to AAV. METHODS: We identified patients from the United States Renal Data System with ESRD due to AAV between 2000 and 2016. We examined the association between renal transplantation and the risk of non-fatal and fatal myocardial infarction or ischemic stroke among waitlisted patients using Medicare claims and death data through 2017. We used time-varying Cox proportional hazards models with age as the time scale to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for myocardial infarction and ischemic stroke events among patients who received a renal transplant compared to those who remained on the waitlist. RESULTS: Of 1029 waitlisted patients, 593 (58%) were transplanted over a mean of 5.7 years. There were 17 events (4.6/1,000 person-years) in the transplanted group and 40 events (13.7/1,000 person-years) in the group that remained waitlisted. A renal transplant was associated with a 78% lower risk of myocardial infarction or ischemic stroke (HR=0.22, 95% CI 0.11 to 0.47). These findings persisted across sex and age groups and when censoring patients after living donor transplantation. CONCLUSIONS: Among AAV patients with ESRD, renal transplantation can substantially reduce the risk of myocardial infarction and ischemic stroke. Improving access to transplantation for this population may further improve outcomes.

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.

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.

Rituximab in Membranous Nephropathy.

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of "the new standard."

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

No Abstract.

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.

Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown?

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.