Clinical applications to main durable remission, minimize relapse and prevent infection in ANCA GN.

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The goals of therapeutic intervention in ANCA glomerulonephritis (GN) have evolved from preventing mortality to minimizing adverse effects of immunosuppression. Reduction of complications requires: 1) minimizing duration of immunotherapy for patients in complete durable remission and 2) prevention of infections in patients who need continued immunotherapy. The objective of this Project is to improve long-term outcomes of patients with ANCA GN by maintaining durable remission and minimizing complications of immunotherapy. Aim 1 evaluates the concept of remission and disease cure by seeking a molecular “remission signature” that can be used to identify those at very low relapse risk. We will measure immunologic, cellular, genetic and epigenetic markers in patients in complete remission off therapy for at least 2 years compared to matched patients with active disease. While Aim 1 strives to define patients who may be cured of disease, Aim 2 builds on the evidence that robust regulatory B cell populations impart a lower risk of relapse and identify patients who do not need maintenance immunosuppression. We propose a proof-of-concept prospective, randomized, open-label clinical trial evaluating time to relapse in patients who have attained remission with traditional induction therapy. Patients with recovery of a high proportion of B regulatory cells will be managed expectantly without further immunotherapy. Those with a low proportion of regulatory B cells will be randomized to maintenance immunosuppressive therapy or to close clinical monitoring with immunotherapy guided by clinical signs of active vasculitis. Although Aim 1 and Aim 2 focus on reducing immunosuppression, it is irrefutable that immunosuppression is a requirement for all patients with ANCA GN. Aim 3 focuses on limiting infectious complications of immunosuppression, the chief cause of death in ANCA GN. Knowing that respiratory infections are the leading cause of total and serious infections in ANCA GN, we propose a feasibility trial whereby patients with active disease will be randomized to receive placebo or daily azithromycin for 12 months, in in conjunction with standard immunotherapy. Azithromycin was selected for its antimicrobial and anti-inflammatory properties. The primary outcome will be incidence of respiratory tract infections, with secondary outcomes of incidence of serious infections, time to relapse, all-cause mortality, and adverse events associated with study medication also evaluated. Overall this Project aims to improve morbidity and mortality in ANCA GN through elimination of unnecessary immunosuppression in those with low risk of disease flare and to find protective strategies to reduce infectious burden in those requiring immunosuppression.