Keogh, Karina A.

ObjectiveDisease 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.MethodsThe 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.ResultsTwenty‐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).ConclusionRe‐treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

Objective Diffuse alveolar hemorrhage (DAH) is an uncommon complication of primary antiphospholipid syndrome (APS). We aimed to describe the clinical characteristics, treatment, and outcomes of primary APS–associated DAH in a single center. Methods We conducted a retrospective review of all adults with primary APS–associated DAH evaluated at Mayo Clinic over a 15‐year period. DAH was defined as bilateral pulmonary infiltrates and bronchoalveolar lavage (BAL) fluid documenting progressively bloody returns and/or the presence of >20% hemosiderin‐laden macrophages. Patients with other causes of DAH were excluded. Results Eighteen patients were identified (median age 43 years). Capillaritis was present in surgical lung biopsy samples of 3 patients. BAL differential cell counts revealed predominantly neutrophils. All patients were treated initially with glucocorticoids. Cyclophosphamide (CYC) was used in 8 patients; complete remission was achieved in 3 patients treated with CYC alone and in 1 patient receiving combination therapy with rituximab (RTX). RTX was used in 9 patients; 2 patients achieved remission with RTX alone, whereas 3 patients required combination therapy with CYC or mycophenolate mofetil (MMF). No patient achieved complete remission while receiving single therapy with MMF, azathioprine, or plasma exchange. Intravenous gamma globulin therapy was administered in 5 patients; no patient achieved control of the disease. Six patients died, all because of complications related to uncontrolled DAH or its therapy. Conclusion We present the largest case series of primary APS–associated DAH reported in the literature. DAH carries a very poor prognosis and therapeutic options are limited. Immunosuppression with either CYC or RTX is associated with the highest likelihood of remission induction and should be considered early.

ObjectiveTo evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA).MethodsThe Rituximab in AAV trial was a randomized, double‐blind, placebo‐controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other).ResultsAlthough remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty‐four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety‐one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)–ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3‐ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare.ConclusionCurrent treatment regimens are largely successful in controlling AAV, but in approximately one‐fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3‐ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Granulomatosis with polyangiitis (Wegener’s) (GPA) may mimic IgG4-related disease (IgG4-RD) on histologic examination of some biopsies, especially those from head and neck sites. IgG4 immunostain is often performed in this context for differential diagnosis with IgG4-RD. However, the prevalence of IgG4+ cells in GPA has not been explored. We examined the IgG4+ cells in 26 cases confirmed as GPA by a thorough clinical and pathologic assessment. Twenty-six biopsies consisted of 14 sinonasal/oral cavity/nasopharynx, 7 orbit/periorbital, 3 lung/pleura, 1 iliac fossa/kidney, and 1 dura specimens. Eight of 26 (31%) biopsies revealed increased IgG4+ cells (>30/HPF and >40% in IgG4+/IgG+ ratio). The IgG4+ cells and IgG4+/IgG+ ratio ranged 37–137/hpf and 44–83%, respectively. Eight biopsies with increased IgG4+ cells were from sinonasal(n=4)or orbital/periorbital(n=4)sites. In conclusion, increased IgG4+ cells are not uncommonly seen in sinonasal or orbital/periorbital biopsies of GPA, which could pose as a diagnostic pitfall.

Abstract Rationale Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data. Objectives To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis. Methods A prospective open-label pilot trial was conducted with 10 patients monitored for 1 yr. Included were patients with active severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, ANCA positivity, and resistance to (or intolerance of) cyclophosphamide. The remission induction regimen consisted of oral prednisone (1 mg/kg/d) and four weekly infusions of rituximab (375 mg/m2). Prednisone was tapered and discontinued over 5 mo. Failure to achieve remission, a clinical flare in the absence of B lymphocytes, and inability to complete the glucocorticoid taper were considered treatment failures. Main Results Three women and seven men (median age, 57 yr; range, 25–72 yr) were enrolled. All had ANCA reacting with proteinase-3. The median activity score at enrollment was 6 (range, 5–10). All patients tolerated rituximab well, achieved swift B-lymphocyte depletion and complete clinical remission (activity score, 0) by 3 mo, and were tapered off glucocorticoids by 6 mo. Five patients were retreated with rituximab alone for recurring/rising ANCA titers according to protocol. One patient experienced a clinical flare after B lymphocyte reconstitution. Conclusion In this cohort, rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener's granulomatosis.