M. Ruivard

Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis

BACKGROUND Current standard therapy for Wegeners granulomatosis and microscopic polyangiitis combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine or methotrexate for maintenance therapy. However, azathioprine and methotrexate have not been compared with regard to safety and efficacy. METHODS In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegeners granulomatosis or microscopic polyangiitis who entered remission with intravenous cyclophosphamide and corticosteroids to receive oral azathioprine (at a dose of 2.0 mg per kilogram of body weight per day) or methotrexate (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that methotrexate would be less toxic than azathioprine. The secondary end points were severe adverse events and relapse. RESULTS Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (+/-SD) period of 29+/-13 months. Adverse events occurred in 29 azathioprine recipients and 35 methotrexate recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the azathioprine group and 11 patients in the methotrexate group (P=0.11). The primary end point was reached in 7 patients who received azathioprine as compared with 12 patients who received methotrexate (P=0.21), with a corresponding hazard ratio for methotrexate of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the methotrexate group. Twenty-three patients who received azathioprine and 21 patients who received methotrexate had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug. CONCLUSIONS These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegeners granulomatosis and microscopic polyangiitis after initial remission. (ClinicalTrials.gov number, NCT00349674.)

Autoimmune thrombocytopenic purpura and common variable immunodeficiency: Analysis of 21 cases and review of the literature

Abstract: To describe the main characteristics and outcome of autoimmune thrombocytopenic purpura (AITP) in patients with common variable immunodeficiency (CVID), we analyzed data from 21 patients and reviewed additional cases from the literature. To be included in this study, patients had to have CVID and a previous history of AITP with a platelet count ≤50 × 109/L at onset. A complete response to treatment was defined by a platelet count ≥150 × 109/L, and a partial response by a platelet count >50 × 109/L with an increase of at least twofold the initial level. The median platelet count at AITP diagnosis was 20 × 109/L (range, 2-50 × 109/L). The median age at AITP diagnosis was 23 years (range, 1-51 yr), whereas the median age at CVID diagnosis was 27 years (range, 10-74 yr). CVID was diagnosed before the onset of AITP in only 4 patients (19%), 3 of whom were being treated with intravenous immunoglobulin (IVIg) replacement therapy. CVID was diagnosed more than 6 months after AITP in 13 cases (62%), and the 2 conditions were diagnosed concomitantly in 4 cases. Eleven patients (52%) had at least 1 autoimmune manifestation other than AITP, among which autoimmune hemolytic anemia (7 cases) and autoimmune neutropenia (5 cases) were preeminent. Seventeen of the 21 patients (80%) received at least 1 treatment for AITP; 13 patients received corticosteroids alone and 7 (54%) achieved at least a partial response; 8 patients received IVIg at 1-2 g/kg alone or in combination with steroids, leading to a short-term response rate of 50%. Four patients underwent a splenectomy (2 complete responses, 2 failures); 2 additional splenectomies were performed for associated autoimmune hemolytic anemia. With a mean follow-up of 5.6 years after the surgical procedure, none of the 6 splenectomized patients had a life-threatening infection. With a median follow-up after AITP onset of 12 years, 13/21 patients (62%) were in treatment-free remission (7 complete responses, 6 partial responses), 7 patients (23%) were in remission while on prednisone ≤20 mg/day with or without azathioprine, and only 1 patient still had a platelet count <50 × 109/L. Five patients had died at the time of the analysis; none of the deaths was related to a hemorrhage. Severe infections including 3 fatal bacterial infections and 2 opportunistic infections occurred in 6 patients during or after treatment of AITP. In conclusion, AITP, alone or in combination with autoimmune hemolytic anemia (Evans syndrome) and/or autoimmune neutropenia, is frequent in patients with CVID, and is not prevented by IVIg substitutive therapy. Since AITP frequently precedes the diagnosis of CVID, testing for immunoglobulin levels should be performed in every patient diagnosed with AITP. Steroids and splenectomy seem to have the same efficacy as in idiopathic AITP, but the increased risk of severe infections must be taken into consideration. Abbreviations: AITP = autoimmune thrombocytopenic purpura, CVID = common variable immunodeficiency, IVIg = intravenous immunoglobulin.

Igg4-related Systemic Disease: Features and Treatment Response in a French Cohort

AbstractIgG4-related systemic disease is now recognized as a systemic disease that may affect various organs. The diagnosis is usually made in patients who present with elevated IgG4 in serum and tissue infiltration of diseased organs by numerous IgG4+ plasma cells, in the absence of validated diagnosis criteria. We report the clinical, laboratory, and histologic characteristics of 25 patients from a French nationwide cohort. We also report the treatment outcome and show that despite the efficacy of corticosteroids, a second-line treatment is frequently necessary. The clinical findings in our patients are not different from the results of previous reports from Eastern countries. Our laboratory and histologic findings, however, suggest, at least in some patients, a more broad polyclonal B cell activation than the skewed IgG4 switch previously reported. These observations strongly suggest the implication of a T-cell dependent B-cell polyclonal activation in IgG4-related systemic disease, probably at least in part under the control of T helper follicular cells.

The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From a European Registry

BACKGROUND The systemic capillary leak syndrome (SCLS) is a rare disease characterized by life-threatening attacks of capillary hyperpermeability. OBJECTIVE To describe the clinical characteristics, laboratory findings, treatments, and outcomes of patients with SCLS who were not previously reported in the literature. DESIGN Case series. SETTING Patients referred to a European multicenter SCLS registry between January 1997 and July 2010. PATIENTS 28 patients with SCLS. MEASUREMENTS Frequency, severity of attacks, and vital status were assessed every 6 months, from diagnosis to the end of the study. RESULTS 13 men and 15 women referred to the registry who were not previously reported in the literature had 252 attacks. Median age at disease onset was 49.1 years (range, 5.4 to 77.7 years), and median annual frequency of attacks was 1.23 (range, 0.13 to 21.18) per patient. Monoclonal IgG gammopathy was observed in 25 patients (89%). Preventive treatment included intravenous immunoglobulin (n = 18), terbutaline (n = 9), and aminophylline (n = 10). Eight patients died (29%); 1-year survival was 89%, and 5-year survival was 73%. Death was directly related to SCLS attacks in 6 of 8 cases (75%). In 10 patients with a prediagnosis period greater than 6 months who received preventive treatment, the annual frequency of attacks after diagnosis decreased by a median of 1.55 (range, 0.14 to 8.84) per patient. Five years after diagnosis, survival was 85% in 23 patients who had received prophylactic treatment and 20% in 5 patients who had not. LIMITATION The benefits of preventive treatment could not be precisely ascertained because of the small sample size and because most patients received several treatments. CONCLUSION Clinical experience with these 28 patients with SCLS suggests that prophylactic treatment with β(2)-agonists or intravenous immunoglobulin may reduce the frequency and severity of attacks and may improve survival. PRIMARY FUNDING SOURCE Université Pierre et Marie Curie, Paris, France.

Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients.

Patients with common variable immunodeficiency (CVID) are at high risk of developing immune thrombocytopenia (ITP) and/or autoimmune haemolytic anaemia (AHA). Given their underlying immunodeficiency, immunosuppressive treatment of these manifestations may increase the risk of infection. To assess efficacy and safety of rituximab in patients with CVID‐associated ITP/AHA, a multicentre retrospective study was performed. Thirty‐three patients, 29 adults and four children, were included. Patients received an average of 2·6 treatments prior to rituximab including steroids, intravenous immunoglobulin and splenectomy (21%). The median ITP/AHA duration at time of first rituximab administration was 12 months [range 1–324] and the indication for using rituximab was ITP (22 cases), AHA (n = 5) or both (n = 7); 1 patient was treated sequentially for ITP and then AHA. The overall initial response rate to rituximab was 85% including 74% complete responses. After a mean follow‐up of 39 ± 30 months after rituximab first administration, 10 of the initial responders relapsed and re‐treatment with rituximab was successful in 7/9. Severe infections occurred after rituximab in eight adults (24%), four of whom were not on immunoglobulin replacement therapy. In conclusion, rituximab appears to be highly effective and relatively safe for the management of CVID‐associated severe immune cytopenias.

Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors

The purpose of this study was to assess the long-term outcomes of patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS)-defined poor-prognosis factors (FFS=0) and enrolled in a prospective clinical trial. Patients were followed (2005-2012) under routine clinical care in an extended study and data were recorded prospectively. Long-term survival, disease-free survival (DFS), relapses, therapeutic responses and sequelae were analyzed. Mean±SD follow-up was 98.2±41.9months. After having initially received glucocorticoids (GC) alone, according to the study protocol, 82% (97/118) patients achieved remission but 18% (21/118) required ≥1 immunosuppressant(s) (IS) before 19/21 achieved remission. Two patients died before entering remission. After remission, 53% (61/116) patients relapsed 25.6±27.9months after starting treatment. The 5- and 8-year overall survival rates were 93% and 86%, respectively, with no difference between PAN and MPA, and between relapsers and nonrelapsers. DFS was shorter for MPA than PAN patients (P=0.02). Throughout follow-up, 47% of patients required ≥1 IS. At the last follow-up visit, 44% were still taking GC and 15% IS. The mean vasculitis damage index score was 1.9±1.9; the most frequent sequelae were peripheral neuropathy, hypertension and osteoporosis. For PAN or MPA patients without poor-prognosis factors at diagnosis and treated initially with GC alone, long-term survival was excellent. However, relapses remained frequent, requiring IS introduction for nearly half of the patients. To lower the frequencies of relapses and sequelae remains a challenge for FFS=0 PAN and MPA patients.

The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura.

The response to high‐dose intravenous immunoglobulin (IVIg) was recently reported to be predictive of outcome after splenectomy in patients with autoimmune thrombocytopenic purpura (AITP). We analysed the records of 75 adults with chronic AITP who received IVIg and subsequently underwent splenectomy. There was no significant difference in the response rate to splenectomy according to whether or not patients had responded to IVIg (81% v 67%, P = 0.36). Age, the time from diagnosis to splenectomy, and the response to steroids were also not significantly associated with outcome after splenectomy. These results indicate that the response to IVIg or steroids is not predictive of the efficacy of splenectomy.

Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial

Objectives To study the efficacy of rescue treatment strategies and outcomes in patients with Wegeners granulomatosis (WG) and microscopic polyangiitis (MPA) not achieving remission with first-line induction with corticosteroids (CS) and intravenous cyclophosphamide (CYC). Methods 159 eligible patients in the Wegeners Granulomatosis-Entretien (WEGENT) trial newly diagnosed with systemic or renal WG or MPA with ≥1 poor prognosis factors were included in this prospective study. Rescue treatment strategies and outcomes in patients with induction-refractory disease were analysed and patient characteristics at diagnosis were compared with those of induction-responders. Results Most patients (n=126, 79.2%) achieved remission; 1 stopped induction because of allergy and 32 were induction-refractory (24 WG and 8 MPA); 11 died rapidly within a median of 2.5 months, 6 of uncontrolled disease, 1 of an infectious complication and 4 of both. Treatment was discontinued in 1 patient with MPA with end-stage renal disease. Induction was switched to oral CYC in 20 patients, combined with infliximab in 1; 15 (75%) achieved remission or low disease activity state, 3 subsequently died of uncontrolled disease and 2 entered remission using several other agents including biological agents. Alveolar haemorrhage and a creatinine level >200 μmol/l were independently associated with induction-refractory disease. Among patients with induction-refractory disease, massive alveolar haemorrhage was associated with higher mortality. Conclusion Switching to oral CYC can be an effective rescue treatment for patients with systemic forms of WG or MPA who fail to achieve remission with first-line CS and intravenous CYC. However, a more rapidly effective regimen remains to be identified for most severely affected patients whose outcomes can be rapidly fatal.

Autoimmune hemolytic anemia and common variable immunodeficiency: a case-control study of 18 patients.

To describe the main characteristics and treatment of autoimmune hemolytic anemia (AHA) in patients with common variable immunodeficiency (CVID), we analyzed data from 18 patients, 4 from an earlier study and 14 from the French DEF-I cohort on adult patients with primary hypogammaglobulinemia. To be included, patients had to have CVID and a previous history of AHA with a hemoglobin level ≤90 g/L at onset. To determine whether AHA is associated with a particular clinical phenotype of CVID, we conducted a case-control study from the DEF-I cohort. The estimated frequency of AHA in CVID patients from the DEF-I cohort was 5.5% (14/252). Median age at AHA diagnosis was 26 years (range, 1-57 yr), and 27.5 years (range, 5-61 yr) at CVID diagnosis. CVID was diagnosed before the onset of AHA in only 2 patients (11%). CVID was diagnosed more than 6 months after AHA in 10 cases (55.5%), and the 2 conditions were diagnosed concomitantly in 6 cases. The 14 patients included in the DEF-I cohort were compared with 238 control patients with CVID but without AHA. Corticosteroids were used as initial treatment for all patients in the current study. An initial response was obtained in 15 of 18 (83%) patients. Overall, 9 of these (60%) achieved a lasting response with steroids alone (7 patients) or in combination with intravenous immunoglobulin (2 patients). Seven patients underwent splenectomy, and 5 additional splenectomies were performed for associated autoimmune thrombocytopenic purpura. After splenectomy, a lasting response was obtained in 3 of the 7 patients with AHA. However, 5 of the 12 splenectomized patients experienced life-threatening infection. Severe infection occurred in 2 of 4 patients receiving immunosuppressive drugs. At the end of follow-up, 13 of 18 (72%) patients were in treatment-free remission (13 complete responses), and 4 of 18 (22%) were in remission while on prednisone ≤20 mg/d. One patient had died, of cancer. Abbreviations: AHA = autoimmune hemolytic anemia; AITP = autoimmune thrombocytopenic purpura; CVID = common variable immunodeficiency; IVIg = intravenous immunoglobulin; NHL = non-Hodgkin lymphoma.

Long‐term outcomes of the WEGENT trial on remission‐maintenance for granulomatosis with polyangiitis or microscopic polyangiitis

Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with polyangiitis (Wegeners) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.