Alfred Mahr

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort.

OBJECTIVE Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long-term outcomes. METHODS A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis. RESULTS We identified 383 patients diagnosed between 1957 and June 2009 (128 [33.4%] before 1997 or earlier) and followed up for a mean±SD of 66.8±62.5 months. At diagnosis, their mean±SD age was 50.3±15.7 years, and 91.1% had asthma (duration 9.3±10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA-positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA-negative patients. Vasculitis relapses occurred in 35.2% of the ANCA-positive versus 22.5% of the ANCA-negative patients (P=0.01), and 5.6% versus 12.5%, respectively, died (P<0.05). The 5-year relapse-free survival rate was 58.1% (95% confidence interval [95% CI] 45.6-68.6) for ANCA-positive and 67.8% (95% CI 59.8-74.5) for ANCA-negative patients (P=0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse. CONCLUSION The characteristics and long-term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.

Clinical features and outcomes in 348 patients with polyarteritis nodosa: A systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French vasculitis study group database

OBJECTIVE Previous studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long-term outcomes in patients with well-characterized PAN diagnoses. METHODS We conducted a systematic retrospective study of 348 patients who were diagnosed as having PAN between March 1963 and October 2005, were registered in the French Vasculitis Study Group database, and satisfied the American College of Rheumatology and CHCC criteria. Patient characteristics and outcomes were analyzed and compared according to hepatitis B virus (HBV) status. RESULTS At diagnosis, the mean +/- SD age was 51.2 +/- 17.3 years. The most frequent findings were general symptoms (93.1%), neurologic manifestations (79%), skin involvement (49.7%), abdominal pain (35.6%), and hypertension (34.8%); 66.2% had renal artery microaneurysms; 70.1% had histologically proven PAN. Patients with HBV-related PAN (n = 123) had more frequent peripheral neuropathy, abdominal pain, cardiomyopathy, orchitis, and hypertension compared with patients with non-HBV-related PAN (n = 225). During a mean +/- SD followup of 68.3 +/- 63.5 months, 76 patients (21.8%) relapsed (63 with non-HBV-related PAN [28%] versus 13 with HBV-related PAN [10.6%]; P < 0.001); 86 patients (24.7%) died (44 with non-HBV-related PAN [19.6%] versus 42 with HBV-related PAN [34.1%]; P = 0.003). Five-year relapse-free survival rates were 59.4% (95% confidence interval [95% CI] 52.6-67.0) versus 67.0% (95% CI 58.5-76.8) for non-HBV-related PAN and HBV-related PAN, respectively. Multivariate analysis retained age >65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non-HBV-related PAN had a higher risk of relapse. CONCLUSION Our findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.

Treatment of Churg-Strauss syndrome without poor-prognosis factors: A multicenter, prospective, randomized, open-label study of seventy-two patients

OBJECTIVE To assess the efficacy of systemic corticosteroids (CS) alone as first-line treatment in patients with Churg-Strauss syndrome (CSS) without poor-prognosis factors, as defined by the Five-Factors Score (FFS), and to compare the efficacy and safety of oral azathioprine (AZA) versus intravenous pulse cyclophosphamide (CYC) as adjuvant immunosuppressive therapy for treatment failure or relapse. METHODS This multicenter, prospective, randomized, open-label therapeutic trial included 72 patients with newly diagnosed CSS (FFS of 0) treated with CS alone. At treatment failure or relapse, patients were randomized to receive 6 months of oral AZA or 6 pulses of CYC. Analyses were performed according to an intent-to-treat strategy. RESULTS The mean +/- SD followup was 56.2 +/- 31.7 months. Among the 72 patients studied, 93% achieved remission with CS therapy alone, and 35% relapsed, mainly during the first year of treatment. Among the 19 patients randomized to additional immunosuppression because of treatment failure or relapse, 5 of 10 receiving AZA and 7 of 9 receiving pulse CYC achieved remission, but the difference was not statistically significant. Survival rates in all patients at 1 and 5 years were 100% and 97%, respectively. At the end of followup, 79% of the patients whose disease was in remission required low-dose CS therapy, mainly to control respiratory disease. CS-related adverse events were observed in 31% of the 72 patients. CONCLUSION In CSS patients with an FFS of 0, survival was excellent, confirming the predictive value of the FFS in this disease. First-line therapy with CS achieved remission in most patients, but relapses were common, and one-third of them required additional immunosuppressive therapy. AZA or pulse CYC was fairly effective in treating CS-resistant disease or major relapses. Over the long term, most patients continued to take oral CS, which might explain the high rate of CS-related adverse events.

Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients

Objectives: To describe presentation and outcome of patients with scleroderma renal crisis (SRC). Methods: SRC was defined as rapidly progressive oliguric renal insufficiency and/or rapidly progressive arterial hypertension occurring during the course of systemic sclerosis (SSc). Chronic dialysis-free survival was analysed using multivariate Cox proportional hazards regression models. The risk for developing SRC associated with corticosteroid (CS) exposure during the preceding 1- or 3-month periods was analysed according to a case–crossover design. Results: A total of 50 SSc patients aged 53.3 (14.5) (mean (SD)) years were included in the study. SRC occurred between 1979 and 2003, after a mean (SD) disease duration of 27.7 (49.1) months. A total of 43 (86%) patients had diffuse SSc, 5 (10%) had limited cutaneous SSc and 2 (4%) had SSc sine scleroderma. At the time of SRC, 10 (20%) patients were taking angiotensin converting enzyme inhibitors, and mean creatininaemia was 468 (293) μmol/l. A total of 28 (56%) patients required haemodialysis. In all, 11 patients underwent a renal biopsy, all of them had specific vascular lesions of SRC. Multivariate analyses retained age >53 years and normal blood pressure as independent predictors of decreased dialysis-free survival. Exposure to CS prior to SRC was identified in 30 (60%) patients. The odds ratios for developing SRC associated with CS exposure during the preceding 1- or 3-month periods were 24.1 (95% CI 3.0–193.8) and 17.4 (95% CI 2.1–144.0), respectively. Conclusion: SRC remains associated with severe morbidity and mortality. CS might increase the risk of developing SRC. Further studies are needed to confirm these results.

Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: Results of a multicenter, prospective, open‐label study of twenty‐two patients

OBJECTIVE To evaluate at 9 months and 24 months the safety and efficacy of intravenous immunoglobulins (IVIGs) administered for 6 months to treat relapses of Wegeners granulomatosis (WG) or microscopic polyangiitis (MPA) occurring either under treatment or during the year following discontinuation of corticosteroids and/or immunosuppressants. METHODS Patients received IVIGs (0.5 gm/kg/day for 4 days) as additional therapy administered monthly for 6 months and were assessed every 3-6 months. Corticosteroids could be maintained or reintroduced at the time of relapse; immunosuppressants could be continued but could not be reintroduced. At months 9 (end point) and 24 (followup), the following information was collected: complete or partial remission, relapse as assessed with the Birmingham Vasculitis Activity Score (BVAS) 2005, and tolerance and safety of IVIG therapy. RESULTS Twenty-two Caucasian patients (7 men and 15 women) were studied: 19 had WG, and 3 had MPA. Their median age was 53 years (range 19-75 years), and their median duration of systemic vasculitis was 27 months (range 7-109 months). Their median BVAS 2005 score was 11 (range 3-25). At study entry, 21 patients were ANCA positive, and 21 patients were taking steroids and/or immunosuppressants. All patients experiencing relapse were treated with the same drug(s) plus IVIGs. All patients initially responded to IVIG therapy. By month 9, 13 patients had complete remission, 1 had partial remission, 7 had relapse, and 1 had treatment failure. In 8 of the 14 patients who had remission, the response persisted at month 24. Seven patients experienced minor side effects. CONCLUSION IVIGs induced complete remissions of relapsed ANCA-associated vasculitides in 13 of 22 patients at month 9. Because of the good safety and tolerance profiles of IVIGs, these agents can be included in a therapeutic strategy with other drugs used to treat relapses of WG or MPA.

Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: A prospective randomized study of one hundred twenty-four patients

OBJECTIVE To assess the efficacy of systemic corticosteroids alone as first-line treatment of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) without poor-prognosis factors as defined by the Five-Factors Score (FFS), and to compare the efficacy and safety of azathioprine versus pulse cyclophosphamide as adjunctive immunosuppressive therapy for patients experiencing treatment failure or relapse. METHODS This prospective, multicenter, therapeutic trial included 124 patients with newly diagnosed PAN or MPA (FFS of 0) treated with corticosteroids alone. At the time of treatment failure or disease relapse, patients were randomized to receive 6 months of therapy with oral azathioprine or 6 pulses of cyclophosphamide. Analyses was performed according to an intent-to-treat strategy. RESULTS The mean +/- SD followup period was 62 +/- 33 months. Treatment with corticosteroids alone induced remission in 98 patients; 50 (40%) of these patients had sustained disease remission, 46 (37%) experienced a relapse, and 2 became corticosteroid dependent (daily prednisone dose > or = 20 mg). In 26 patients (21%), treatment with corticosteroids alone failed, and 49 patients (40%) required additional immunosuppression. Among the 39 patients randomized, 13 of 19 achieved remission with cyclophosphamide pulses, and 14 of 20 achieved remission with azathioprine. Among all patients, the 1-year and 5-year survival rates were 99% and 92%, respectively. Six deaths occurred in the cyclophosphamide-treated group compared with 2 deaths in the azathioprine-treated group. Disease-free survival was significantly lower for patients with MPA than for those with PAN (P = 0.046). CONCLUSION For patients with PAN or MPA with an FFS of 0, overall 5-year survival was good, but first-line corticosteroid treatment was able to achieve and maintain remission in only about half of the patients, and 40% of the patients required additional immunosuppressive therapy. Azathioprine or pulse cyclophosphamide was fairly effective for treating corticosteroid-resistant disease or major relapses.

Treatment of Systemic Necrotizing Vasculitides in Patients Aged Sixty‐Five Years or Older: Results of a Multicenter, Open‐Label, Randomized Controlled Trial of Corticosteroid and Cyclophosphamide–Based Induction Therapy

To investigate a new therapeutic strategy, with rapid corticosteroid dose tapering and limited cyclophosphamide (CYC) exposure, for older patients with systemic necrotizing vasculitides (SNVs; polyarteritis nodosa [PAN], granulomatosis with polyangiitis [Wegneners] [GPA], microscopic polyangiitis [MPA], or eosinophilic GPA [Churg‐Strauss] [EGPA]).

Pathogénie des vascularites systémiques primitives (I) : vascularites ANCA-positives

Points essentiels ● La pathogenie des vascularites systemiques associees aux anticorps anti-cytoplasme de polynucleaires neutrophiles (ANCA) est incompletement elucidee. ● Parmi les vascularites ANCA-positives qui interessent les vaisseaux de petit calibre, on distingue la granulomatose de Wegener (GW), la polyangeite microscopique (MPA) et le syndrome de Churg et Strauss (SCS). Au cours de ces pathologies, les ANCA constituent un outil precieux d’aide au diagnostic. ● Des ANCA diriges contre la proteinase 3 sont detectes chez plus de 90 % des malades atteints de forme systemique de GW, tandis que des ANCA anti-myeloperoxydase (MPO) sont presents chez 60 a 75 % des malades atteints de MPA et 40 a 60 % des malades atteints de SCS. ● Le role pathogene des ANCA est bien documente in vivo, et le transfert passif des ANCA anti-MPO est suffisant pour induire des lesions de glomerulonephrite extra-capillaire dans un modele de souris invalidees pour le gene de la MPO et immunisees avec cet antigene. In vitro, chez la souris et chez l’homme, les ANCA anti-proteinase 3 sont capables d’activer les polynucleaires neutrophiles en presence de TNF-α et contribuent a la survenue des lesions. ● Des lymphocytes T (LT) pourraient jouer un role dans la pathogenie de la GW, des LT helper de type 1 ayant ete detectes dans les tissus de patients ayant une GW localisee, tandis que des LT helper de type 2 ont ete identifies au sein de lesions de vascularites de malades ayant une forme systemique de GW. ● Les polynucleaires eosinophiles pourraient jouer un role dans la pathogenie du SCS.The pathogenesis of different types of systemic vasculitis negative for antineutrophil cytoplasm antibodies (ANCA) and involving small or medium-sized vessels is not very well documented. During polyarteritis nodosa (PAN), which is related to hepatitis B virus (HBV) infection, as well as during cryoglobulinemic vasculitides, associated with hepatitis C virus (HCV), and probably during Henoch Schönlein purpura, histological lesions may result from the deposition of immune complexes formed from viral antigens and from antibodies responsible for the activation of the classic complement pathway and for recruitment of polymorphonuclear neutrophils. Two other mechanisms are discussed for other types of ANCA-negative systemic vasculitis: immune complex deposition and sheer stress at arterial bifurcation points. A bacterial superantigen is suspected in Kawasaki disease but remains unproved.

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.

Serum eosinophil cationic protein: a marker of disease activity in Churg-Strauss syndrome.

Abstract:  The cytotoxic proteins released by activated eosinophils should play a role in the development of Churg‐Strauss syndrome (CSS). Eighteen patients (15 males and 3 females, age 41 ± 13.3 years) with CSS according to the American College of Rheumatology criteria were included in the study. Thirteen serum samples from 11 patients were obtained at the time of disease flare, and the sera from 6 of them were also obtained at the time of clinical remission. Sera from seven other patients were obtained in clinical remission. Anti‐neutrophil cytoplasm antibodies were detected in four (22.2%) patients. Fifteen healthy individuals were used as controls. Mean eosinophil count differed significantly between CSS patients with active disease and patients in clinical remission (3,407/mm3 vs. 258/mm3; P < 0.01), between CSS patients with active disease and healthy individuals (3,407/mm3 vs. 211/mm3; P < 0.01). Mean serum ECP levels differed significantly between patients with active or inactive disease (219 μg/L vs. 56.8 μg/L; P < 0.0001), between patients with active disease and healthy individuals (219 μg/L vs. 26.2 μg/L; P < 0.0001), but not between patients with inactive disease and healthy individuals (ns). Peripheral blood eosinophils count correlated with serum ECP during CSS flares disease (R= 0.6264; P < 0.05) and during periods of remission (R= 0.4798; P < 0.05). Our results support that ECP might be used as a disease activity marker in CSS.