Dominique Lauque

Antineutrophil Cytoplasmic Antibodies and the Churg–Strauss Syndrome

Context Patients with the ChurgStrauss syndrome, a rare small-sized vessel vasculitis, sometimes have antineutrophil cytoplasmic autoantibodies (ANCAs). Contribution In this cross-sectional study, 43 of 112 (38%) patients who recently had received a diagnosis of the ChurgStrauss syndrome were ANCA-positive. Compared with ANCA-negative patients, ANCA-positive patients more often had peripheral neuropathy (84% vs. 65%) and renal manifestations (35% vs. 4%). Also, ANCA-negative patients more often had fever (55% vs. 30%) and cardiac manifestations (49% vs. 12%). Implications Phenotypes of patients with ANCA-positive and ANCA-negative ChurgStrauss syndrome may differ. The Editors The ChurgStrauss syndrome is a rare, small-sized vessel vasculitis that develops in patients who have usually had asthma and other allergic manifestations for several years or months. The syndrome is characterized by pulmonary involvement and extrapulmonary manifestations that can be serious and life-threatening when the heart, central nervous system, gastrointestinal tract, or kidneys are affected. It is associated with antineutrophil cytoplasmic antibodies (ANCAs) in 39% to 59% of patients (1, 2). For most ANCA-positive patients, the fluorescence pattern is perinuclear and IgG recognizes myeloperoxidase, as assessed by enzyme-linked immunosorbent assay (ELISA). No analysis of a large homogeneous cohort of patients with the ChurgStrauss syndrome has been reported since systematic ANCA testing became available, and the association of ANCA status with clinical characteristics and outcome has not been evaluated. We aimed to describe the clinical characteristics of patients who recently received a diagnosis of the ChurgStrauss syndrome and who were included in prospective therapeutic trials organized by the French Vasculitis Study Group (FVSG) and to compare the characteristics of patients with and without ANCA. Methods Patients and Treatments All patients had ChurgStrauss syndrome that satisfied the classification criteria established by the American College of Rheumatology (3) or the Chapel Hill nomenclature (4). We selected the cohort of 112 patients from those who were recruited by members of the FVSG and the European Vasculitis Study Group (EUVAS) and were enrolled in different prospective trials. We initially screened the report forms of 127 patients. We did not select 15 patients for several reasons: No data were forwarded for 7 patients, diagnosis was not confirmed for 6 patients, and 2 patients declined to give written informed consent. We enrolled all consecutive patients with the ChurgStrauss syndrome who met the inclusion criteria, except patients who were older than 75 years of age. We recruited most patients in France (58 centers) and other patients in Belgium (3 centers), Latvia (1 center), and the United Kingdom (1 center). The trials aimed to evaluate the optimal treatment of the ChurgStrauss syndrome. We considered only patients who had recently received a diagnosis, were older than 18 years of age, and were presenting their first flare for the trials. Treatment choice did not consider the patients ANCA status. Once we confirmed the diagnosis, we stratified patients according to the 5-factor score, which we prospectively devised and retrospectively validated to predict the overall mortality of patients with the ChurgStrauss syndrome according to the presence or absence of symptoms at diagnosis (5). The following items of poor prognosis make up the 5-factor score: classes of serum creatinine levels (140 mol/L [1.58 mg/dL] and >140 mol/L [>1.58 mg/dL]) and proteinuria (1 g/d and >1 g/d), severe gastrointestinal tract involvement, cardiomyopathy, or central nervous system involvement. We assigned 1 point for the presence of each factor. We also retrospectively applied the Birmingham Vasculitis Activity Score in its first presentation (6) at diagnosis. The score is a clinical index of disease activity based on symptoms and signs in 9 separate organ categories (systemic signs, skin, mucous membranes and eyes, earnosethroat, chest, heart and vessels, gastrointestinal, kidney, and central nervous system). According to the number and severity of clinical and biological symptoms, we accorded a predefined number of points to each category, then added the individual category scores to yield a maximum possible score of 63 points. We considered disease features only when they are attributable to active vasculitis. Because the Birmingham Vasculitis Activity Score was created after the therapeutic protocols had been designed, we did not use it to select the patients treatment. We also did not use it for follow-up or to define remission, failure, or relapse. We used only clinical and biological manifestations for this purpose. We assigned patients with a 5-factor score of 1 point or greater to receive 6 or 12 pulses of cyclophosphamide in combination with corticosteroids. We assigned patients without a poor prognosis factor (5-factor score of 0 points) to steroids alone and to receive immunosuppressants only when steroid therapy failed. Because the therapeutic trials are ongoing, their results are not yet available. We prospectively recruited patients between 1995 and December 2002. Analysis Once the ChurgStrauss syndrome was diagnosed, we recorded all data in a computerized databank. The pathologist provided histologic reports and slides that could be reviewed if desired. We obtained clinical reports, recorded on standardized report forms and completed by the treating physician, every month during the first year of follow-up, then every 3 months for the following year. When disease-related events occurred during follow-up, we obtained additional reports. We tested serum specimens for the presence of ANCA by indirect immunofluorescence, according to EUVAS recommendations (7), by using serum diluted to 1:16 and ethanol-fixed neutrophils. When we detected ANCA, we recommended but did not require ELISA determination of specificity (antimyeloperoxidase or antiproteinase 3). We performed ANCA tests at diagnosis and before starting treatment. When ANCA test results were initially positive, we checked results at each visit as required by the therapeutic protocols. We routinely tested ANCA in the immunology department of each participating hospital by using commercially available tests. The reproducibility and specificity of biological and immunologic tests are guaranteed, in France, by a national commission of the Ministry of Health. We performed some routine biological analyses (complete blood counts, creatininemia, electrolyte levels, proteinuria, hematuria, and aminotransferase levels) and chest radiography at entry and at each visit as requested by the protocol. Electrocardiography was compulsory at entry but was optional during follow-up. We performed more specific investigations (echocardiography and catheterization) when indicated by clinical manifestations and requested by the treating physician. Some data are missing: Information on a triggering factor was not identified in 3 patients, no data were obtained on earnosethroat status in 4 of 112 patients, and creatinine clearance could not be calculated for 9 of 112 patients. In all but 4 patients, C-reactive protein or erythrocyte sedimentation rate was reported. For 1 of 71 patients with biopsy-confirmed diagnoses, the complete pathologists report form was not sent, and we saw only the conclusion. Definitions We considered asthma to be severe when characterized by continuous dyspnea, when continuous administration of corticosteroids was required, or when oximetry and other pulmonary parameters necessitated hospitalization in an intensive care unit. We diagnosed specific cardiomyopathy after electrocardiography, echocardiography, and coronary artery arteriography in some patients to exclude another cause. Diagnosis was sometimes proven by biopsy. We considered histologically proven glomerulonephritis or proteinuria greater than 0.4 g/d and microscopic hematuria without urinary infection to be sufficient to diagnose renal involvement. We recorded clinical remission when clinical symptoms stabilized or regressed and initial laboratory abnormalities (except ANCA status) returned to normal. We defined relapses as the appearance of new systemic manifestations of vasculitis or worsening of at least 1 initial disease manifestation. Role of the Funding Sources The Ministre de la Recherche and the Institut National de la Recherche Mdicale, Paris, France, provided grants, which were used to monitor the therapeutic studies. The Hospices Civils de Lyon, Lyon, France, sponsored the therapeutic trials and was responsible for all of the legal aspects of the studies but did not support the studies financially. The principal investigators are employees of the Assistance PubliqueHpitaux de Paris. Members of the FVSG and the EUVAS included patients. The authors reviewed all of the data and wrote the manuscript. Results ANCA Status Testing We detected ANCA giving a perinuclear or cytoplasmic immunofluorescence-labeling pattern in serum specimens from 43 (38%) patients: 39 perinuclear ANCApositive patients and 4 cytoplasmic ANCApositive patients. Enzyme-linked immunosorbent assay showed that serum specimens of 34 of 39 patients with perinuclear ANCA (5 patients specimens were not tested) had antimyeloperoxidase specificity, but myeloperoxidase or proteinase 3 activity was not found in the 4 patients with cytoplasmic ANCA. We did not test other antigens. Demographic Characteristics and Clinical Symptoms Tables 1 and 2 detail the clinical characteristics of the 112 patients (57 women and 55 men; mean age, 52 years [SD, 15]) who participated in the study. Every patient had asthma, which preceded the first manifestation of the ChurgStrauss syndrome in 101 patients. Asthma and the ChurgStrauss syndrome occurred simultaneously in 9 patients, whereas asthma occurred 9 and 17 months after other clinical manifesta

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

OBJECTIVEnTo 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.nnnMETHODSnThis 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.nnnRESULTSnThe 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.nnnCONCLUSIONnIn 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.

Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature

Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis primarily associated with necrotizing glomerulonephritis and pulmonary capillaritis. In this retrospective study of 29 patients with MPA and alveolar hemorrhage (AH), we characterized the pulmonary manifestations at presentation and assessed the short- and long-term outcome. AH was diagnosed when bronchoalveolar lavage was macroscopically bloody, or contained hemosiderin-laden macrophages, in the absence of lung infection or pulmonary edema. MPA was diagnosed when AH was associated with focal segmental necrotizing glomerulonephritis at kidney biopsy or pathologically proved small-vessel vasculitis. There were 17 women and 12 men, with a mean age of 55.8 +/- 16.7 years. The onset was rapidly progressive, but in 8 (28%) patients, symptoms preceded the diagnosis for more than 1 year. The most constant systemic findings associated with AH were glomerulonephritis in 28 (97%) patients; fever (62%); myalgia and arthralgia (52%); weight loss (45%); ear, nose, and throat symptoms (31%); and skin involvement (17%). Lung opacities were bilateral in 26 (90%) patients, most frequently involving the lower part of the lungs. Bronchoalveolar lavage, performed in 27 patients, was hemorrhagic in 25 (93%), and contained numerous siderophages in others. Most patients were severely anemic (mean hemoglobin, 8.1 +/- 1.8 g/dL). ANCA, present in 27 (93%) patients, gave a perinuclear (14), cytoplasmic (11), or mixed (1) pattern. Mean serum creatinine level was 407 +/- 415 mumol/L. Renal biopsy confirmed the presence of necrotizing glomerulonephritis in 27 patients. Patients were treated with corticosteroids (100%), cyclophosphamide (79%), plasmapheresis (24%), dialysis (28%), and mechanical ventilation (10%). The overall mortality rate was 31% (9 patients). Deaths were related to vasculitis (5 patients) or side effects of treatment (4). Deaths were more frequent in aged or mechanically ventilated patients. The 5-year survival rate was 68%. The recovery of respiratory function among survivors was clinically considered complete in 20 (69%) patients. However, 7 patients (24%) had persistent alterations on pulmonary function tests. Of the 11 patients who had relapses, 2 died from AH.

idiopathic Chronic Eosinophilic Pneumonia: A Clinical and Follow-up Study of 62 Cases

Idiopathic chronic eosinophilic pneumonia (CEP) is a rare disorder of unknown cause with nonspecific respiratory and systemic symptoms but rather characteristic peripheral alveolar infiltrates on imaging, developing mainly in women and in atopic subjects. The disorder is highly responsive to oral corticosteroid therapy, but relapses are frequent on reducing or stopping treatment. The long-term course of the disease and data regarding outcome, particularly the need for prolonged oral corticosteroid therapy and the development of severe asthma, are somewhat contradictory. A multicentric retrospective study was conducted in an attempt to describe better the initial features and, above all, the later course of CEP in a large homogeneous series of 62 stringently selected patients of whom 46 were followed for more than 1 year. The prevalence of smokers was low (6.5%) and about half of our patients (51.6%) had a previous, and often prolonged, history of asthma. The clinical and roentgenographic features were in keeping with previous studies, but we found that computed tomography could disclose ground glass opacities not detected by X-ray, and that migratory infiltrates before treatment were more frequent (25.5%) than reported previously. The bronchoalveolar lavage cellular count always showed a striking eosinophilic pattern, thus allowing distinction between CEP and cryptogenic organizing pneumonia, both syndromes sharing many common clinical and imaging features. About two-thirds of the patients (68%) showed a ventilatory defect in pulmonary function tests, with about one-half of these presenting with an obstructive pattern, sometimes without previous asthma. Along with the submucosal eosinophilic infiltration noted in 2 patients without ventilatory defect, this is strong evidence to confirm that CEP is not only an alveolointerstitial but also an airway disease. The dramatic response to oral corticosteroid therapy was observed in all treated patients. Although only 1 patient initially treated for less than 6 months did not relapse, longer oral corticosteroid therapy in no way provided protection from further relapses. We thus propose to try to wean oral corticosteroid therapy after 6 months in patients without severe asthma, because recurrences remain responsive to oral steroids. However, prolonged oral corticosteroid therapy was necessary in the majority of patients, with 68.9% of those followed for more than 1 year still on oral corticosteroid therapy at the last follow-up, either because of relapse or because of severe asthma.

Hierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity.

The clinical phenotype and evolution of antisynthetase syndrome (ASS) are heterogeneous. This study was therefore undertaken to identify subgroups of ASS patients with similar clinico-biological features and outcomes. This retrospective multicentric study included 233 consecutive patients with three different anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS): anti-Jo1 (n=160), anti-PL7 (n=25) and anti-PL12 (n=48). To characterise ASS patients, bivariate, multiple correspondence (MCA), cluster and survival analyses were performed. Interstitial lung disease (ILD) and myositis were the most common ASS manifestations. However, their respective frequencies were correlated to anti-ARS specificity: ILD was more frequent (80% and 88% vs 67%, p=0.014) whereas myositis was less common (44% and 47% vs 74%, p<0.001) in patients with anti-PL7 and anti-PL12 compared to anti-Jo1. The MCA suggested that anti-PL7 and anti-PL12 phenotypes were close to one another and distinct from anti-Jo1. The clustering analysis confirmed these data, identifying subgroups strongly defined by the anti-ARS specificity and other clinical features. Cluster 1 (n=175, 86% of anti-Jo1) defined patients with the most diffuse phenotype, whereas patients from cluster 2 (n=48, 96% of anti-PL12 and anti-PL7) exhibited a disease more restricted to the lung. Patient survival was also conditioned by the anti-ARS specificity, and was significantly lower in patients with anti-PL7/12 rather than anti-Jo1 (p=0.012). Other factors associated with poor survival were mostly related to pulmonary involvement, including severe dyspnea (p=0.003) and isolated ILD (p=0.009) at diagnosis. In patients with ASS, the phenotype and the survival were correlated with the anti-ARS specificity.

Idiopathic chronic eosinophilic pneumonia and asthma: how do they influence each other?

Since idiopathic chronic eosinophilic pneumonia (ICEP) and asthma are frequently associated, their possible reciprocal influence on clinical presentation and evolution were investigated. The clinical and follow-up features of 53 cases of ICEP, of which 41 (77%) had asthma, were reviewed retrospectively. Asthma preceded the diagnosis of ICEP in 26 patients, was contemporaneous in eight patients, and developed 17±12 months after ICEP in seven patients. Presentation of ICEP was similar in asthmatics and nonasthmatics with the exception of a higher level of total immunoglobulin E in the former group. Patients with asthma at the time of diagnosis of ICEP were more likely to remain free of relapse of ICEP (56 versus 23%) and had a lower number of relapses per year of follow-up (median 0 versus 0.24). Moreover, they were treated more frequently with long-term inhaled corticosteroids (88 versus 31%) at last follow-up. Asthma got worse after the diagnosis of ICEP and frequently required long-term oral corticosteroids. To conclude, among patients with idiopathic chronic eosinophilic pneumonia, asthmatics have a lower frequency of relapse than nonasthmatics, possibly because of a higher use of inhaled corticosteroids. The occurrence of idiopathic chronic eosinophilic pneumonia in asthmatics is often associated with the development of severe asthma.

Clinical manifestations of anti-synthetase syndrome positive for anti-alanyl-tRNA synthetase (anti-PL12) antibodies: a retrospective study of 17 cases

OBJECTIVEnTo describe the clinical manifestations of the anti-synthetase syndrome (ASS) specifically associated with anti-alanyl-tRNA (anti-PL12) synthetase antibodies.nnnMETHODSnIn a retrospective study, 17 patients (eight males, nine females, mean age = 60.3 years) with ASS symptoms confirmed by two consecutive tests (cyto-dot and/or immunoblot, or both), with positive results for anti-PL12 antibodies, were included.nnnRESULTSnAll patients presented with interstitial lung disease (ILD), which was associated with mild myositis in 41% of the cases. RP and general impairment were common, whereas rheumatic and dermatological symptoms were uncommon. Four patients suffered from SS, and four others had an atypical oesophageal involvement. The long-term course was assessable for 10 patients (follow-up of 41.1 months). Five patients required immunosuppressive drugs. Two patients are waiting for a lung transplant because of disproportionate and refractory pulmonary hypertension.nnnCONCLUSIONnThe severity of anti-PL12 ASS varied because of the constant pulmonary involvement. ILD was the predominant prognosis factor, which was notable in cases associated with pulmonary hypertension.