François Lhote

Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients.

Churg-Strauss syndrome (CSS) is a systemic vasculitis characterized by the presence of asthma, hypereosinophilia, and necrotizing vasculitis with extravascular eosinophil granulomas. In this retrospective study of 96 patients between 1963 and 1995, we analyzed clinical manifestations, identified prognostic factors, and assessed the long-term outcome. CSS was diagnosed when asthma, hypereosinophilia > 1,500/mm3 or > 10%, and clinical manifestations consistent with systemic vasculitis, with or without histologic evidence, were present. Asthma was the most frequently observed manifestation at presentation, with mononeuritis multiplex the second. Other common manifestations were weight loss, fever, myalgia, skin involvement, paranasal sinusitis, arthralgia, pulmonary infiltrate, and gastrointestinal involvement. Mean eosinophilia at presentation was 7.193 +/- 6.706/mm3; ANCA, present in 20 of 42 (47.6%) patients, predominantly gave the perinuclear labeling pattern. All the patients were treated with corticosteroids alone or in combination with cyclophosphamide or plasma exchanges. Clinical remission was obtained in 91.5%; 22 (25.6%) patients relapsed. Twenty-three patients died during follow-up: 11 of these deaths were directly due to vasculitis. The presence of severe gastrointestinal tract or myocardial involvement was significantly associated with a poor clinical outcome. The long-term prognosis of CSS is good and does not differ from that of polyarteritis nodosa, although most patients need low doses of oral corticosteroids for persistent asthma, even many years after clinical recovery from vasculitis.

PROGNOSTIC FACTORS IN POLYARTERITIS NODOSA AND CHURG-STRAUSS SYNDROME : A PROSPECTIVE STUDY IN 342 PATIENTS

We undertook this study to determine the clinical, biologic, immunologic, and therapeutic factors associated with the prognoses of polyarteritis nodosa (PAN) and Churg-Strauss syndrome (CSS). Three hundred forty-two patients (260 with PAN, 82 with CSS) followed from 1980 to 1993 were included in a prospective study on prognostic factors. Two hundred eighty-eight of these patients were included in the prospective studies on PAN and CSS. Items to be considered for analysis were collected at the time of diagnosis, during the acute phase of the disease. A survival curve was plotted for each clinical and biologic symptom observed in PAN or CSS. Each treatment arm of the prospective therapeutic trials was also tested: 1) prednisone (CS) + oral cyclophosphamide (CYC) + plasma exchanges (PE) versus CS E, 2) CS + PE versus CS, 3) CS + oral CY versus CS + pulse CY, 4) CS + pulse CY + PE versus CS + pulse CY in severe PAN and CSS, and 5) PE + antiviral agents after short-term CS in hepatitis B virus-related PAN. Of the parameters thus evaluated, the following had significant prognostic value and were responsible for higher mortality: proteinuria > 1 g/d (p < 0.0001; relative risk [RR] 3.6), renal insufficiency with serum creatinine > 1.58 mg/DL (p < 0.02; RR 1.86), GI tract involvement (p < 0.008. RR 2.83 for surgery). Cardiomyopathy and CNS involvement were associated with a RR of mortality of 2.18 and 1.76, respectively; these were not statistically significant. Similar survival rates were obtained with the prospectively tested therapies. The five-factors score (FFS) we established considered the prognostic factors creatinemia, proteinuria, cardiomyopathy, GI tract involvement, and CNS signs. Multivariate analysis showed that proteinuria (due to vascular or glomerular disease) and GI tract involvement were independent prognostic factors. When FFS = 0 (none of the 5 prognostic factors present), mortality at 5 years was 11.9%; when FFS = 1 (1 of the 5 factors present), mortality was 25.9% (p < 0.005); when FFS > 2 (3 or more of the 5 factors present), mortality was 45.95% (p < 0.0001 between 0 and 2, p < 0.05 between 1 and 2). We conclude that an initial assessment of PAN or CSS severity enables outcome and mortality to be predicted. The FFS is a good predictor of death and can be used to help the clinician choose the most adequate treatment. Renal and GI signs are the most serious prognostic factors.

Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.

OBJECTIVE To retrospectively analyze the clinical symptoms, laboratory findings, and outcomes in patients with microscopic polyangiitis (MPA) who were enrolled in various clinical trials conducted by the French Vasculitis Study Group. METHODS A cohort of 85 patients meeting the Chapel Hill criteria for MPA participated in the study. Seventy-one of them were included in prospective therapeutic trials. Eighty-one diagnoses were biopsy proven. In the other patients, diagnosis was based on clinical findings. RESULTS Forty-seven men and 38 women, with a mean +/- SD age of 56.8 +/- 14.6 years, met the criteria for MPA. Their main clinical symptoms were renal manifestations (78.8%), weight loss (72.9%), skin involvement (62.4%), fever (55.3%), mononeuritis multiplex (57.6%), arthralgias (50.6%), myalgias (48.2%), hypertension (34.1%), lung involvement (24.7%; alveolar hemorrhage 11.8%), and cardiac failure (17.6%). The mean +/- SD serum creatinine level before treatment was 2.59 +/- 2.96 mg/dl; 47 patients had renal insufficiency (serum creatinine > 1.36 mg/dl). Eight patients underwent dialysis at the time of diagnosis, and long-term dialysis was necessary for 10 patients. Antineutrophil cytoplasmic antibodies (ANCA) were present in 38 of 51 patients (74.5%), of whom 33 had a perinuclear staining pattern (pANCA) and 5 had a cytoplasmic pattern. Antibodies to proteinase 3 were present in 4 patients and antibodies to myeloperoxidase were detected in 31, as determined by enzyme-linked immunosorbent assay. Of the 30 patients who underwent renal and celiac angiography, 4 had microaneurysms. Of the 29 patients (34.1%) who had relapses, 8 died during or after the relapse. During followup, 28 of the 85 patients (32.9%) died. The mean +/- SD duration of followup of the group was 69.9 +/- 60.6 months. Deaths were less frequent when patients had been treated with steroids and immunosuppressive drugs (13 patients [24.1%]) than with steroids alone (15 patients [48.4%]) (P < 0.01). The 5-year survival rate was 74%. CONCLUSION This study demonstrated that MPA is a multisystemic disease in which renal symptoms are frequent, but the disease is also associated with general symptoms, arthritis, mononeuritis multiplex, and other manifestations that are also seen in various vasculitides. The rarity of abnormal angiogram findings and the high frequency of pANCA are characteristic of MPA. In most cases, the outcome is comparable with those of other systemic vasculitides, but relapses are frequent.

Long‐term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg‐Strauss syndrome: Analysis of four prospective trials including 278 patients

OBJECTIVE To determine the long-term outcome of patients with polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS), to compare the long-term outcome with the overall French population, to evaluate the impact on outcome of the type of vasculitis, prognostic factors, and treatments administered at diagnosis, and to analyze treatment side effects and sequelae. METHODS Data from PAN, MPA, and CSS patients (n = 278) who were enrolled between 1980 and 1993 were collected in 1996 and 1997 and analyzed. Two prognostic scoring systems, the Five-Factors Score (FFS) and the Birmingham Vasculitis Activity Score (BVAS), were used to evaluate all patients at the time of diagnosis. RESULTS The mean (+/- SD) followup of the entire population was 88.3 +/- 51.9 months (range 3 days to 192 months). Of the 85 deaths recorded, at least 41 were due to progressive vasculitis or its consequences. Death rates reflected disease severity, as assessed by the FFS (P = 0.004) and the BVAS (P < 0.0002), and the 2 scores were correlated (r = 0.69). Relapses, rarer in hepatitis B virus (HBV)-related PAN (7.9%) than in MPA (34.5%) (P = 0.004), occurred in 56 patients (20.1%) and did not reflect disease severity. Survival curves were similar for the subpopulation of 215 patients with CSS, MPA, and non-HBV-related PAN who were given first-line corticosteroids (CS) with or without cyclophosphamide (CYC). However, CS with CYC therapy significantly prolonged survival for patients with FFS scores > or =2 (P = 0.041). Relapse rates were similar regardless of the treatment regimen; only patients treated with CS alone had uncontrolled disease. CYC was associated with a greater frequency of side effects (P < 0.00001). CONCLUSION Rates of mortality due to PAN (related or unrelated to HBV), MPA, and CSS reflected disease severity and were higher than the mortality rate in the general population (P < 0.0004). Rates of relapse, more common in MPA than HBV-related PAN patients, did not reflect disease severity. Survival rates were better among the more severely ill patients who had received first-line CYC. Based on these findings, we recommend that the intensity of the initial treatment be consistent with the severity of the disease. The use of the FFS and BVAS scores improved the ability to evaluate the therapeutic response.

Polyarteritis nodosa related to hepatitis B virus. A prospective study with long-term observation of 41 patients.

Hepatitis B virus (HBV)-related polyarteritis nodosa (PAN) is a rare disease whose frequency has been decreasing over the past 10 years. We evaluated 41 patients with HBV-related PAN to determine the circumstances leading to infection, the clinical features of vasculitis, the prognostic factors, and the response to therapy. Most patients were first treated briefly with corticosteroids, and all were included in 2 nonrandomized prospective therapeutic trials of an antiviral agent (35 patients with vidarabine, 6 patients with interferon-alpha 2b) and plasma exchanges. The mean duration of follow-up was 69.6 +/- 44.8 months. At the end of the study, 21 (51.2%) patients had seroconverted to anti-HBeAb and 10 (24.4%) also had seroconverted to anti-HBsAb. In all, 23 (56%) patients no longer expressed serologic evidence of HBV replication. All 33 (80.5%) patients still alive at the end of follow-up recovered from PAN. Nineteen also recovered from HBV infection and were considered to be cured; 13 patients had persistent HBV infection and were considered to be in clinical recovery; and 1 patient was in remission, maintained with steroid therapy. Eight patients died during the study period; 3 deaths were directly attributable to PAN. HBV-related PAN is an acute disease, occurring shortly after infection and sharing the characteristics of classic PAN. It is not an antineutrophil cytoplasm antibodies (ANCA)-mediated vasculitis. The outcome was good for patients treated with short-term steroid therapy, antiviral agents, and plasma exchanges. We propose this protocol as the first treatment for HBV-related PAN, because it surpasses the conventional treatment with corticosteroids and cyclophosphamide, which facilitates viral replication and the development of chronic HBV infection.

Population-Based Prevalence Study of Behçet's Disease : Differences by Ethnic Origin and Low Variation by Age at Immigration

OBJECTIVE To estimate the prevalence of Behçets disease (BD) in a multiethnic population living in France, with particular focus on disease risk among immigrants. METHODS The study was conducted in a county in the Paris metropolitan area that is home to 1,094,412 adults (ages > or =15 years), of whom 26% are of non-European ancestry. Patients with BD living in this area during 2003 were identified using 3 sources (hospitals, community physicians, and the National Health Insurance database), and diagnoses were verified using the International Study Group criteria. Standardized, year-2003 prevalence rates were computed for the overall population and for each ethnic group. Stratified prevalence rates according to age at immigration to France were calculated to investigate the relationship between age at immigration and BD risk. RESULTS Seventy-nine subjects fulfilled our search criteria. The overall prevalence per 100,000 adults was 7.1 (95% confidence interval [95% CI] 3.5-14.4), and the prevalence for populations of European, North African, and Asian ancestry was 2.4 (95% CI 0.6-7.2), 34.6 (95% CI 24.4-47.5), and 17.5 (95% CI 10.7-27.2), respectively. Within the migrant population of either North African or Asian ancestry, BD prevalences were similar for residents born in France, residents <15 years old at immigration, and residents > or =15 years old at immigration. CONCLUSION Our findings indicate that the prevalence of BD among immigrants of North African or Asian ancestry is significantly higher than that in the European-origin population, and comparable with rates reported from North Africa and Asia. Moreover, our results suggest that BD risk is not related to age at immigration. These findings support the hypothesis that BD has a primarily hereditary basis.

Treatment of polyarteritis nodosa related to hepatitis B virus with interferon-alpha and plasma exchanges.

OBJECTIVES--To test the effectiveness of and tolerance to interferon-alpha 2b (INFa2b) in association with plasma exchanges for the treatment of polyarteritis nodosa (PAN) related to hepatitis B virus (HBV). METHODS--A prospective, non blinded, multicentre trial was carried out in which patients with multisystemic HBV-related PAN were included. Each patient received the association of INFa2b and plasma exchanges. The end point of the study was control of the disease (recovery or remission) or death. RESULTS--Six patients were included in the study. Each patient had histopathological or arteriographic evidence of vasculitis and was infected with actively replicating HBV. All patients were alive at the end of the study and no longer presented clinical or laboratory evidence of systemic vasculitis. HBeAg/anti-HBeAb seroconversion was observed in four patients (66.6%) and HBsAg/anti-HBsAb in 3/6 (50%). Two patients are still being treated with INFa2b because of chronic active hepatitis. CONCLUSIONS--It is considered that this new therapeutic approach to HBV-related PAN effectively cured systemic vasculitis and was associated with control of HBV infections. Antiviral therapy may have a role to play as the first line treatment regime of virus-induced vasculitis.

THE SPECTRUM AND TREATMENT OF VIRUS-ASSOCIATED VASCULITIDES

It is admitted that viral infections can be responsible for systemic vasculitides. Viruses can be responsible for various types of vasculitis that affect vessels of different sizes. Clinical manifestations are the same as those observed in previously described vasculitides such as polyarteritis nodosa or cryoglobulinemia. When viral infection is diagnosed and considered to be responsible for vasculitis, a specific therapeutic approach must be prescribed. Treatment is based on the combination of antiviral agents and symptomatic or immunomodulating therapies. Antiviral therapy facilitates virus clearance and seroconversion to specific antibodies. In systemic vasculitides, plasma exchanges are a powerful treatment that clears circulating immune complexes. In the case of digital ischemia, vasodilators are also useful. Conversely, steroids and cytotoxic agents stimulate virus replication and favor disease chronicity and deleterious effects due to the presence of the virus. Hepatitis B virus-related polyarteritis nodosa can be cured with the combination of antiviral agents (mainly interferon alpha) and plasma exchanges. Hepatitis C virus-related cryoglobulinemia responds to interferon alpha and sometimes to plasma exchanges, but responses are usually partial and relapses occur in the majority of cases. In HIV-related vasculitides, currently available antiretroviral agents are not able to definitively eradicate the virus but their combination with plasma exchanges can cure the vasculitis. Due to common epidemiologic factors, several viruses can be present in the same patient, and determining their responsibility in the vasculitic process requires careful clinical and virologic analysis and then the selection of a specifically adapted therapeutic regimen. The therapeutic strategy applied in virus-associated vasculitides is therefore based on the etiologic investigations and the choice of a treatment is adapted to the pathogenetic mechanisms.

Polyarteritis nodosa and microscopic polyangiitis

vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988; 318:1651-1657. 24 Jennette JC. Wilkman AS. Falk RJ. Anti-neutrophil cytopiasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989; 135: 921-30. 25 Cohen Tervaert JW. Limburg PC. Elema JD. Huitema MG. Horst G. Hauw The T. Kallenberg CGM. Detection of autoantibodies against myeloid lysosomal enzymes: a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis. Am J Med 1991; 59-66. 26 Guillevin L. Visser H. Noel LH. Pourrat J. Vernier I. Gayraud M. Oksman F. Lesavre P. Antineutrophil cytoplasm antibodies in systemic polyarteritis nodosa with and without hepatitis B virus infection and Churg-Strauss syndrome 62 patients. J Rheumatol 1993; 20: 1345-9. 27 Hunder GG. Arend WP. Bloch DA. Calabrese LH. Fauci AS. Fries JF. Leavitt RY. Lie JT. Lightfoot Jr RW. Masi AT. McShane DJ. Michel BA. Mills JA. Stevens MB. Wallace SL and Zvaifier NJ: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 1990; 33: 1065-1067.

POLYARTERITIS NODOSA, MICROSCOPIC POLY ANGIITIS, AND CHURG-STRAUSS SYNDROME: CLINICAL ASPECTS, NEUROLOGIC MANIFESTATIONS, AND TREATMENT

Polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) all have neurologic symptoms and share characteristics and outcomes. Clinical aspects, neurologic manifestations, and treatment of these three diseases are examined in this article.