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.

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.

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.

Hepatitis C virus in patients with polyarteritis nodosa. Prevalence in 38 patients.

In order to assess the prevalence of hepatitis C virus (HCV) in polyarteritis nodosa (PN), 38 patients with systemic necrotizing angiitis were retrospectively tested for the presence of anti-HCV antibodies (Ab). Twenty-one patients were hepatitis B virus (HBV) positive, comprising group A, and 17 were HBV negative, comprising group B. Two patients from group A had anti-HCV Ab (2/21: 9.5%). One was treated unsuccessfully with corticosteroids, then with vidarabine and plasma exchanges; HBe/anti-HBe seroconversion was not observed and anti-HCV Ab disappeared 8 months after the onset of PN. The second patient was successfully treated with corticosteroids, then vidarabine and plasma exchanges; he recovered from PN, HBV seroconversion occurred, and the anti HCV Ab remained detectable. These results show that: 1) the prevalence of anti HCV Ab in PN related to HBV is nearly the same (9.5%) as the prevalence of HCV Ab observed in patients with chronic hepatitis related to HBV infection; 2) the course of these two viral infections can be different and the role of HCV as an etiologic factor in PN has not been established.

Prevalence of cryoglobulins and hepatitis C virus infection in HIV-infected patients.

PURPOSE AND METHODS: In order to evaluate the prevalence of positive hepatitis C virus (HCV) serology and cryoglobulinemia in human immunodeficiency virus (HIV)-infected patients, the prevalence and the clinical significance of cryoglobulinemia were prospectively studied in a cohort of 86 HIV-infected subjects seen as outpatients. They were compared to a control group consisting of 101 HIV-HCV+ patients being followed at the same hospital. RESULTS: HCV serology was positive in 53/86 (61.6%) patients, 25 (47.2%) of whom had detectable cryoglobulins in their sera although only 1 had clinical symptoms consistent with cryoglobulinemia. Cryoglobulinemia was also detected in 9/33 (27.3%) HCV- patients, with only one of them presenting clinical symptoms. Although the mean cryoglobulin concentration was lower for HIV+ patients than in controls (268 versus 585 mg/l, p < 0.01), their prevalence (39.5% and 27.2%, respectively) was higher (p < 0.03). CONCLUSION: Cryoglobulinemia is frequently detected in HIV-infected patients, regardless of their HCV serology, but is poorly correlated with clinical symptoms.

Increased risk of Pneumocystis carinii pneumonia in patients with Wegener's granulomatosis.

Combining cyclophosphamide (Cy) and corticosteroids has dramatically improved the prognosis of Wegener's granulomatosis (WG). But this treatment carries the risks of severe infectious complications and drug toxicity. During a 10-month period, we observed 6 cases of Pneumocystis carinii pneumonia (PCP) in 23 patients with biopsy-proven WG and renal involvement. These 23 patients were enrolled in a multicenter controlled clinical trial designed to evaluate the efficacy and safety of either intermittent high-dose pulse Cy or daily oral low-dose Cy in combination with oral prednisone. Mean delay of onset of PCP was 2.5 months after the beginning of the immunosuppressive therapy. In all cases, the diagnosis of PCP was established by cytological examination of bronchoalveolar lavage fluid. None of the patients experienced severe leukopenia at the time of diagnosis, but the mean lymphocyte count decreased to 495/mm3 (range 100 to 830/mm3) and 2 patients had inverted CD4/CD8 T-cell ratios. Renal function was significantly impaired (creatininemia = 493.5 vs 195.4 micromol/l; p = 0.03) in the 6 patients presenting PCP vs those without. High-dose co-trimoxazole therapy was successful in 3 patients, but 3 others who required mechanical ventilation died. Treatment of WG with daily prednisone and either pulse or oral Cy may have contributed to higher rates of PCP in the past than previously thought and, therefore, patients currently receiving such a regimen may be at greater risk for PCP. For these patients, this opportunistic infection must remain highly suspect in order to reach a diagnosis earlier and rapidly initiate treatment. In addition, recommendations for prophylactic therapy are needed.

[Periarteritis nodosa complicated by intrapancreatic vascular rupture]. / Périartérite noueuse compliquée d'une rupture vasculaire intra-pancréatique.

Clinical pancreatic manifestations are unusual in polyarteritis nodosa. A case of intrapancreatic hemorrhage due to vascular rupture occurring during the course of histologically proven polyarteritis nodosa is described. The patient presented with massive hemoperitoneum requiring emergency laparotomy. Splenopancreatectomy was performed to control bleeding. Steroid therapy was continued during the postoperative course, with favorable outcome. The mechanism of vascular rupture is not clear, but is probably related to focal arteritis with consequent infarction. No ruptured microaneurysm was found in this case.

[Pneumocystis carinii pneumonia: an opportunistic infectious risk associated with systemic diseases and their treatment]. / Pneumocystose pulmonaire: un risque infectieux opportuniste associé aux maladies systémiques et à leur traitement.

Pneumocystis carinii, an opportunistic pathogen, often causes pneumonia in persons with human immunodeficiency virus (HIV) infection. In patients free of HIV infection, the risk is clearly associated with certain diseases and immunosuppressive therapy. Pneumocystis carinii pneumonia can complicate solid or hematologic malignancies, organ transplantation and connective tissue diseases. Recent therapeutic strategies based on aggressive immunosuppression have increased the risk of opportunistic infection with Pneumocystis carinii, particularly in patients with Wegener's syndrome and systemic lupus erythematosus. The risk of interhuman nosocomial transmission of Pneumocystis carinii in units caring for HIV-infected patients and patients with immunosuppressive diseases should also be considered. The undeniable progress in therapeutic immunosuppression has increased the risk of opportunistic infections. The gravity of Pneumocystis carinii pneumonia demonstrates the importance of optimizing treatment choice in order to strike the right balance between beneficial effect and risk of opportunistic infection.

[Prevention of opportunistic infections in HIV seropositive patients. Prevention of parasitic infections]. / Prévention des infections opportunistes chez le sujet VIH+. Prévention des infections parasitaires.

PNEUMOCYSTIS CARINII PNEUMONIA: Below a threshold 200 CD4 cont, the risk of P. carinii infection is sufficiently high to propose systematic prophylaxis. Trimethoprim-sulfamethoxazole is the treatment of choice for primary and secondary prevention. Pentamidine-isothionate can also be used, possibly with dapsone. TOXOPLASMOSIS: There is a consensus on primary prevention in patients with positive toxoplasmosis serology whose CD4 count is under 100. Trimethoprime-sulfamethoxazole is the first intention drug, but poor tolerance may require conversion to dapsone-pyrimethamine. For secondary prophylaxis, the consensus is for life-long treatment with low-doses after initiating treatment with sulfadiazine and pyrimethamine. LEISHMANIASIS: Secondary prevention is reasonable using monthly infusions of pentamidine.

[Prevention of opportunistic infections in HIV seropositive patients. Prevention of bacterial infections]. / Prévention des infections opportunistes chez le sujet VIH+. Prévention des infections bactériennes.

TUBERCULOSIS: Primary prophylaxis is indicated in subjects at risks, i.e. those with a positive tuberculine test or a negative test and major immunodepression. BCG vaccine is definitely contraindicated in case of AIDS. Prescription of isoniazid in combination with vitamin B6 has been found to be effective. MYCOBACTERIUM AVIUM INTRACELLULARE: Prophylaxis concerns highly immunodepressed patients and is based on rifabutine. Prophylaxis is contraindicated in case of active tuberculosis. OTHER GERMS: Preventive care in food intake for potential digestive tract infections is required as well as antipneumococcal vaccine. Secondary prophylaxis is based on continuous antibiotics. The positive effect of intravenous immunoglobulins, especially in children, remains a question of debate.

[Prevention of opportunistic infections in HIV seropositive patients. Prevention of viral infections and mycoses]. / Prévention des infections opportunistes chez le sujet VIH+. Prévention des infections virales et des mycoses.

CYTOMEGALOVIRUS INFECTION: Primary prophylaxis is logical in high-risk subjects (CD4 < 50) who are asymptomatic; per os ganciclovir is under evaluation. Systematic secondary prophylaxis relies on intravenous ganciclovir or foscarnet. HERPES SIMPLEX AND ZOSTER: Secondary prevention with acyclovir is not recommended due to the risk of resistance. Herpes zoster retinitis is an absolute indication for continuous oral treatment with acyclovir. CRYPTOCOCCUS: Oral fluconazol is required for secondary prophylaxis. CANDIDIASIS: Due to the risk of resistant strains, neither primary nor secondary prophylasis is recommended. HISTIOPLASMOSIS: Risk of recurrence justifies secondary prophylaxis with itraconazole or fluconazole. COCCIDIODOMYCOSIS: Secondary prophylaxis with amphotericin B or fluconazole is mandatory. ASPERGILLOSIS: Itraconazole is the best agent when prophylaxis is needed.

[Systemic diseases and infections: current questions]. / Maladies systémiques et infections: questions actuelles.

Infections are a major cause of morbidity and mortality in patients with connective tissue diseases. Infectious consequences are caused by systemic disorders by themselves and the immunosuppressive treatments. Systemic lupus erythematosus and Wegener's granulomatosis are associated with the higher risk of infection. Primary prophylaxis of Pneumocystis carinii pneumonia has to be systematically given in patients with Wegener's granulomatosis and in other patients with connective tissue diseases if their CD4-cell count is lower than 200/mm3. Intensitification of immunosuppression during the course of systemic disorders can not be performed before any infection has been eliminated.

[Failure of intravenous immunoglobulins in certain systemic diseases. 5 cases]. / Echec des immunoglobulines intraveineuses au cours de certaines maladies systémiques. 5 observations.

Human polyvalent immunoglobulins administered intravenously have shown to be effective in some immune diseases. We administered high dose-IV Ig (2g/kg/session) in five patients with severe chronic systemic diseases. Their condition did not improve, except in one case where a transient response was noticed. Considering the inconsistent results and high cost of IV Ig, double blind studies are required to determine the conditions in which high dose IV Ig may be more effective than conventional treatments.

[Periarteritis nodosa related to hepatitis B virus. Determination of a new therapeutic strategy: 13 cases]. / Périartérite noueuse liée au virus de l'hépatite B. Détermination d'une stratégie thérapeutique nouvelle: 13 observations.

The treatment and prognosis of periarteritis nodosa associated with hepatitis B virus were reconsidered from a series of 13 patients representing 32.5 per cent of the 40 patients with periarteritis nodosa admitted during the same period. HBs and HBe antigens were present in every case, and hepatitis B virus replication was demonstrated by the finding of viral DNA in serum. One patient had anti-HBc IgM's. Five patients were treated with corticosteroids, cyclophosphamide and occasional plasma exchanges. All were cured or achieved complete remission. Eight patients were treated with plasma exchanges and vidarabine, either as first-line therapy (3 cases) or after failure of corticosteroids and/or immunosuppressants (5 cases). This treatment was clinically effective in 5/8 cases, including 3 with seroconversion. The 2 patients in whom the combined treatment failed were given corticosteroids; one of them also had plasma exchanges. The 8th patient died after a few days of treatment. Eleven of the 13 patients are still alive and either cured or in complete remission. Two patients who developed severe chronic hepatitis after steroids were discontinued received vidarabine alone: arrest of viral replication was obtained in both cases, with emergence of an anti-HBe (but not anti-HBs) antibody. The overall positive virological response rate to vidarabine alone or combined with plasma exchanges was 50 per cent. When vidarabine was prescribed as treatment of acute periarteritis nodosa (the 2 cases where it was used for chronic hepatitis being excluded), this response rate was 37.5 per cent. This, in patients with periarteritis nodosa associated with hepatitis B virus immunosuppressive drugs should be withdrawn and replaced by plasma exchanges and antiviral agents. This would be the first-line treatment to be replaced by corticosteroid therapy if it fails.

[Synchronization of plasma exchange and cyclophosphamide in severe systemic diseases. A consecutive study of 10 patients]. / Synchronisation d'échanges plasmatiques et de cyclophosphamide dans les maladies systémiques sévères. Etude consécutive de 10 malades.

Ten patients with severe systemic diseases, including systemic lupus erythematosus (n = 2), polymyositis (n = 2), essential mixed cryoglobulinaemia (n = 2), rheumatoid arthritis vasculitis (n = 3) and Wegener's granulomatosis (n = 1), were treated with 3 consecutive plasma exchanges synchronized with pulse cyclophosphamide. This therapeutic regimen was applied every 4 weeks initially and thereafter every 6 weeks in case of positive response after the first 3 cycles; it was combined in all patients with corticosteroid therapy. The treatment was administered for severe flare-up of the disease in 7 patients and for failure of previous treatments, including corticosteroids, cyclophosphamide and plasmapheresis, in 3 patients. Three kinds of response were observed: lasting complete remission without relapse after synchronization had ceased in 4 patients, partial clinical remission with post-synchronization relapse in 5 patients, and primary failure without any clinical response to treatment in only 1 patient. These results suggest that repeated plasma exchanges synchronized with cyclophosphamide are effective against progressive autoimmune diseases and in cases where conventionally administered immunosuppressive treatments had failed. However, this type of treatment cannot prevent long-term relapses, and only a prospective study can evaluate its success in terms of survival.

[Nodular and granulomatous form of periarteritis nodosa caused by the hepatitis B virus]. / Forme cutanée nodulaire et granulomateuse d'une périartérite noueuse liée au virus de l'hépatite B.

Polyarteritis nodosa (PAN) is, in rare cases, associated with subcutaneous nodules and pathology does not usually show the presence of peri and extravascular granulomas. When present in patients with hepatitis B virus (HBV) related PAN these facts demonstrate that classification of PAN is not homogeneous. CASE REPORT. A patient infected by HBV developed a PAN demonstrated by clinical symptoms and pathology. The disease was characterized by the presence of subcutaneous nodules and histologically by peri- and extra-vascular granuloma which surrounded necrosis of medium-sized vessels. Outcome was also unusual in the patient who did not respond to the association of plasma exchanges and antiviral agents and was only slightly improved by steroids and cyclophosphamide. COMMENTS. HBV-related PAN is considered to be an immune complex disorder. In the present case report granuloma were present as observed in Churg Strauss syndrome or Wegener's granulomatosis which are the consequence of other pathogenetic mechanisms as anticytoplasmic neutrophil antibodies (ANCA). This case reports underlines the heterogeneity of the PAN group of vasculitis and the probable role for various pathogenetic mechanisms.