Mortality in Behçet's disease.

OBJECTIVE: To report the long-term mortality in patients with Behçet's disease (BD). METHODS: A cohort of 817 patients fulfilling the international criteria for BD from a single center in France were analyzed for causes of death, the standardized mortality ratio (SMR), and the factors associated with mortality. RESULTS: Among the 817 patients with BD, 41 (5%) died after a median followup of 7.7 years, of whom 95.1% were male. The mean ± SD age at death was 34.8 ± 11.9 years. Main causes of death included major vessel disease (mainly, arterial aneurysm and Budd-Chiari syndrome) (43.9%), cancer and malignant hemopathy (14.6%), central nervous system involvement (12.2%), and sepsis (12.2%). The mortality rate at 1 year and 5 years was 1.2% and 3.3%, respectively. There was an increased mortality among patients ages 15-24 years (SMR 2.99, 95% confidence interval [95% CI] 1.54-5.39) and those ages 25-34 years (SMR 2.90, 95% CI 1.80-4.49) as compared with age-and sex-matched healthy controls. The mortality decreased in patients older than age 35 years (SMR 1.23, 95% CI 0.75-1.92). In multivariate analyses, male sex (hazard ratio [HR] 4.94, 95% CI 1.53-16.43), arterial involvement (HR 2.51, 95% CI 1.07-5.90), and a high number of BD flares (HR 2.37, 95% CI 1.09-5.14) were independently associated with the risk of mortality. CONCLUSION: The overall mortality in our BD cohort was 5% after a median followup of 7.7 years. Male sex, arterial involvement, and the number of flares were associated with mortality in BD.

[Liver disease and pregnancy]. / Pathologies hépatiques et grossesse.

Liver dysfunction during pregnancy can be related or not to pregnancy itself. The purpose of this review is to summarize the possible causes of liver dysfunction during pregnancy and their management. Liver dysfunction during pregnancy can be chronic or acute, independent or specific to pregnancy. Management of liver disease can be different during pregnancy. The knowledge of liver dysfunction during pregnancy is of help for a better management of the mother in order to avoid maternal and fetal mortality and morbidity.

[Pregnancy and systemic lupus erythematosus]. / Grossesse et lupus systémique.

Pregnancy is widely authorized in systemic lupus erythematosus (SLE). Fertility is similar in SLE and in the general population although the age of menarche seems higher. Some cases of sterility might be attributed to SLE because of autoimmune ovaritis or antiphospholipid antibodies (aPL). These antibodies might lead to endothelial activation and thrombosis by influencing homeostasis, complement activation, inhibition of protein C and annexin V. They might have a deleterious effect on embryonic implantation by adhesion to the trophoblast, inhibition of invasion and placentation and decreased hCG production. The most important part of sterility seems secondary to the use of cyclophosphamide and might be prevented by acetate leuprolide administration. Maternal morbidity seems correlated to SLE activity (controlled by pregnancy planning), hypertension, preeclampsia, Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP) syndrome, therapy and aPL. Hydroxychloroquine (HCQ) should be maintained throughout pregnancy. Aspirin is prescribed alone in patients with asymptomatic aPL and in addition to heparin if there is a history of thrombosis or fetal loss with aspirin. Fetal and neonatal morbidity correlate with prematurity, adverse effects or maternal steroid therapy and maternal anti-SSA antibodies with 1 to 2% risk of congenital atrioventricular block. Abnormal obstetrical echography-doppler examination is the best predictor of pregnancy outcome. Abnormal umbilical artery flow on the second trimester echodoppler examination and history of thrombophlebitis predict fetal or neonatal death. Abnormal uterine notch on the second trimester echodoppler examination predicts adverse pregnancy outcome. Except for the preventive therapy of congenital atrioventricular block, modalities of SLE pregnancy monitoring and therapy are now well established.

[Therapy of chronic non infectious uveitis]. / Traitement des uvéites chroniques non infectieuses.

PURPOSE: Chronic non infectious uveitis represents two-thirds of the causes of chronic uveitis referred in tertiary referral ophthalmology centre. One case out of 5 may evolve towards blindness. Therapy should be discussed on the basis of the uveitis severity and the diagnosis; it uses topics or systemic drugs, mainly corticosteroids and immunosuppressors. CURRENT KNOWLEDGE AND KEY POINTS: Besides corticosteroids and ciclosporin, use of immunosuppressors and biotherapy in chronic non infectious uveitis is not an indication of the Autorisation de Mise sur le Marché. However, immunosuppressors and biotherapy were the subjects of several studies, although controlled studies are scarce. Controlled studies concerned cyclosporine, azathioprine and intravenous cyclophosphamide in Behçet's disease, ciclosporine and tacrolimus in uveitis of various causes. Therapy of chronic non infectious uveitis was recently enriched by new drugs: mycophenolate mofetil, initially used in transplantation, has its indications extended to systemic diseases; TNF inhibitors initially used in therapy of systemic diseases; interferon efficacy revealed in Behçet's disease is now used in uveitis due to other causes. FUTURE PROSPECTS AND PROJECTS: Controlled studies are suitable in order to determinate the respective part of immunosuppressors and biotherapies in the treatment of chronic non infectious uveitis.

Subacute bacterial endocarditis presenting as polymyalgia rheumatica or giant cell arteritis.

OBJECTIVE: To report on several patients with subacute bacterial endocarditis who were initially presumed, incorrectly, to have polymyalgia rheumatica or giant cell arteritis. METHODS: We report 3 cases of subacute streptococcal endocarditis mimicking giant cell arteritis in 2 cases and polymyalgia rheumatica in one. We reviewed the literature through Medline search of French and English-language articles published between 1966 and 2005 and found 5 similar cases. RESULTS: Shoulder and/or pelvic girdle pain was associated with neck or back pain in all patients. Scalp tenderness, bilateral jaw pain, amaurosis fugax were present in 2 patients. One patient had no fever. Two patients were treated with corticosteroids with initial good clinical response in one. Appropriate antibiotic therapy resulted in the rapid disappearance of rheumatic complaints in 2 patients and achieved a definitive cure of endocarditis in all cases. CONCLUSION: Rheumatologic symptoms may hinder the correct diagnosis of infective endocarditis in patients who present with a clinical picture suggesting polymyalgia rheumatica or giant cell arteritis. In such cases, blood cultures should be systematically drawn.

[Portal thrombosis complicating an acute cytomegalovirus infection in an immunocompetent patient]. / Thrombose portale compliquant une infection à cytomégalovirus aiguë chez un sujet immunocompétent.

INTRODUCTION: The cytomegalovirus (CMV) infection is most often asymptomatic. The grave forms concern the immunocompromised patients. We report a new case pf acute CMV hepatitis complicated with portal thrombosis in an immunocompetent patient. EXEGESIS: A 29 year old man has presented a CMV hepatitis proved by the presence of pp65 protein and the viral DNA in serum. This infection was complicated by a portal thrombosis and the evolution was rapidly favourable under anticoagulant treatment. Eleven cases of major thrombosis complicating acute CMV infection in immunocompetent patients were previously reported in the English and French literature. The absence of local and general cause, the remission without anticoagulation, the elevated risk of thrombosis in both HIV and CMV seropositive patients, and in CMV seropositive renal transplant patients suggest a causal relation. Various pathogenic hypotheses were raised: presence of antiphospholipid antibodies, absent in our case, procoagulant phenotype induction of infected endothelial cells, proliferation induction of smooth cells. CONCLUSION: The acute CMV infection can be considered such as a possible cause of major thrombosis.

[Choroidal metastasis revealing pulmonary adenocarcinoma]. / Métastase choroïdienne révélatrice d'un adénocarcinome bronchique.

Lung cancer is the first cause of choroidal metastasis in man. Generally, its discovery is made at end-stage of the disease. It can be uncommonly the presenting sign as in our case. We report a case of a 28-year-old patient with no prior medical history. He presented with visual decrease and metamorphopsia that lead to the diagnosis of a metastatic adenocarcinoma of the lung (bone, liver, choroid, nodles). Chemotherapy permitted to improve visual acuity, in parallel with disappearance of choroidal metatasis. Discovery of choroidal tumor should evoke in first line metastasis. Chemotherapy can improve visual acuity and the quality of life.

[Obstetrical management of patients at risk of neonatal lupus syndrome: review of the literature]. / Prise en charge obstétricale des patientes à risque de "lupus néonatal"

Fetuses and infants of women with anti-SSA/Ro and anti-SSB/La antibodies are at risk of neonatal lupus syndrome, featuring skin lesions, hematological and hepatic disorders, and congenital heart block (CHB) in the absence of severe cardiac malformation. The prevalence of CHB in newborns of anti-SSA/Ro positive women with known connective tissue disease is 1 to 2% and the risk of recurrence ranges from 10 to 17%. CHB is definitive and is associated with significant morbidity (pacemaker must be implanted in 2/3 of cases) and mortality (16 to 19%). Myocardial involvement may either be associated or appear subsequently. Other manifestations are discussed. For anti-SSA/Ro positive pregnant women, echocardiograms should be performed every 2 weeks from 16 to 24 weeks of gestation, and every week in case of past history of CHB. Electrocardiogram should be performed in the first days of life for all children to detect incomplete CHB. Therapy for CHB detected in utero is based on fluorinated steroids, especially betamethasone. Its efficiency is variable.

[Pleading to maintain hydroxychloroquine throughout Lupus pregnancies]. / Plaidoyer pour le maintien de l'hydroxychloroquine dans les grossesses lupiques.

PURPOSE: The use of Hydroxychloroquine (HCQ) during pregnancy has remained controversial for a long time. However, it is generally agreed that pregnancy per se increases disease activity in patients with systemic lupus erythematosus (SLE) and that withdrawal of HCQ at the onset of pregnancy may result in exacerbation of SLE. Therefore, stopping HCQ at the onset of pregnancy may result in exacerbation of SLE which could be detrimental to both mother and fetus. CURRENT KNOWLEDGE AND KEY POINTS: The available data suggest that HCQ can be continued safely throughout pregnancy. After the first report by Parke of successful continuation of HCQ throughout gestation, more than 250 pregnancies resulting in live births have been reported and no increase in the rate of birth defects have been demonstrated. When studied, no retinal toxicity and ototoxicity have been found in the children. Data concerning lactation and HCQ treatment are rare. However, the amount of HCQ received by children through lactation seems very low. FUTURE PROSPECTS AND PROJECTS: For patients with SLE already taking HCQ, the benefits of continuing treatment with this medication throughout pregnancy seem to outweigh the hypothetical risks associated with its use. HCQ should probably be maintained throughout pregnancy in these patients with SLE and it does not seem necessary to advise against breastfeeding. Further studies with prospective follow-up of children exposed in utero to HCQ remain however needed to provide a definitive answer.

[Current concepts on the physiopathology of adult-onset Still's disease]. / Physiopathologie de la maladie de Still de l'adulte.

PURPOSE: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown origin. It is characterized by hectic fever, evanescent rash, polyarthralgias or polyarthritis, sore throat, hepatosplenomegaly, lymphadenopathy, polynuclear leukocytosis, liver cytolysis, and high serum level of ferritin with low glycosylated fraction. CURRENT KNOWLEDGE AND KEY POINTS: An increased serum level of ferritin, IL-8, IL-6, IL-18 and TNF-alpha indicates that macrophages are highly activated in AOSD. Interleukin 18 (IL-18) seems to be a key cytokine in the pathogenesis of AOSD. Serum IL-18 levels are increased in AOSD patients compared to other systemic inflammatory diseases such as rheumatoid arthritis and they are well correlated with serum ferritin levels and disease activity. IL-18 could cause acute liver injury and arthritis. Macrophages could be activated by infectious agents such as viruses and by an inadequate control of T cell response secondary to depressed Natural Killer lymphocyte function, similarly to that observed in systemic juvenile idiopathic arthritis. Sustained macrophage activation can lead to the hemophagocytic syndrome, a severe complication of both AOSD and systemic juvenile idiopathic arthritis. FUTURE PROSPECTS: Cytotoxic cell functions should be probably studied in AOSD as they were in the hemophagocytic syndrome and systemic juvenile idiopathic arthritis because AOSD, characterised by a marked macrophage activation may be related to an immunological deficiency.

Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus.

OBJECTIVE: Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. METHODS: We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded. RESULTS: To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug-drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23-58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504-2,229 ng/ml] versus 917 ng/ml [range 208-3316 ng/ml]) (P < 0.001). CONCLUSION: We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.

Pregnancy and its outcome in systemic lupus erythematosus.

In a multi-centre prospective study of systemic lupus erythematosus and pregnancy in France, 117 cases were identified from 1987 to 1992. We report significant morbidity and mortality for mother and fetus from an analysis of 103 cases. Pregnancy outcome was as follows: 28 full-term births, 48 premature births, 18 fetal losses (13 early and two late spontaneous abortions, three stillbirths), five therapeutic abortions and four elective abortions (for unwanted pregnancy). Four preterm neonates died. Lupus was active at pregnancy onset in 28 patients. Of 75 patients with inactive lupus at conception, 27 relapsed during pregnancy, and seven postpartum. Two patients with nephrotic syndrome treated with high-dose corticosteroids died from opportunistic infections. Fetal loss correlated with a history of proteinuria and absence of anti-SSA antibodies. Prematurity was related to a history of fetal loss, active lupus at pregnancy onset, hypertension and > or = 20 mg/day prednisone during pregnancy. Intrauterine growth retardation correlated with pregnancy of short duration, low serum C3 or C4, hypertension, and absence of SSA antibodies. Three of 22 newborns whose mothers had anti-SSA antibodies developed neonatal lupus: two with cutaneous involvement and one with complete atrioventricular block.

The multiple clinical aspects of lupus.

New insights about the following aspects of lupus erythematosus are developed: (1) thrombotic and neurological manifestations associated with the presence of antiphospholipid antibodies; (2) cardiac complications, especially coronary ischemia, conduction abnormalities and valvular involvement; (3) pregnancy, with particular attention to fetal and maternal prognoses, Soulier-Boffa syndrome and congenital atrioventricular heart blocks; (4) subacute lupus erythematosus, bullous lupus and cutaneous manifestations associated with the lupus anticoagulant.

Monthly intravenous pulse cyclophosphamide therapy in Wegener's granulomatosis.

OBJECTIVE: To study the long term effects of monthly intravenous cyclophosphamide therapy in Wegener's granulomatosis. METHODS: Fourteen consecutive patients with active Wegener's granulomatos treated with a first-line combination of high-dose prednisone and monthly intravenous pulse cyclophosphamide were retrospectively studied. RESULTS: One patient died from septicemia complicating severe leukopenia after the first pulse. At 8 months after instituting intravenous pulse cyclophosphamide therapy, failure was observed in 6 other patients. Between month 16 and 18, 2 other patients relapsed when the time between 2 pulses was lengthened. Five patients developed cyclophosphamide-related side-effects: infection (n = 2), amenorrhea (n = 1), alopecia (n = 2) and vomiting (n = 2). Except for one fatal infection, no major side-effect of intravenous cyclophosphamide therapy was observed. At the end of the study, all patients were off intravenous cyclophosphamide therapy with more than 6 months of followup. The 6 responders were in remission on low-dose prednisone or without treatment. CONCLUSION: A combination of high-dose prednisone and intravenous cyclophosphamide may achieve long-term remission in 42% of patients with Wegener's granulomatosis. Responders to intravenous cyclophosphamide therapy had less extensive disease than non-responders.

[Myocardial infarction in Behçet's disease]. / Infarctus du myocarde au cours de la maladie de Behçet.

A case of myocardial infarction in a 23-year old male patient with Behçet's disease is reported. The infarction occurred 4 years after the onset of the disease, which had been marked by recurrent venous thrombosis. Coronary arteriography showed stenosis of the anterior interventricular artery and occlusion of the first diagonal artery; the other coronary vessels were normal. A search for vascular risk factors, including haemostasis, was undertaken, yielding only moderate cigarette-smoking. About 10 cases of myocardial infarction associated with Behçet's disease have been reported. They concerned young, usually male subjects. Infarction usually occurred late in the course of the disease, and vascular risk factors were seldom elicited. The leukocytoclastic vasculitis of Behçet's disease alone may be responsible for stenosis, thrombosis and false arterial aneurysms, as shown by anatomical studies. The physiopathological mechanisms involved (reduction of endothelial or systemic fibrinolytic activity, rise in fibrinogen and factor VIII) are still unclear; we believe that these abnormalities are inconstant. Behçet's disease may be regarded as a possible cause of myocardial infarction in young subjects.

[Digestive manifestations of periarteritis nodosa in a series of 120 cases]. / Les manifestations digestives de la périartérite noueuse dans une série de 120 cas.

In a series of 120 patients with periarteritis nodosa (PAN), 50 had gastrointestinal manifestations; 34 had transient abdominal pain which regressed spontaneously or in response to corticosteroid therapy and required no further investigation. Thirty one more serious episodes occurred in the remaining 26 patients. Eight of these were in fact the initial signs of PAN and 13 required laparotomy. There were 20 episodes of abdominal pain (peritonitis: 9, pancreatitis: 4, acute cholecystitis: 2, duodenal ulcer: 3, intestinal infarction: 1, unexplained pain without diagnosis at laparotomy: 1) and 11 of gastrointestinal hemorrhage (melaena or hematemesis: 4; hematochezia: 5). Clinical and biological features of patients with and without gastrointestinal manifestation were not significantly different except for cardiac involvement which was significantly more frequent (p less than 0.05) in the second group. Corrected survival rates were significantly lower (p less than 0.05) in patients with gastrointestinal manifestations. These results show that, in patients with PAN, digestive manifestations, particularly perforations, carried a poor prognosis. Nevertheless exploratory laparotomy and surgery unrelated to PAN (eg appendicectomy) were well tolerated.

[Medical treatment of Behçet's disease]. / Traitement médical de la maladie de Behçet.

The treatment of Behçet's disease is essentially symptomatic and depends on the severity of the manifestations. Colchicine is usefull in the minor, particularly mucocutaneous forms. It can be safely used at a dose of 1 mg/day as maintenance treatment to prevent or limit the acute episodes. Other immunomodulators have been proposed: levamisole, disulon, thalidomide, the indications for which are limited by the side effects. Non-steroidal anti-inflammatory agents are indicated in the articular forms. Steroid therapy remains essential in the severe neurological and ophthalmological forms at an initial dose of 1 mg/kg/day. It can be preceded by the intravenous bolus administration of high doses of methylprednisolone. Immunosuppressants are useful in the same indications. Although some authors propose them right from the start, we prefer to reserve them for second line treatment in the event of steroid dependence or recurrence, because of their short-term infectious and long-term oncogenic risks. Cyclosporin, which has been proven to be effective by randomized studies, is difficult to manage and responsible for complications, in particular renal. It can therefore only be used as second line treatment by experienced users. Plasmapheresis is reserved as an emergency procedure for functionally threatening forms. Venous or arterial thromboses justify long-term anticoagulation, possibly associated with platelet anti-aggregants. In this chronic disease, the quality of follow-up and the patient's cooperation are essential in order to intervene rapidly and to detect as early as possible the complications of the disease and of the treatment.

[Aortic aneurysm with vena cava thrombosis occurring in Behcet's disease]. / Anévrisme aortique avec thrombose cave contiguë au cours d'une maladie de Behcet.

We report a case of Behcet's disease complicated by aortic aneurysm and contiguous vena cava thrombosis due to compression. Arterial aneurysms are uncommon in the course of Behcet's disease and are associated with a poor prognosis owing to the risk of rupture. Vena cava thrombosis is found in 10% of cases; pulmonary embolism is infrequent. Venous and arterial lesions usually evolve independently. In most cases they are consecutive to vasculitis. The case reported herein is uncommon because of simultaneous and contiguous venous and arterial lesions. Eighteen months after aorto bi-iliac graft and inferior vena cava ligature, there is no recurrence of thrombosis nor aneurysm with a treatment including heparin, colchicine and azathioprine.

[Venous thrombosis in Behçet's disease]. / Les thromboses veineuses dans la maladie de Behçet.

Venous lesions in Behçet's disease (BD) were defined by Adamantiades and represent one of the most suggestive signs of the disease. They are occasionally the first sign of the disease and are frequently the basis for the diagnosis in a case of recurrent thrombosis in a young subject, the preferential context of BD. Involvement of superficial vessels is virtually constant. Venous vasculitis is responsible for non-specific hypersensitivity and erythema nodosa, which constitute some of the major diagnostic criteria. Ocular periphlebitis is one of the elements responsible for posterior uveitis. The originality of the venous involvement is due to the involvement of deep territories. Any vein may be affected, but the remarkable features are the size of the thrombosed vessels: superior and inferior vena cava, iliofemoral veins and the unusual site of the involvement: supra-hepatic veins, cerebral vessels, etc. Inferior vena cava thrombosis may be associated with aneurysms of the pulmonary arteries in the context of Hughes-Stovin syndrome. Cerebral phlebitis, which can now be identified more easily by means of digital angiography, is responsible for a typical picture: headaches, bilateral papilloedema and raised CSF pressure. The classical pictures of optic chiasmatic arachnoiditis and so-called benign intracranial hypertension actually correspond to unrecognised phlebitis. They may also be associated with other neurological lesions. In one half of cases, phlebitis cutaneous manifestations. However, they may precede the diagnostic signs or may occur very late in the course of the disease. They are recurrent and affect a number of different territories.(ABSTRACT TRUNCATED AT 250 WORDS)

[Popliteal venous aneurysm revealed by recurring pulmonary embolism. Echographic, phlebographic, x-ray computed tomographic and nuclear magnetic resonance aspects]. / Anévrisme veineux poplité révélé par des embolies pulmonaires récidivantes. Aspect échographique, phlébographique, tomodensitométrique et en résonance magnétique nucléaire.

We report a characteristic case of popliteal vein aneurysm which was demonstrated not only by Doppler ultrasonography and venographic examination, but also by CT scan and magnetic resonance imaging. A review of the literature underlines the rarity of these aneurysms, since less than 20 cases have been published. They are always true aneurysms, most often revealed after an episode of pulmonary embolism. Doppler ultrasonography and venography confirm the diagnosis. The place of CT scan and magnetic resonance imaging remains to be defined. Even if asymptomatic, the embolic risk necessitates surgical resection of the aneurysm and restoration of venous continuity.