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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.

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Antiphospholipid syndrome (APS) is associated with a risk of obstetrical complications, affecting both the mother and the fetus. Obstetrical APS is defined by a history of three consecutive spontaneous miscarriages before 10 weeks of gestation (WG), an intra-uterine fetal death after 10 WG, or a premature birth before 34 WG because of severe pre-eclampsia, eclampsia or placental adverse outcomes (intrauterine growth retardation, oligohydramnios). Pregnancy in women with a diagnosis of obstetric APS is at increased risk for placental abruption, HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome and thrombosis that may be part of a catastrophic antiphospholipid syndrome (CAPS). A previous thrombosis and the presence of a lupus anticoagulant are risk factors for pregnancy failure. A multidisciplinary approach, associating the internist, the anesthesiologist and the obstetrician, is recommended for these high-risk pregnancies. Preconception counseling is proposed to identify pregnancy contraindications, and to define and adapt the treatment prior and during the upcoming pregnancy. Heparin and low-dose aspirin are the main treatments. The choice between therapeutic or prophylactic doses of heparin will depend on the patient's medical history. The anticoagulant therapeutic window for delivery should be as narrow as possible and adapted to maternal thrombotic risk. There is a persistent maternal risk in the postpartum period (thrombosis, HELLP syndrome, CAPS) justifying an antithrombotic coverage during this period. We suggest a monthly clinical and biological monitoring which can be more frequent towards the end of pregnancy. The persistence of notches at the Doppler-ultrasound evaluation seems to be the best predictor for a higher risk of placental vascular complications. Treatment optimization and multidisciplinary antenatal care improve the prognosis of pregnancies in women with obstetric APS, leading to a favorable outcome most of the time.

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The coexistence of systemic lupus erythematosus (SLE) and myasthenia gravis (MG) is rarely reported, and most of the published studies are case reports. Hydroxychloroquine, an antimalarial agent, is an essential treatment in patients with SLE but special caution is recommended when used in MG patients. We retrospectively analyzed the clinical features, laboratory findings, and outcome of 17 patients with both diseases with a special focus regarding hydroxychloroquine use and with a review of the literature. All patients were women. The mean age at MG onset and SLE diagnosis was 34.5 [14-64] and 37.8 [18-72] years, respectively. The presenting symptoms of MG were limb weakness (94%), ocular (88%) and bulbar involvement (53%). Autoantibodies against the acetylcholine receptor were positive in 94% of cases. The main manifestations of SLE included arthritis (88%), cytopenias (53%) and skin rash (41%). Treatment of SLE required hydroxychloroquine (94%), steroids (47%) and immunosuppressive drugs (18%). Among eight patients (47%) who developed MG after initiation of hydroxychloroquine, the question of induction of MG by hydroxychloroquine was raised in one patient. On the other hand, an exacerbation of myasthenic symptoms was only seen in one of the eight patients who received hydroxychloroquine after the diagnosis of MG. Including our cases, we reviewed a total of 70 patients with SLE and MG. Compared with a large series of 1,000 unselected SLE patients, those with associated MG were older, had lower incidence of cutaneous, renal, and neurological manifestations, and higher frequency of anticardiolipin antibodies and lupus anticoagulant. In conclusion, the clinical pattern of patients with SLE and MG seems to be characterized by a less severe course of SLE and higher frequency of antiphospholipid antibodies. Hydroxychloroquine treatment appears to be safe in this setting.

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OBJECTIVE: To investigate the efficacy and tolerance of azathioprine in severe uveitis related to Behçet's disease (BD). METHODS: We reported 157 consecutive patients with severe uveitis (active posterior uveitis or panuveitis) fulfilling the international criteria for BD and treated with corticosteroids (0.5-1 mg/kg/day) and azathioprine (2.5 mg/kg/day). Long-term outcome and factors associated with complete remission were assessed. RESULTS: Mean±SD age at diagnosis was 29.9±10.1 years, with 71.3% men. At baseline, 59 patients (37.6%) had loss of useful vision, 54 (34.4%) had retinal vasculitis, 66 (42.0%) had panuveitis, and 132 (84.1%) had bilateral uveitis. Following azathioprine therapy, 81 patients (51.6%) were complete responders, 65 (41.4%) were partial responders, and 11 (7%) were nonresponders. The visual acuity significantly improved (P<0.001), and a significant decrease in the mean oral prednisone dosage (55.3 to 10.5 mg/day; P<0.001) was observed after therapy. Patients with retinal vasculitis (odds ratio [OR] 0.45 [95% confidence interval (95% CI) 0.2-0.9], P=0.02) and severe visual loss (OR 0.28 [95% CI 0.2-0.7], P<0.0001) at diagnosis were less likely to be complete responders. Azathioprine was well tolerated, with only 3 withdrawals due to hepatotoxic effects (n=2) and bacterial septicemia (n=1). CONCLUSION: Azathioprine represents an effective and safe therapy in patients with severe uveitis of BD.

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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.

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OBJECTIVE: To analyze the clinical findings, treatment, outcome, and prevalence of cerebral venous thrombosis (CVT) in a large cohort of patients with Behçet's disease (BD) from a single center. METHODS: We reported a series of 64 consecutive patients with CVT who fulfilled the international criteria for BD. Multivariate analysis was performed to define factors that affect prognosis. RESULTS: Among a cohort of 820 patients with BD, CVT was present in 64 (7.8%). Compared with BD patients without CVT, those with CVT had lower parenchymal central nervous system involvement (4.7% versus 28.7%; P = 0.0001) and higher extraneurologic vascular lesions (62.5% versus 38.8%; P = 0.03). Up to 90% of patients responded to anticoagulation therapy without severe hemorrhagic complications. Neither steroid nor immunosuppressant use provided better outcome. Severe visual loss due to optic atrophy was the main complication of CVT, being found in 15% of patients. In multivariate analysis, papilledema (odds ratio [OR] 7.1, 95% confidence interval [95% CI] 1.6-31.9) and concurrent prothrombotic risk factors (OR 4.6, 95% CI 1.1-20.2) were independently associated with the occurrence of sequelae. Factors associated with relapse of thrombosis were concurrent prothrombotic risk factors (hazard ratio [HR] 4.9, 95% CI 1.5-15.4) and a peripheral venous thrombosis (HR 2.8, 95% CI 0.7-10.5). After a mean +/- SD followup of 8.2 +/- 6.9 years, 4 deaths unrelated to CVT were noted. CONCLUSION: CVT in patients with BD may result in serious neurologic outcomes. Anticoagulation represents a safe and effective therapy. Extensive investigation of prothrombotic disorders should be considered.

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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.

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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.

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Posterior reversible encephalopathy syndrome (PRES) associates various neurological manifestations (headaches, seizures, altered mental status, cortical blindness, focal neurological deficits, vomiting) and transient changes on neuroimaging consistent with cerebral edema. Posterior reversible encephalopathy syndrome mainly occurs in the setting of hypertension, eclampsia, renal failure and/or use of immunosuppressive drugs. We report four cases of PRES complicating systemic lupus erythematosus (SLE). In all our cases, renal involvement and hypertension were present. Neurological symptoms were typical. Magnetic resonance imaging showed posterior cerebral edema and in one case hemorrhagic complication. With symptomatic treatment and immunosuppressor withdrawal when they were previously used, symptoms fully resolved within 15 days in all cases, but one who had only partial regression related to cerebral hemorrhage. Including our cases, we reviewed a total of 46 patients with SLE and PRES. Their clinical and radiological presentation was not specific. The peculiar role of SLE itself in the occurrence of PRES was not clear, since hypertension (95%), renal involvement (91%), recent onset of immunosuppressive drugs (54%) and/or recent treatment with high intravenous dose of steroids (43%) were often present. The hypertension and other worsening factors should be treated. Finally, the evolution of this clinical and radiological spectacular syndrome is generally rapidly favorable.

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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.

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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.

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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.

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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.

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OBJECTIVE: To examine the prevalence and characteristics of patients with reactive haemophagocytic syndrome (RHS) complicating adult-onset Still's disease (AOSD). METHODS: Of 50 patients with AOSD fulfilling Yamaguchi and Fautrel criteria followed in our department, clinical and laboratory data, course and treatment of six patients with histologically proven RHS and without any obvious cause other than AOSD were retrospectively recorded. RESULTS: RHS led to AOSD in two cases, whereas it appeared after a mean duration of 3.5 years from onset of AOSD in the other cases. The main symptoms were fever (n = 6), polyarthralgias or myalgias (n = 4), lymphadenopathy or splenomegaly (n = 3), pharyngitis (n = 3), rash (n = 3), pleuritis (n = 3), hepatomegaly (n = 1), normal or low leucocyte count (n = 4), anaemia (n = 6), lymphocytopenia (n = 6), thrombocytopenia (n = 4), hyperbasophilic lymphocytes (n = 2), abnormal liver function tests (n = 6) and increased serum triglyceride level (n = 6). Serum ferritin concentration was constantly increased (>10,000 microg/l in five cases, with <5-35% in glycosylated form). Two patients presented with coagulopathy. Treatment comprised corticosteroids (n = 4) and intravenous immunoglobulins (n = 3), whereas prednisone was unchanged in one case. One death due to pneumonia occurred 15 days after RHS. With a follow-up ranging from 2 to 7.5 years, the other patients were in remission with prednisone plus etanercept (n = 1), prednisone plus methotrexate (n = 1), low-dose prednisone (n = 2) or without treatment (n = 1). CONCLUSION: RHS is not uncommon in AOSD. It should be evoked in a patient with AOSD in the absence of hyperleucocytosis, thrombocytopenia, lymphopenia and coagulopathy, or in the presence of high serum ferritin and triglyceride levels.

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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.

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OBJECTIVE: To examine the predictive value of clinical examination, laboratory tests and Doppler ultrasound examination in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) pregnancies. METHODS: A prospective study of 116 pregnancies followed in a single tertiary referral centre. Outcomes analysed were fetal/neonatal death and adverse pregnancy outcome. Univariate analysis was performed for: (i) medical and obstetric history; (ii) medical and obstetric clinical examination; (iii) biological data; (iv) Doppler ultrasound examination. Variables significantly associated with the outcomes in the univariate analysis were entered into a logistic regression model. RESULTS: Sixteen out of 116 pregnancies ended in 12 fetal deaths and 4 embryonic losses. Hence, data for 100 pregnancies were analysed. Seven fetal deaths and one neonatal death occurred, associated with abnormal end-diastolic umbilical artery Doppler flow at the second trimester (P < 0.006), a history of thrombophlebitis (P < 0.001) or notched uterine artery and growth restriction at the second trimester (P < 0.002). Multivariate analysis retained abnormal end-diastolic umbilical artery Doppler flow (P = 0.047) and history of thrombophlebitis (P = 0.018) as significant predictors. Thirty-one adverse pregnancy outcomes occurred, associated with notched uterine artery (P < 0.00003), abnormal end-diastolic umbilical artery Doppler flow (P < 0.0006) and fetal growth restriction at the second trimester (P < 0.008), growth restriction (P < 0.00001) and notched uterine artery at the third trimester (P < 0.0008), use of heparin (P < 0.05) and history of thrombophlebitis (P < 0.04). Notched uterine artery at the second trimester remained the only predictor in multivariate analysis (P = 0.001). CONCLUSIONS: Results of the second trimester Doppler ultrasound examination are the best predictors for late pregnancy outcome in SLE and/or APS.

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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.

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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.

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