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Background Catastrophic antiphospholipid syndrome (CAPS) is the most severe complication of antiphospholipid syndrome (APS). Vitamin K antagonists (VKAs) are the reference treatment for preventing relapsing thrombotic complications in patients with APS, but direct oral anticoagulants (DOACs), such as rivaroxaban, are nonetheless sometimes used in patients with antiphospholipid antibody profiles or APS. Recent studies showed that DOACs were associated with more arterial thromboses among patients with APS. The potential role of DOACs as a trigger factor of CAPS is not known. Methods We describe two patients who developed a CAPS in the week following the institution of rivaroxaban. Results We report the onset of definite CAPS in the week following introduction of rivaroxaban treatment in two patients, one with APS and the other with antiphospholipid laboratory findings only. Both were triple positive for antiphospholipid antibodies. The affected organs were the heart, kidneys, skin, and liver for Patient 1, and the heart, kidneys, skin, adrenal gland, and central nervous system for Patient 2. The causative role of rivaroxaban is highly probable given that (1) CAPS occurred rapidly after this treatment was started, (2) an alternative trigger factor was found in Patient 1 only (a colonoscopy), and (3) Patient 1 had been clinically stable for 18 years with VKA as anticoagulant treatment, while Patient 2 did not have APS and had had no symptoms for 4 months (rivaroxaban had been introduced because at a scheduled visit, she reported neurological symptoms that occurred four months before and were retrospectively compatible with a brain transient ischemic accident). One similar case was reported in 2017, also following the introduction of rivaroxaban, in a patient with triple positive venous thrombotic APS who was stable for years on warfarin and who developed definite CAPS (involvement of the myocardium and adrenal glands as well as a pulmonary embolism) in the week after rivaroxaban 20 mg daily replaced warfarin to meet the patient‘s desire for a less burdensome treatment.1 Finally, in the randomized study published by Ordi-Ros et al, one of the patients treated with rivaroxaban developed a CAPS.2 Conclusions These two cases, as well as two previous reported cases, underline the importance of avoiding DOACs in patients with APS, especially those triple positive for antiphospholipid antibodies. VKAs must remain the reference anticoagulation treatment in this setting. References Crowley MP, Cuadrado MJ, Hunt BJ. Catastrophic antiphospholipid syndrome on switching from warfarin to rivaroxaban. Thromb Res 2017; 153; 37–9. Ordi-Ros J, Saez-Comet L, Perez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomo A, et al. Rivaroxaban versus vitamine K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. doi: 10.7326/M19-0291. [Epub ahead of print]; 2019

Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on pathophysiology are scarce and suggest an autoimmune mechanism. Recently, the possibility of dividing patients with RP into three distinct clinical phenotypes has been suggested: the hematological form representing less than 10% of patients, essentially older men with associated myelodysplasia and poor prognosis, the respiratory form representing about 25% of patients with predominant tracheobronchial involvement, and the mild and most frequent form, representing 65% of patients, with a good prognosis. Recent data on survival shows an improvement of overall prognosis compared to historical series. Reported poor prognosis factors are male gender, associated haemopathies and cardiac involvement. Few recent series suggest an interest for positron emission tomography for the diagnosis and the follow-up of treatment. Due to the lack of randomized therapeutic trial, treatment remains empirical and is mainly based on oral corticosteroids sometimes associated with immunosuppressive agents. The use of biologic agents has recently been reported in small retrospective series with different outcome. Finally, some selected patients with mild and occasional peripheral chondritis might justify a treatment with colchicine or a therapeutic abstention with occasional short-term corticosteroids therapy.

Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by high-performance liquid chromatography. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ

Background:One of the 3 features of obstetrical antiphospholipid syndrome (APS) is severe preeclampsia (PE). Its time of occurrence, the associated risk of thromboses and systemic lupus erythematosus (SLE) have not been reported yet.Objectives:We analyzed severe PE in a series of women with APS.Methods:We retrospectively collected data of female patients from 5 French internal medicine and 1 Italian rheumatology units. Inclusion criteria were: a severe PE/eclampsia(1), that occurred before 34 weeks of gestation (WG) in patients who met the APS classification criteria(2).Results:40 patients were enrolled (Table 1). Because of known APS/positive aPL/previous obstetrical complications, 23(57.5%) patients were treated during the index PE: 4 with low dose aspirin (LDA), 4 with low molecular weight heparin (LMWH), and 15 with a combination of both. 7 patients were also treated with hydroxychloroquine, 8 with corticosteroids and 3 with immunosuppressants. 17(42.5%) patients received no treatment. 24(60%) live births were observed. During a follow-up period of 3 years, 26(65%) patients had at least 1 new pregnancy, with a total of 38 pregnancies which resulted in 33(86.8%) live births. 57.5% pregnancies who resulted in live births occurred without any maternal or fetal complications. All 26 patients who had at least 1 pregnancy after index PE were treated with LDA; LMWH was given at prophylactic and therapeutic dosage in 13(50%) patients, respectively. No patient experienced 3 consecutive miscarriages.Table 1.40 APS patients with severe PEOverall features (n, %)Patients40 (100)Age at PE, (median, IQR)30.5 (27-33)PE term, WG (median, IQR)25.5 (23-29) Live births24 (60) Birth term, WG (median, IQR)25.5 (23.7-30.3) Associated SLE12 (30)Maternal complications (n, %)25 (62.5) HELLP18 (45) E6 (15) CAPS3 (7.5) Placental abruptions3 (7.5)Fetal complications (n, %)31 (77.5) IUGR18 (45) IUFD11 (2.5) Preterm delivery22 (55)Obstetrical history (n, %) Primiparous21 (52.5) Index PE before APS12 (30)Thrombosis (n, %) Thrombosis before PE index14 (35.0) Thrombosis after PE index2 (5.0)Abs at APS diagnosis (n, %) aPL triple positivity21 (52.5) IgG/IgM anti-cardiolipin34 (85.0) IgG/IgM anti-β2GPI25 (62.5) LAC33 (82.5)Legend to Table 1:PE: preeclampsia; APS: antiphospholipid syndrome; IQR: interquartile range; WG: weeks of gestation; SLE: systemic lupus erythematosus; HELLP: Hemolysis, elevated liver enzymes, low platelet; E: eclampsia; CAPS: catastrophic APS; IUGR: intrauterine growth restriction; IUFD: intrauterine fetal death; CHB: congenital atrioventricular block; aPL: antiphospholipid antibodies; LAC: lupus anticoagulant.Conclusion:Among the APS criteria, “3 consecutive miscarriages criterion” was not found. The majority of patients also experienced thrombosis and SLE before the index PE.References:[1]Diagnosis and Management of preeclampsia and eclampsia. International Journal of Gynecology &Obestetrics 2002;77:67-75.[2]Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295e 306.Disclosure of Interests:Maddalena Larosa: None declared, Nathalie Morel: None declared, Meriem BELHOCINE: None declared, Amelia Ruffatti: None declared, Nicolas Martin Silva: None declared, Romain Paul: None declared, Luc Mouthon: None declared, Michel DREYFUS: None declared, Jean-Charles PIETTE: None declared, Odile Souchaud-Debouverie: None declared, Catherine Deneux-Tharaux: None declared, Vassilis Tsatsaris: None declared, Emmanuelle Pannier: None declared, Gaêlle Guettrot Imbert: None declared, Véronique LE GUERN Grant/research support from: UCB for GR2 study (to our institution), Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institution

Background The diagnosis of systemic lupus erythematosus (SLE) is based on the association of clinical and biological manifestations and on clinical experience. In 2012, a major revision by the Systemic Lupus International Collaborating Clinics (SLICC) group sought to improve their sensitivity and specificity. In replications, the SLICC classification produced fewer errors than the previous version; its higher sensitivity but lower specificity meant that some patients could be classified with SLE although they had another disease. In fact, the distinction between PAPS, APS associated with SLE, and isolated SLE may be difficult in some cases because the two diseases share some clinical and biological manifestations. Objectives To assess the limitations of the SLICC (Systemic Lupus International Collaborating Clinics) classification criteria for systemic lupus erythematosus (SLE), in patients with primary antiphospholipid syndrome (PAPS). Methods Retrospective study of a cohort of APS patients (Sydney criteria). We successively excluded patients with1 at least one “SLE-specific” manifestation (biopsy-proven SLE nephropathy, arthritis, cutaneous, or neurologic SLE manifestations, pericarditis, autoimmune haemolytic anaemia, oral and nasal ulcers, non-scarring alopecia, anti-dsDNA, and anti-Sm antibodies),2 any other autoimmune connective tissue disease, and/or3 antinuclear antibodies>1/320. Careful file review confirmed PAPS among the remaining patients. We then assessed the number of SLICC criteria each patient met. Results Among these 214 APS patients, we excluded 85 with at least one SLE-specific manifestation, 8 with another connective tissue disease, and 21 with antinuclear antibodies>1/320, leaving 100 patients with primary APS. Among them, 28% met at least 4 SLICC classification criteria including one clinical and one immunological criterion (antiphospholipid antibodies, aPL, by definition) and could thus theoretically be classified with SLE. Fourteen had an arterial phenotype (50%), 9 a history of catastrophic APS (32%), and 18 a triple-positive profile for aPL (64%). None had developed SLE during a median follow-up of 12 [6.5–17] years. Conclusions Because 28% of our patients with longstanding and strictly defined PAPS could be mistakenly classified as SLE, they were at risk of deleterious therapeutic management. We therefore suggest that any future classification for SLE should specifically require at least one SLE-specific criterion for patients with aPL. References [1] Petri M, Orbai A-M, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum2012;64:2677–86. doi:10.1002/art.34473 [2 ] Piette JC, Wechsler B, Frances C, et al. Exclusion criteria for primary antiphospholipid syndrome. J Rheumatol1993;20:1802–4. [3] Asherson RA, Khamashta MA, Ordi-Ros J, et al. The ‘primary’ antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989;68:366–74. [4] Gomez-Puerta JA, Martin H, Amigo M-C, et al. Long-term follow-up in 128 patients with primary antiphospholipid syndrome: do they develop lupus? Medicine (Baltimore) 2005;84:225–30. Disclosure of Interest None declared

Objective To assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome. Methods This study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy. Results One hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23–30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26–31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5–33], P 1) (odds ratio 28.7 [95% confidence interval 7.89–104.7]) were independently associated with obstetric and maternal complications. Conclusion TAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.

International audience; Objective. We describe myelodysplastic syndrome (MDS)–associated systemic inflammatory and autoimmune diseases (SIADs), their treatments and outcomes and the impact of SIADs on overall survival in a French multicentre retrospective study. Methods. In this study, 123 patients with MDS and SIADs were analysed. Results. Mean age was 70 years (s.d. 13) and the male:female ratio was 2. The SIADs were systemic vasculitis in 39 (32%) cases, CTD in 31 (25%) cases, inflammatory arthritis in 28 (23%) cases, a neutrophilic disorder in 12 (10%) cases and unclassified in 13 cases (11%). The SIADs fulfilled the usual classification criteria in 75 (66%) cases, while complete criteria were not reached in 21 (19%) cases. A significant association was shown between chronic myelomonocytic leukaemia (CMML) and systemic vasculitis (P = 0.0024). One hundred and eighteen (96%) SIAD patients were treated (91% with steroids), with an 83% response to first-line treatment, including 80% for steroids alone. A second-line treatment for SIADs was required for steroid dependence or relapse in 48% of cases. The effect of MDS treatment on SIADs could be assessed in 11 patients treated with azacytidine and SIAD response was achieved in 9/11 (80%) and 6/11 (55%) patients at 3 and 6 months, respectively. Compared with 665 MDS/CMML patients without SIADs, MDS/CMML patients with SIADs were younger (P \textless 0.01), male (P = 0.03), less often had refractory anaemia with ring sideroblasts (P \textless 0.01), more often had a poor karyotype (16% vs 11%, P = 0.04) and less frequently belonged to low and intermediate-1 International Prognostic Scoring System categories, but no survival difference was seen between patients with MDS-associated SIADs and without SIADs (P = 0.5). Conclusion. The spectrum of SIADs associated to MDS is heterogeneous, steroid sensitive, but often steroid dependent

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.

RésuméLa survenue d’une grossesse au cours du lupus systémique est une situation fréquente qui reste associée à une morbi-mortalité maternelle et fœtale plus importante que dans la population générale. Les complications incluent les poussées lupiques, les complications obstétricales (pertes fœtales, retard de croissance in utero, pré-éclampsie, prématurité) et le lupus néonatal. Une biologie ou un syndrome des antiphospholipides augmente nettement le risque de complications obstétricales. L’amélioration de la prise en charge de ces grossesses est conditionnée par leur planification systématique, idéalement au cours d’une consultation pré-conceptionnelle, et par une prise en charge multidisciplinaire avec une collaboration étroite entre interniste/rhumatologue, obstétricien et anesthésiste. L’absence d’activité du lupus, un traitement compatible avec la grossesse adapté aux antécédents et aux risques ainsi qu’une surveillance régulière sont les principaux éléments permettant une issue favorable à ces grossesses à risque. Cette revue a pour objectif de proposer une mise au point sur la prise en charge actuelle de la grossesse au cours du lupus systémique ou du syndrome des antiphospholipides afin de limiter le risque de complications et d’assurer le meilleur pronostic tant maternel que fœtal.AbstractPregnancy in systemic lupus erythematosus patients is a common situation that remains associated with higher maternal and fetal mortality/morbidity than in the general population. Complications include lupus flares, obstetrical complications (fetal loss, in utero growth retardation, prematurity) and neonatal lupus syndrome. The association with antiphospholipid antibodies or antiphospholipid syndrome increases the risk of obstetrical complications. Improving the care of these pregnancies depends upon a systematic pregnancy planning, ideally during a preconception counseling visit and a multidisciplinary approach (internist/rheumatologist, obstetrician and anesthetist). The absence of lupus activity, the use of appropriate medications during pregnancy adjusted to the patient's medical history and risk factors, and a regular monitoring are the best tools for a favorable outcome for these high-risk pregnancies. The aim of this review article is to perform an update on the medical care of pregnancy in systemic lupus erythematosus or antiphospholipid syndrome to reduce the risk of complications and to ensure the best maternal and fetal prognosis.

Fertility is not impaired in systemic lupus erythematosus or antiphospholipid syndrome, but, similarly to the general population, these patients may undergo in vitro fertilization. This type of treatment increases the risk of lupus flare, thrombosis, and ovarian hyperstimulation syndrome. This review will focus on in vitro fertilization in systemic lupus erythematosus or antiphospholipid syndrome. Literature data are relatively scant with only 3 reported studies. The first one included 17 patients and 63 cycles of induction ovulation/in vitro fertilization leading to 25 % of lupus flare, no thrombosis, and 3 % of ovarian hyperstimulation syndrome. The second study included 10 patients and 40 cycles of in vitro fertilization showing 31 % of lupus flare, no thrombosis and no ovarian hyperstimulation syndrome. The last one included 34 patients and 83 procedures of in vitro fertilization leading to 8 % of flares, 5 % of thrombosis and no ovarian hyperstimulation syndrome. Interestingly, in this last study, half of the complications were explained by poor adherence to treatment. These data are reassuring but it is important to remember that in vitro fertilization should be scheduled and carefully supervised in the same way as the high-risk pregnancies occurring in these patients.

Objective.To assess the longterm frequency of thrombotic recurrences, obstetrical complications, organ damage, severe comorbidities, and evolution toward connective tissue disease (CTD) in primary antiphospholipid syndrome (PAPS).Methods.Medical records of patients with PAPS followed in 6 centers for ≥ 15 years were retrospectively reviewed.Results.One hundred fifteen patients were studied: 88% women, followed between 1983 and 2014 with a mean (± SD) age at diagnosis of 33 (± 10) years. During a median followup of 18 years (range 15–30), 50 patients (44%) had at least a thrombotic event for a total of 75 events and an annual incidence of 3.5%. Thromboses were more frequent in patients with previous thrombotic history (p = 0.002). A catastrophic antiphospholipid syndrome occurred in 6 patients (5%). The use of oral anticoagulants in patients with thrombotic onset did not appear to be protective against recurrences (p = 0.26). Fifty-two women had 87 pregnancies, successful in 78%. Twenty-nine percent of patients accrued functional damage. Damage was significantly associated with a thrombotic history (p = 0.004) and with arterial events (p < 0.001), especially stroke, but not with demographics, serology, or treatment. Twenty-four major bleeding episodes were recorded in 18 patients, all receiving anticoagulants. Severe infections affected 6 patients (5%), with 1 fatality. A solid cancer was diagnosed in 8 patients (7%). Altogether, 16 patients (14%) developed an autoimmune disease and 13 (11%) a full-blown picture of CTD.Conclusion.Despite therapy, a high proportion of patients experienced new thrombotic events and organ damage, while evolution toward CTD was infrequent.

Objective: To report the long-term outcome of neurological involvement in patients with Behcet's disease (BD). Methods: Retrospective analysis of 115 patients fulfilling the international criteria for BD [57% male with median [Q1-Q3] age of 37 [30-46] years] and with neuro-Behcet's disease (NBD) after exclusion of cerebral venous thrombosis. Factors associated with relapse of NBD, dependence and mortality were assessed. Results: Seventy-eight (68%) patients presented with acute NBD and 37 (32%) with a progressive course. The HLA B51 allele was carried by 49% of patients. Overall, 46/115 (40%) patients had a severe baseline disability status, represented by a Rankin score ≥ 3. The 5 and 7 years event-free survival rates were 65% and 53%, respectively. In multivariate analysis, a positive HLA-B51 status was independently associated with the risk of NBD relapse (OR=3.6 [1.5-9.1]). After a median follow-up of 73 [59-102] months, 21 (25.2%) patients became dependent or died. Factors independently associated with poor outcome were paresis at onset (OR=6.47 [1.73-24.23]) and a brainstem location of inflammatory lesions on MRI (OR=8.41 [1.03-68.43]). All 115 patients were treated with glucocorticosteroids, including 53/115 (46.1%) with cyclophosphamide and 40/115 (34.8%) with azathioprine. A trend towards longer event-free survival was observed in severe NBD patients (i.e. Rankin score ≥ 3 at onset) receiving intravenous cyclophosphamide compared with those treated with azathioprine (p =0.06). Conclusion: NBD is a severe condition in which patients with the HLA-B51 allele appear to experience a worse prognosis. © 2013 American College of Rheumatology.

Vascular involvement is a common complication of Behcet's disease (BD) and affects up to 40% of BD patients. These complications worsen the prognosis of BD. The concept of vasculo-Behcet has been adopted for cases in which vascular complications dominate the clinical features. Vascular manifestations affect particularly young men, during the first years following onset of the disease. Venous complications are the most frequent vascular complications, affecting 14 to 40% of BD patients. Superficial and deep lower limb thrombosis is the most frequent venous complications but one third of venous thrombosis concern large vessels (such as cerebral venous thrombosis, pulmonary embolism, and inferior or superior vena cava, etc.). Budd-Chiari syndrome is the worst prognostic factor increasing mortality by 9 times. Arterial complications (2 to 17% of BD patients) include aneurysms and occlusions/stenosis. Main locations of arterial lesions are aortic (abdominal and thoracic), femoral, pulmonary and iliac arteries. Aneurysms are the most severe arterial complications, particularly pulmonary aneurysms associated with a high risk of massive bleeding. Cardiac complications (up to 6% of BD patients) include pericarditis, endocardial lesions (aortic regurgitation and less often mitral insufficiency), myocardial lesions (myocardial infarction, myocarditis and endomyocardial fibrosis) and intracardiac thrombosis (right ventricle and atrium). Coronary lesions complicated to myocardial infarction are the most severe cardiac complications. Treatment is based on corticosteroids and immunosuppressive drugs. The use of anticoagulation in venous thrombosis is still controversial.

International audience; Pulmonary hyalinizing granuloma (PHG) is a rare disease characterized by single or multiple benign lung nodules mimicking lung neoplasma. Histologic analysis reveals homogenous hyaline lamellae, usually surrounded by collection of plasma cells, lymphocytes and histiocytes in a perivascular distribution. The clinical and radiological findings have been described in small series, but the long-term outcomes have rarely been reported. The objectives were to describe the clinical, radiological and outcomes of PHG in new cases and through a literature review. Patients with PHG were found by a multicenter search among French departments of internal medicine, pulmonology and anatomo-pathology. Review of the literature was made through the National Library of Medicine’s MEDLINE database using keywords “hyalinizing granuloma.” Five news cases and 135 cases of the literature were found. There were 82 men and 57 women, mean age at the diagnosis 44.6 years (15–83). Patients were frequently asymptomatic (n = 39, 27.4 %). The nodule was unique in 37 cases (28.9 %) and multiple in 91 cases (71.1 %). 18FDG PET scan revealed hypermetabolism of the nodule in 9/15 cases (60 %). A systemic disease was associated in 65 cases (mainly mediastinal and retroperitoneal fibrosis, autoimmune, tumoral or infectious disease or thromboembolism). The outcomes were evaluated in 73 patients when follow-up was available: 14 patients had a surgical resection of the nodule. Forty-five patients did not receive any immunosuppressive drug. Among these patients, 2 improved, 29 were stable and 14 worsened. Corticosteroids were used as a monotherapy in 19 patients and led to radiological improvement in 8 cases, stabilization in 8 cases and worsening in 3 cases. Five patients were treated with corticosteroids and at least one immunosuppressive drug and 4 patients improved. PHG is a rare benign disease, mimicking lung neoplasma, frequently associated with systemic diseases.

Background— A recent case-control study suggested a benefit of hydroxychloroquine (HCQ) in lowering the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in pregnancies of anti-SSA/Ro–positive patients with systemic lupus erythematosus. A historical cohort assembled from 3 international databases was used to evaluate whether HCQ reduces the nearly 10-fold increase in risk of recurrence of cardiac-NL independently of maternal health status. Methods and Results— Two hundred fifty-seven pregnancies of anti-SSA/Ro-positive mothers (40 exposed and 217 unexposed to HCQ) subsequent to the birth of a child with cardiac-NL were identified from 3 databases (United States, England, and France). Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation before 10 weeks of gestation. The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5% (3 of 40) compared with 21.2% (46 of 217) in the unexposed group ( P =0.050). Although there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 21.7%. In a multivariable analysis that adjusted for database source, maternal race/ethnicity, and anti-SSB/La status, HCQ use remained significantly associated with a decreased risk of cardiac-NL (odds ratio, 0.23; 95% confidence interval, 0.06–0.92; P =0.037). Similar results were obtained with propensity score analysis, an alternative approach to adjust for possible confounding by indication. Conclusion— Aggregate data from a multinational effort show that in mothers at high risk of having a child with cardiac-NL, the use of HCQ may protect against recurrence of disease in a subsequent pregnancy.

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.

The effects of vitamin D on calcium homeostasis and bone metabolism are well known. In recent years, suboptimal vitamin D status has been recognized as a pandemic. Meanwhile, extra-skeletal effects of vitamin D are becoming better documented, particularly its effects on immunity. The authors present their actions on myeloid dendritic cells, T cells, B cells, as well as on the synthesis of antimicrobial peptides and autophagy, and the potential beneficial effects in autoimmune and inflammatory diseases.

Vitamin D is often confined to its role in calcium homeostasis and bone metabolism. An exponential literature discusses its non-skeletal effects, especially its central role in the physiology of the immune system, where it acts at several levels to maintain self-tolerance. Here, the authors review the experimental, epidemiological and clinical studies, illustrating the potential role of vitamin D in the development and perpetuation of autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases or rheumatoid arthritis.

Pulmonary hypertension (PH) is a serious complication of connective tissue diseases. The prevalence of PH in systemic lupus erythematosus (SLE) ranges from 0.5 to 17.5%, depending on whether echocardiography or right heart catheterization is used as the gold standard for diagnosis. The recent guidelines for the diagnosis and treatment of pulmonary hypertension include several potential causes of PH in SLE, including: a primary vasculopathy similar to idiopathic pulmonary arterial hypertension (PAH); left heart diseases; post-thromboembolic disease; hypoxia and fibrosis resulting from interstitial lung disease; and the infrequent SLE-associated pulmonary veno-occlusive disease. The pathogenesis of PAH associated with lupus is yet unclear, but likely includes a role for the genetic background, the presence of antiphospholipid antibodies, and some level of endothelial dysfunction. The evolution of SLE-associated PH is highly variable and difficult to elicit because the published series have used heterogeneous inclusion criteria. Optimal therapeutic management of PAH associated with lupus is unclear because no dedicated randomized controlled trial is yet available. Treatment usually includes arterial pulmonary vasodilators and immunosuppressive agents when the patients have NYHA functional class II, III or IV dyspnea.

Objective To assess the factors influencing the efficacy of 2 injections of a pandemic 2009 influenza A (H1N1) vaccine in patients with systemic lupus erythematosus (SLE). Methods We conducted a single-center, observational prospective study of 111 patients who were vaccinated with a monovalent, inactivated, nonadjuvanted, split-virus vaccine during December 2009 and January 2010 and received a second dose of vaccine 3 weeks later. The antibody response was evaluated using the hemagglutination inhibition assay according to the guidelines recommended for the pandemic vaccine, consisting of 3 immunogenicity criteria (i.e., a seroprotection rate of 70%, a seroconversion rate of 40%, and a geometric mean ratio [GMR] of 2.5). Results The 3 immunogenicity criteria were met on day 42 (seroprotection rate 80.0% [95% confidence interval (95% CI) 72.5–87.5%], seroconversion rate 71.8% [95% CI 63.4–80.2%], and GMR 10.3 [95% CI 2.9–14.2]), while only 2 criteria were met on day 21 (seroprotection rate 66.7% [95% CI 57.9–75.4%], seroconversion rate 60.4% [95% CI 51.3–69.5%], and GMR 8.5 [95% CI 3.2–12.0]). The vaccine was well tolerated. Disease activity, assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, the British Isles Lupus Assessment Group score, and the Systemic Lupus Activity Questionnaire, did not increase. In the multivariate analysis, vaccination failure was significantly associated with immunosuppressive treatment or a lymphocyte count of ≤1.0 × 109/liter. The second injection significantly increased the immunogenicity in these subgroups, but not high enough to fulfill the seroprotection criterion in patients receiving immunosuppressive treatment. Conclusion Our findings indicate that the efficacy of the vaccine was impaired in patients who were receiving immunosuppressive drugs or who had lymphopenia. A second injection increased vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients receiving an immunosuppressive agent. These results open possibilities for improving anti-influenza vaccination in SLE.

ObjectivesTo develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations.MethodsThe authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design.ResultsSystemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence >5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1–5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD.ConclusionsNeuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

The aim of this study was to determine the characteristics, treatment, and outcome according to each etiology of pachymeningitis.We conducted a retrospective multicenter French nationwide study between 2000 and 2016 to describe the characteristics, outcome, and treatment of pachymeningitis.We included 60 patients (median age 55.5 years; interquartile range [IQR] 30-80, female/male ratio 0.43). Neurologic signs were present in 59 patients (98%) and consisted of headache in 43 (72%), cranial nerve palsy in 33 (55%), confusion in 10 (17%), seizures in 7 (12%), and focal neurologic signs in 9 (15%). Fever and weight loss were present in 8 (13%) and 13 cases (22%), respectively. Cerebral venous thrombosis was present in 8 cases (13%). Analysis of cerebrospinal fluid showed moderate hyperproteinorachia (median 0.68 g/L; IQR 0.46-3.2) with or without pleiocytosis. Diagnosis included idiopathic pachymeningitis (n = 18; 30%); granulomatosis with polyangiitis (n = 13; 17%); Erdheim-Chester disease (n = 10; 17%); IgG4-related disease and tuberculosis (n = 3; 5% each); Rosai-Dofman disease, microscopic polyangiitis, and sarcoidosis (n = 2, 3% each); cryptococcal meningitis, Lyme disease, ear-nose-throat infection, postlumbar puncture, low spinal-fluid pressure syndrome, and lymphoma (n = 1 each). We found no difference in demographics and neurologic presentation among idiopathic pachymeningitis, Erdheim-Chester disease, and granulomatosis with polyangiitis. In contrast, frequencies were lower with idiopathic pachymeningitis than Erdheim-Chester disease for general signs (6% and 40%, respectively, P = .041) and complete neurologic response (0% vs 39%, P = .045).The detection of extraneurologic signs and routine screening are needed to classify the pachymeningitis origin. Prospective studies are warranted to determine the best treatment in each case.

Since the association between antiphospholipid antibodies and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies. These aPL are usually associated neither with anti-beta2 glycoprotein I antibodies (anti-beta2-GPI) nor with thrombotic events, even if cases of arterial and deep venous thrombosis have been reported in such circumstances. A literature review shows that anticardiolipin antibodies occur frequently in viral infections, particularly in HIV (49.8%), HBV (24%) and HCV (20%). The prevalence of anti-beta2 glycoprotein I antibodies (anti-beta2GPI) is lower (HCV: 1.7%, HIV: 5.6%, HBV: 3.3%) and there is no demonstrated association with a risk of thrombotic events or hematological manifestations defining antiphospholipid syndrome (APS). Regarding other viral infections, including viral hepatitis A, herpes virus (CMV, EBV, VZV), parvovirus B19 and HTLV-1 infections, only a few studies are available but data confirm the high prevalence of antiphospholipid antibodies at the acute phase. Finally, antiphospholipid antibodies, mainly anticardiolipin, are frequently associated with viral infections. Their presence may probably reflect an intense or chronic antigenic stimulation of the immune system. However, their evolution under antiviral therapy and correlation with the quality of the virological control and/or the immune restoration remain to be determined.

In black population, the skin-bleaching with cutaneous topical corticosteroids on a large body area is a widespread practice and is associated with numerous cutaneous complications. We report a 25-year-old Congolese woman who was admitted for weakness, arthralgias and abdominal pain. The association of a relative hyperpigmentation of the small joints of hands and feet with clinical features of hypercorticism led to suspect a chronic use of cutaneous topical steroids for skin-bleaching. On biological tests, plasma cortisol and corticotropin levels were undetectable and the short corticotropin (ACTH) stimulation test was negative, leading to the diagnosis of adrenal insufficiency complicating the chronic use of topical steroids. Clinical symptoms resolved with hydrocortisone therapy. One year later, the patient admitted a five-year continuous use of cutaneous topical steroids (betamethasone, 0.05%). Skin-bleaching through chronic use of cutaneous topical steroids, is a common practice in black women, and should be suspected in the presence of adrenal insufficiency with or without clinical features of hypercorticism, and conversely, skin-bleaching users should be tested for hypothalamo-pituitary-adrenal function.

Objective:To assess available evidence on the use of end-points (outcome measures) in clinical trials in systemic lupus erythematosus (SLE), as a part of the development of evidence-based recommendations for points to consider in clinical trials in SLE.Methods:The European League Against Rheumatism (EULAR) Task Force on SLE comprised 19 specialists, a clinical epidemiologist and a research fellow. Key questions addressing the evidence for clinical trial end-points in SLE were compiled using the Delphi technique. A systematic search of the PubMed and Cochrane Library databases was performed using McMaster/Hedges clinical query strategies and an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence and agreement on the statements was measured across the 19 specialists.Results:Eight questions were generated regarding end-points for clinical trials. The evidence to support each proposition was evaluated. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not been formally validated in clinical trials, although some indirect validation has been undertaken.Conclusion:This systematic literature review forms the evidence base considered in the development of the EULAR recommendations for end-points in clinical trials in SLE.

International audience; PURPOSE OF REVIEW: Hepatitis C virus infection is the main cause of mixed cryoglobulinemia vasculitis. The disease expression of mixed cryoglobulinemia vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). Treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis may target either the viral trigger (hepatitis C virus) or the downstream B-cell arm of autoimmunity. This review focuses on recent advances in our understanding of the treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis. RECENT FINDINGS: Aggressive antiviral therapy with Peg-IFNalpha and ribavirin should be considered as induction therapy for hepatitis C virus-mixed cryoglobulinemia vasculitis with mild to moderate disease severity and activity. In patients presenting with severe disease, an induction phase of immunosuppression is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab and Peg-IFNalpha plus ribavirin appears logical as it may target both the viral trigger (hepatitis C virus) and cryoglobulin-producing B-cells. SUMMARY: Antiviral therapy and rituximab are the main therapeutic options in hepatitis C virus-mixed cryoglobulinemia vasculitis. Further studies are needed to better define the therapeutic strategy.

Background: Melkersson-Rosenthal syndrome (MRS) is a rare disease whose full-blown form is characterized by orofacial swelling, facial palsy and lingua plicata. Objective: To investigate the complement system as well as its role in patients with MRS. Methods: Seven patients presenting at this hospital between November 2002 and May 2003 and meeting the diagnostic criteria according to Hornstein were evaluated retrospectively. The investigations included clinical signs, an analysis of the complement system including levels of CH50, C3, C4, C1 inhibitor (INH) functions and C1-INH antigen detection. Results: Two female patients showed isolated low levels of functional C1-INH as determined by duplicate tests. Both patients took estrogen-progestin contraceptives. Conclusion: Since deficiency in plasma protease C1-INH is known to lead to recurrent angioedema, we hypothesize that low levels of functional C1-INH may have contributed to the orofacial swelling in the 2 patients.

Antinuclear antibodies (ANA) are widely detected by immunofluorescence on HEp-2 cells in patients with connective tissue diseases and other pathological conditions. We evaluated the first-automated chemiluminescence immunoassay for the detection of ANA (LIAISON ANA screen, DiaSorin). This study was carried out simultaneously in two laboratories by testing 327 patient samples with clinically defined connective diseases, 273 routine samples for ANA screening, and 300 blood donors. A total of 268 out of 337 IIF-positive sera were positive with LIAISON ANA screen (79.5% of agreement) and 240 out of 263 IIF-negative sera were negative with LIAISON ANA screen (91.2% of agreement). After resolution of discrepant results, the concordance reached, respectively, 94.9% and 98.8%. The specificity was 99.3% and the sensitivity was 94%. Unlike results obtained by other ANA screening assays, we observed acceptable sensitivity and specificity. Despite the presence of HEp-2 cell extract, we failed to detect some antibodies as antinucleolar, antinuclear envelope, and antiproliferating cell nuclear antigen. This automated assay allows quick process to results and exhibits satisfactory sensitivity for the detection of the main ANA specificities of connective tissue diseases.

Resume Introduction Depuis la decouverte du virus de l'hepatite C (VHC), de nombreuses manifestations dites extrahepatiques ont ete rapportees avec plus ou moins de preuves solides. Actualites et Points forts Dans cet article, nous proposons une revue des principales manifestations extrahepatiques (MEH) associees au virus de l'hepatite C (VHC) et qui restent un sujet d'actualite plus de quinze ans apres la decouverte de ce virus. La cryoglobulinemie et ses manifestations systemiques, a type de vascularite, restent parmi les plus frequentes et l'avenement des therapeutiques ciblees de type anti-CD20 devrait modifier significativement leur traitement voire leur pronostic. Parmi les autres manifestations extrahepatiques liees au VHC, on n'oubliera pas le syndrome de fatigue chronique, le syndrome sec, le diabete non insulinodependant, les lymphoproliferations B malignes en particulier le lymphome splenique a cellules villeuses et enfin la production d'auto-anticorps. Perspectives et Projets Les mecanismes physiopathologiques sous-tendant ces manifestations extrahepatiques sont encore mal elucides et font l'objet de travaux soutenus. Il en est de meme pour la place des anticorps anti-CD20 dans le traitement des vascularites cryoglobulinemiques.

Resume Propos Les uveites chroniques non infectieuses representent deux tiers des causes des uveites chroniques adressees dans les services d'ophtalmologie de reference. Un cas sur cinq se compliquerait de cecite. Selon la severite de l'uveite et l'orientation diagnostique, le traitement sera decide, traitement local ou traitement par voie generale base sur la corticotherapie et les immunosuppresseurs. Actualites et points forts En dehors de la corticotherapie et de la ciclosporine, l'utilisation des immunosuppresseurs et des biotherapies dans les uveites chroniques non infectieuses n'est pas une indication retenue dans l'autorisation de mise sur le marche (AMM). Cependant, les immunosuppresseurs et les biotherapies ont fait l'objet de plusieurs etudes, bien que les etudes controlees soient rares. Ces etudes controlees ont concerne la ciclosporine, l'azathioprine et le cyclophosphamide IV dans l'uveite de la maladie de Behcet, la ciclosporine et le tacrolimus dans des uveites de cause variee. Le traitement des uveites chroniques non infectieuses s'est recemment enrichi de nouvelles molecules : le mycophenolate mofetil initialement utilise en transplantation d'organes a vu son indication s'etendre au traitement des maladies systemiques ; les anti-TNF utilises initialement dans le traitement de maladies systemiques ; l'interferon dont l'efficacite s'est revelee dans la maladie de Behcet, est actuellement utilise dans des uveites d'autres causes. Perspectives et projets Des etudes controlees sont souhaitables pour preciser notamment la part respective des immunosuppresseurs par rapport aux biotherapies dans le traitement des uveites.

Resume Propos La physiopathologie de la maladie de Behcet (MB) est complexe. De nouvelles donnees experimentales permettent de mieux comprendre les mecanismes qui president a l'apparition des lesions organiques. Actualites et points forts Ces nouvelles donnees mettent en exergue le role effecteur majeur joue par les polynucleaires neutrophiles et les lymphocytes cytotoxiques. Une susceptibilite genetique, des facteurs environnementaux (infections virales et/ou bacteriennes), des anomalies de la reponse inflammatoire (proteines du choc thermique, dysregulation de la production de NO) et un dysfonctionnement du systeme immunitaire interviennent egalement dans la pathogenie de la MB. Perspectives et projets Cette meilleure comprehension de la physiopathologie de la MB devrait permettre a terme de developper de nouveaux traitements plus specifiques.

The rational way to set a diagnosis and estimate a prognosis in rheumatology is to start by setting a tentative diagnosis and then follow a fixed scheme for laboratory testing, eg, by using an agreed algorithm. The use of order algorithms can be extended to post-test algorithms that will assist clinicians in approaching the right diagnosis and prognosis. New methods used in autoimmune serology do not deliver results that can be directly compared to those of older methods, and thus the new methods need to be thoroughly tested with sera from differential diagnostically relevant disease controls to set a clinically meaningful cut-off for positivity. Borderline positive results need to be treated with special care to avoid misuse. Early diagnosis is of great importance, and serological results can be very useful if used the right way. European efforts to secure rational diagnostic work-up in autoimmune rheumatic disease have led to a better dialogue between clinicians and laboratory scientists in several countries.

Resume Introduction La chorioretinopathie sereuse centrale (CRSC) est une pathologie retinienne relativement rare dont les mecanismes physiopathologiques restent mal connus. Elle est caracterisee par l'accumulation de liquide au pole posterieur de la retine, decollant celle-ci sur une zone circonscrite. Elle se manifeste generalement par une baisse d'acuite visuelle ou une anomalie de la vision des couleurs. Souvent idiopathique, elle peut egalement etre associee a de nombreuses situations pathologiques, l'exposition aux corticoides etant souvent au premier plan. Exegese Nous rapportons le cas de deux patients ayant presente une CRSC. Il s'agissait d'une patiente traitee par corticoides depuis 15 ans pour un lupus systemique et d'un patient traite par corticoides depuis quelques mois pour un syndrome hypereosinophilique idiopathique. Une baisse d'acuite visuelle a conduit au diagnostic de CRSC. La diminution des corticoides a permis une amelioration clinique dans les deux cas. Conclusion La CRSC fait partie des effets indesirables oculaires des traitements par corticoides au meme titre que la cataracte et le glaucome chronique et merite donc d'etre connue par les medecins internistes.

Objective: To investigate the diagnostic reliability of anti-CCP antibodies (anti-CCP Ab) in distinguishing hepatitis C virus (HCV) associated rheumatological manifestations and Sjogren’s syndrome from rheumatoid arthritis. Methods: 147 HCV infected patients (HCV RNA positive) were compared with 64 patients with definite rheumatoid arthritis in a retrospective study. Anti-CCP Ab were detected using the Immunoscan ELISA kit (second generation) and rheumatoid factor (RF) by the FIDIS™ Rheuma kit. Results: Among the 147 HCV infected patients (77 women; mean (SD) age 58 (16) years), 77 (52%) had a mixed cryoglobulin (MC), 38 (26%) an MC associated systemic vasculitis, 35 (24%) arthralgia/arthritis, and seven (5%) definite Sjogren’s syndrome. HCV infected patients with arthralgia were more often RF positive than those without arthralgia (54% v 27%; p = 0.003), but less often than patients with rheumatoid arthritis (54% v 81%; p = 0.009). Anti-CCP Ab were detected in only two HCV infected patients with arthralgia (5.7%), in none without arthralgia or with Sjogren’s syndrome, and in 78% of patients with rheumatoid arthritis. With a specificity of 93.5% and a positive predictive value of 96% for rheumatoid arthritis, anti-CCP Ab were the most specific biological marker. Conclusions: Anti-CCP antibodies are very rarely found in HCV infected patients with rheumatological manifestations or Sjogren’s syndrome. They are reliable serological markers to distinguish these from patients with rheumatoid arthritis.

Resume La maladie de Horton est la plus frequente des vascularites. Elle peut se compliquer par des accidents cardiovasculaires (infarctus du myocarde, accidents vasculaires cerebraux), mais leur incidence reelle et leur risque relatif par rapport a la population generale sont inconnus. Objectif. – Evaluer l'incidence des accidents cardiovasculaires dans une etude en double cohorte prospective de patients avec maladie de Horton par rapport a des temoins, apres ajustement sur les facteurs de risque cardiovasculaire. Patients et methodes. – Quatre cent trente-deux patients nouvellement diagnostiques ont ete inclus sur des criteres preetablis, et apparies par âge et par sexe a des temoins tires au sort dans la population generale. Les facteurs de risque cardiovasculaire majeurs etaient mesures a l'inclusion : tabagisme, maladie atheromateuse, diabete, hypertension arterielle, hypercholesterolemie. Les cas et les temoins ont ete suivis pendant 24 mois avec recueil de la survenue d'accidents cardiovasculaires : infarctus du myocarde, angor, accidents vasculaires cerebraux constitues ou transitoires, arteriopathie obliterante des membres inferieurs. La survenue d'accidents cardiovasculaires au cours du temps a ete etudiee en analyse univariee par un test du log-rank apres stratification sur les facteurs de risque cardiovasculaire et en analyse multivariee par un modele de survie parametrique. Resultats. – Les accidents cardiovasculaires sont globalement plus frequents chez les cas que chez les temoins (RR = 2,15 [1,21–3,81], p = 0,009) ; ils sont lies a l'âge (p = 0,0001), aux antecedents d'accidents cardiovasculaires (p = 0,023) et a la maladie de Horton (p = 0,009). Pris separement, les accidents neurologiques (RR = 2,42 [0,84–7]) et les accidents cardiaques (RR = 1,67 [0,72–3,89]) sont plus frequents sans que les ecarts soient cependant significatifs. Conclusion. – La mise en evidence d'un surrisque d'accidents cardiovasculaires en cas de maladie de Horton doit faire discuter l'adjonction d'un traitement antiagregant preventif au long cours.

Resume Introduction. – L'infection a cytomegalovirus est souvent asymptomatique, les formes graves sont l'apanage de l'immunodeprime. Nous rapportons un nouveau cas d'hepatite aigue a cytomegalovirus (CMV) compliquee de thrombose portale chez un immunocompetent. Exegese. – Un homme de 29 ans presenta une hepatite aigue a CMV confirmee par la presence de la proteine pp65 et de l'ADN viral dans le sang. Elle fut compliquee d'une thrombose portable d'evolution rapidement favorable sous traitement anticoagulant. Aucune autre cause de thrombose portale ne fut decelee. Onze cas de thrombose majeure compliquant une infection aigue a CMV chez un immunocompetent ont ete rapportes dans la litterature anglosaxonne et francaise. L'absence de cause locale et generale, la resolution en l'absence de traitement anticoagulant, le risque eleve de thrombose chez les sujets seropositifs a la fois pour le virus de l'immunodeficience humaine et le CMV, et chez les transplantes renaux seropositifs pour le CMV suggerent une relation causale. Diverses hypotheses physiopathogeniques ont ete evoquees : presence d'anticorps antiphospholipides, absents dans notre observation, induction d'un phenotype procoagulant des cellules endotheliales infectees, induction d'une proliferation des cellules musculaires lisses. Conclusion. – L'infection aigue a CMV peut etre consideree comme une cause possible de thrombose majeure.

Objective: To describe the characteristics of patients with catastrophic antiphospholipid syndrome (APS) included in the International Registry of patients with this condition (CAPS registry) and to analyse the value of the recently proposed preliminary criteria for the classification of catastrophic APS. Methods: A review of the first 220 patients included in the website based CAPS registry was undertaken and the preliminary criteria for their classification were tested; 175 unselected patients with systemic lupus erythematosus or APS, or both, acted as controls. Results: The mean age of the patients was 38 (14) years (range 7 to 74), with a female preponderance (F/M, 153/67). The main clinical manifestations included renal involvement in 154 (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%); 114 patients (52%) recovered after the catastrophic APS event (mortality 48%). Patients who received the combination of anticoagulation plus steroids plus plasma exchange or intravenous immunoglobulins had the best survival rate (63%, p = 0.09). Sufficient data could be analysed for application of the classification criteria in 176 patients. According to the preliminary criteria, 89 patients (51%) could be classified as having “definite” and 70 (40%) as having “probable” catastrophic APS, thus given a sensitivity of 90.3% with a specificity of 99.4%. Positive and negative predictive values were 99.4% and 91.1%, respectively. Conclusions: The preliminary criteria for the classification of catastrophic APS and the CAPS registry are useful tools for epidemiological studies.

Resume Propos. – La malade de Still de l'adulte (MSA) est une maladie systemique rare qui se caracterise par une fievre hectique, une eruption cutanee, des arthralgies ou arthrites, des douleurs pharyngees, une organomegalie, et biologiquement par une hyperleucocytose a polynucleaires neutrophiles, une cytolyse hepatique et une hyperferritinemie a fraction glycosylee effondree. La physiopathologie de la maladie n'est pas connue mais des donnees recentes de la litterature apportent un eclairage nouveau. Actualites et points forts. – La mise en evidence de taux tres eleves de ferritine, IL-8, IL-6, IL-18 and TNF-α au cours de la MSA rend compte d'une activation marquee des macrophages. L'IL-18, synthetisee par les macrophages actives, semble avoir le role cle dans la pathogenie de la maladie. Les taux d'IL-18 sont en effet particulierement eleves au cours de la MSA comparativement a d'autres rhumatismes articulaires inflammatoires comme la polyarthrite rhumatoide et sont correles aux taux de ferritine et a l'activite de la maladie. Son augmentation pourrait expliquer des signes tels que la cytolyse hepatique ou l'atteinte articulaire. La cause de l'activation des macrophages au cours de la MSA n'est pas connue. Elle pourrait etre le fait d'agents infectieux tels que des virus et d'un controle inapproprie de la reponse lymphocytaire T, secondaire a un deficit d'activite des lymphocytes Natural Killer, comme cela a ete montre au cours de la forme systemique de l'arthrite juvenile idiopathique. Cette activation excessive pourrait expliquer l'apparition d'un syndrome hemophagocytaire, complication grave de la maladie de Still de l'enfant et de l'adulte. Perspectives. – Un deficit en lymphocytes cytotoxiques au cours de la MSA constitue une piste etiologique interessante a la lumiere des donnees recentes sur la physiopathologie de la forme pediatrique de la maladie. La MSA pourrait alors constituer une forme particuliere de deficit immunitaire.

Objective: To compare familial inflammatory inclusion body myositis (IBM) with hereditary inclusion body myopathies and sporadic IBM. Patients and methods: Clinical, biological, MRI, and histological data were analysed in two siblings with inflammatory IBM and compared with those of patients with sporadic and hereditary IBM. Results: Both patients had a clinical phenotype of sporadic IBM, which differs from hereditary myopathies because of late age of onset—respectively 65 and 66 years, and different pattern of muscular involvement—asymmetric, mainly distal but also involving quadriceps. MRI showed selective fatty infiltration and oedema in the extensor compartment of thigh muscles. The diagnosis of IBM was confirmed by muscle biopsy, showing muscle fibres containing numerous rimmed vacuoles, a characteristic shared by all types of IBM. In contrast with hereditary IBM, histological analysis also showed inflammatory mononuclear infiltrate invading non-necrotic fibres, ragged red and oxidase c negative fibres, and positive Congo red staining. Moreover, HLA class II typing disclosed DRβ1 0301 haplotype, which is significantly related to sporadic but not to hereditary IBM. With steroid treatment and monthly intravenous immunoglobulins, the disease was stabilised in both patients at protracted follow up. Conclusion: Sporadic and familial inflammatory IBM share the same clinical, biological, MRI, and histological features.

Introduction Analyse diagnostique des uveites associees au syndrome de Vogt-Koyanagi-Harada, a la lumiere des criteres internationaux et evaluation de la strategie therapeutique. Patients et methodes Les patients pris en charge entre janvier 2001 et mars 2003 pour une suspicion de syndrome de Vogt-Koyanagi-Harada ont beneficie d’un bilan oriente afin d’evaluer l’atteinte oculaire et extra-oculaire de la maladie. Les criteres diagnostiques de 1978 et les criteres revises en 2001 ont ensuite ete utilises pour chacun des patients. Une corticotherapie systemique a ete proposee dans la plupart des cas. Lorsque celle-ci n’a pas permis de controler l’inflammation, un traitement immunosuppresseur a ete initie. Resultats Nous avons inclus 22 patients. L’âge moyen etait de 33,5 ans (15-49 ans). L’intensite de l’uveite posterieure, observee chez 20 patients, dependait du stade de la maladie. Une segmentite anterieure etait associee chez 11 patients. L’atteinte neurologique etait presente chez 12 patients et les manifestations dermatologiques etaient observees chez 14 patients. Cinq patients, presentant retrospectivement un syndrome de Vogt-Koyanagi-Harada confirme, ne repondaient pas aux criteres diagnostiques de 1978, et trois patients ne repondaient pas aux criteres de 2001. La corticotherapie a permis le controle de l’inflammation chez 19 patients. Trois patients corticodependants a fortes doses ont beneficie d’un traitement immunomodulateur (azathioprine, cyclophosphamide, interferon-alpha). Au decours de la periode de suivi, l’inflammation a ete controlee dans tous les cas. Discussion La revision des criteres diagnostiques du syndrome de Vogt-Koyanagi-Harada a permis d’affiner la prise en charge des patients mais il reste cependant difficile de rendre compte de la variabilite de la symptomatologie clinique au cours du temps. Les corticoides, utilises a fortes doses precocement, permettent de reduire la duree des poussees et la survenue de recidives. L’interferon-α serait une alternative seduisante aux immunosuppresseurs mais des etudes complementaires sont necessaires avant toute conclusion ulterieure.

Objective To describe dermatologic manifestations of the antiphospholipid syndrome (APS) and to investigate possible correlations between livedo reticularis and other APS manifestations. Methods We conducted a single-center study of 200 consecutive patients with primary or systemic lupus erythematosus–related APS. To qualify for the study, patients had to fulfill clinical and laboratory criteria from the most recent international consensus statement on classification of definite APS. Dermatologic manifestations were systematically evaluated by a dermatologist. Only dermatologic lesions that may be related to APS were included in the analyses. Correlations between livedo reticularis and other APS manifestations were determined using Fisher's 2-tailed, chi-square, and nonparametric Mann-Whitney tests. Results Dermatologic manifestations were noted in 49% of the patients and were the presenting manifestations in 30.5%. Livedo reticularis was the most frequent manifestation, observed in 25.5% of the patients. Livedo reticularis was shown to be significantly associated with cerebral or ocular ischemic arterial events (odds ratio [OR] 10.8, 95% confidence interval [95% CI] 5.2–22.5), seizures (OR 6.5, 95% CI 2.6–16), all arterial events (OR 6, 95% CI 2.9–12.6), heart valve abnormalities detected on echocardiography (OR 7.3, 95% CI 3.6–14.7), and arterial systemic hypertension (≥160/90 mm Hg) (OR 2.9, 95% CI 1.5–5.7). Conversely, it was observed with decreased frequency in patients with only venous thrombosis (OR 0.2, 95% CI 0.1–0.5). Conclusion The dermatologic manifestations of APS are frequently the presenting feature of the syndrome, and livedo reticularis is significantly associated with the arterial subset of APS.

Resume Propos. – Les uveites chroniques severes representent un defi diagnostique et therapeutique permanent pour l’ophtalmologiste et l’interniste. Le developpement des outils diagnostiques moleculaires appliques aux liquides et tissus oculaires et des methodes d’imagerie modernes a permis d’ameliorer le rendement des bilans etiologiques. La mise en jeu du pronostic visuel au cours des uveites chroniques impose une demarche diagnostique exhaustive et une intensification therapeutique progressive. Actualites et points forts. – L’epidemiologie des uveites chroniques severes semble mieux precisee actuellement. Une etude portant sur 927 patients consecutifs, pris en charge sur une periode de 5 ans, a permis de definir une orientation diagnostique dans 67 % des cas. Il a ete possible d’individualiser 4 grands groupes d’atteinte : les uveites infectieuses, les uveites associees a une maladie systemique, les uveites d’origine immunologique pure limitees a l’œil et les uveites idiopathiques limitees a l’œil. Cette subdivision pourrait etre appliquee a chacun des sous-groupes constituant la classification anatomique des inflammations intraoculaires. Le taux de cecite final semble correle a la rapidite de la prise en charge, l’orientation diagnostique, l’adaptation du traitement et a la severite de l’atteinte inflammatoire. Perspectives. – Il faut differencier l’uveite aigue, frequente mais repondant generalement bien a une corticotherapie locale et l’uveite chronique necessitant une strategie diagnostique souvent complexe et une conduite therapeutique precise mettant en question les anciens dogmes. Tout echec d’une corticotherapie bien conduite doit poser le probleme d’une participation infectieuse, qu’elle soit virale, bacterienne ou parasitaire. La mise en evidence d’arguments plus ou moins formels en faveur d’un agent pathogene impose un traitement specifique et reste une etape majeure avant toute intensification therapeutique fondee sur les immunosuppresseurs classiques et les nouvelles molecules disponibles dans le cadre de protocoles de recherche clinique.

Resume Le lupus erythemateux neonatal se manifeste par une atteinte cutanee, hematologique, hepatique ou cardiaque incluant un eventuel bloc auriculo-ventriculaire congenital (BAVc) survenant sur un cœur indemne de cardiopathie malformative, une cardiomyopathie dilatee et une fibroelastose endocardique. Ce syndrome rare est constamment associe a la presence chez la mere d’anticorps anti-SSA/Ro et/ou anti-SSB/La. La frequence du BAVc chez les femmes ayant une connectivite associee a un anticorps anti-SSA/Ro est estimee entre 1 et 2 %, et le risque de recurrence est evalue a environ 19 % lors d’une grossesse ulterieure. Les atteintes cutanees et systemiques sont transitoires, contrairement aux atteintes cardiaques et notamment au BAVc qui est definitif, associe a une morbidite et a une mortalite d’environ 18 %. La mise en place d’un pacemaker est necessaire dans 2/3 des cas. Une myocardite peut etre associee d’emblee ou apparaitre plus tardivement. Les meres d’enfants ayant un BAVc sont le plus souvent asymptomatiques au moment de la decouverte du BAVc. La physiopathologie n’est pas completement elucidee a ce jour. Lorsqu’une femme enceinte est porteuse d’un anticorps anti-SSA/Ro, une surveillance echographique obstetricale sera realisee tous les 15 jours entre 16 et 24 semaines d’amenorrhee et un electrocardiogramme sera fait de principe chez l’enfant. L’interet d’un traitement curatif in utero du BAVc par corticoides fluores n’est a ce jour pas demontre. Un traitement preventif par hydroxychloroquine semble diminuer le risque de recidive du BAVc chez les femmes ayant deja eu un enfant atteint. Une etude prospective est en cours pour confirmer ces resultats.

Resume Introduction . – Nous rapportons 2 cas de thrombose bilaterale des carotides internes secondaire a des tentatives repetees de strangulation. Exegese . – Le premier, chez une femme de 31 ans, fut decouvert devant des manifestations d’allure psychiatrique associees a des troubles de la memoire et un manque du mot qui ont precede l’installation d’une hemiplegie d’aggravation progressive malgre l’instauration d’une anti-agregation plaquettaire par aspirine. Le second, chez une femme de 41 ans, fut decouvert devant l’apparition brutale d’une hemiplegie accompagnee d’une aphasie. Le diagnostic de thrombose bilaterale des carotides internes a ete porte grâce a l’angioscanner ou l’angio-IRM avec un aspect en faveur d’une dissection. Le siege de la thrombose etait identique : bilateral et symetrique, situe immediatement apres la bifurcation carotidienne. Les 2 femmes avaient des facteurs de risque d’atherome : tabagisme actif, « contraception estroprogestative », dyslipidemie et/ou antecedents familiaux cardiovasculaires. La recherche d’une thrombophilie etait negative. Ces patientes etaient des femmes battues par leur conjoint et avaient subi a plusieurs reprises des tentatives de strangulation, mais qui avaient cesse 8 et 6 ans avant le diagnostic de thrombose carotidienne. Plusieurs interrogatoires conduits en tete a tete avec la malade ont ete necessaires pour etablir l’etiologie. Conclusion . – Une thrombose bilaterale et symetrique des carotides internes peu apres la bifurcation doit faire evoquer des tentatives repetees de strangulation, meme en presence de facteurs de risque arteriel, surtout s’il s’agit de femmes d’âge moyen. Le traitement n’est pas codifie mais l’anticoagulation au long cours est le plus souvent proposee.

The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to define an accelerated form of APS resulting in multiorgan failure. Although catastrophicAPS patients represent less than 1% of all patients with APS, they are usually in a life-threatening medical situation that requires high clinical awareness. The careful and open discussion of several proposals by all participants in the pre-symposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of a preliminary set of classification criteria. On the other hand, the optimal management of catastrophicAPS must have three clear aims: to treat any precipitating factors (prompt use of antibioticsif infection is suspected, amputation for any necrotic organ, high awareness in patients with APS who undergo an operation or an invasive procedure), to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ‘storm’. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients.

Venous thromboembolism(VTE) in patients suffering from the antiphospholipidsyndrome (APS) has been reported in almost any location of the vessel tree and the risk of recurrences has been found in several studies to be more closely associated with the presence of lupus anticoagulant than with the positivity for anti-cardiolipin antibodies. The thrombophilic state of APS raises the problem of the secondary prophylaxis to avoid VTE recurrences. For APS patients with VTE, published data appear to support a longer warfarin treatment if compared with the standard management of anti-phospholipid (aPL)-negative patients with VTE. The question of how long oral anticoagulant treatment should be continued for APS patients, however, remains unanswered. Concerning the intensity of anticoagulation, several authors recommend a target international normalized ratio (INR) between 3.0 and 4.0 to efficiently protect from VTE recurrences.A recentdecisionanalysisstudy does support such a suggestion. On the contrary, in a few prospective studies regimens with lower target INRs appear to be effective, and some authors therefore recommend a target INR of between 2.0 and 3.0. Specific large and prospective trials are needed to address this question. Until such information becomes available, individualized treatment according to the patient’s individual risk factors for both bleeding and thrombosis is the general practice.

Objective: To study the levels of procalcitonin (PCT) in various inflammatory states seen in an internal medicine department and to evaluate the possible discriminative role of PCT in differentiating bacterial infection from other inflammatory processes. Methods: PCT, C reactive protein (CRP), and white blood cell count (WBC) were measured in patients admitted to the department for fever or biological inflammatory syndrome, or both. The serum of 173 consecutive patients was analysed according to the aetiological diagnosis. The patients were divided into two groups: group I (n=60) with documented bacterial or fungal infection; group II (n=113) with abacterial inflammatory disease. Results: PCT levels were >0.5 ng/ml in 39/60 (65%) patients in group I. In group II, three patients with a viral infection had slightly increased PCT levels (0.7, 0.8, and 1.1 ng/ml) as did two others, one with crystal arthritis and the other with vasculitis (0.7 ng/ml in both cases). All other patients in group II had PCT levels 0.5 ng/ml was taken as the marker of bacterial infection (sensitivity 65%, specificity 96%). PCT values were more discriminative than WBC and CRP in distinguishing a bacterial infection from another inflammatory process. Conclusion: PCT levels only rose significantly during bacterial infections. In this study PCT levels >1.2 ng/ml were always evidence of bacterial infection and the cue for starting antibiotic treatment.

Two-hundred ninety five patients with the antiphospholipid syndrome (APS) were studied for the presence of antibodies against six anti-beta2GPI-related peptides Abs. The prevalence of a wide spectrum of clinical and laboratory parameters of APS was evaluated in all patients, and correlated with the presence of each anti-beta2GPI peptide antibody. The rates of the various antipeptides Abs ranged from 18.0 to 63.7%. Altogether, 87.1% of the patients had antibody reactivity against at least one of the six beta2GPI-related peptides. A high degree of simultaneous reactivity against several beta2GPI-peptides was found. Positive and negative correlations were found between several antipeptides Abs and the rates of thrombosis and fetal loss. Our results point to a heterogeneous activity of antiphospholipid Abs in APS patients, directed, often concurrently, against various epitopes of the beta2GPI molecule. Evaluation of APS patients for the presence of specific antipeptides Abs may be of a value in predicting the risk for future thrombotic and obstetrical complication, as well as for specific therapeutic purposes.