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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

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.

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.

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.

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.

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.

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.

B-cell lymphoproliferative disorders (BCLD) have been associated with chronic hepatitis C virus (HCV) infection. The HCV glycoprotein E2 (gpE2) hypervariable region I (HVR-I) may be a potential antigenic candidate to promote B-cell proliferation. The purpose of this study was to analyze the influence of HVR-I sequence variability in the development of BCLD. HVR-I sequences were studied in 29 chronically HCV-infected patients with (n=15) or without (n=14) BCLD. After PCR amplification of the gpE2 region, analysis of the 81 bp HVR-I encoding fragment was performed on 7-18 clones per patient. HVR-I sequence complexity was slightly lower in patients with BCLD (mean 0.347) than without (0.468) (P=0.2), though, sequence diversities were similar (0.0370 vs 0.0954, P=0.239). Phylogenetic analysis did not reveal any BCLD-associated clustering. In our population, neither the recently described insertion between positions 1 and 2 of HVR-I nor residues at positions 4 and 13 were particularly linked to BCLD. As previously described, we confirm the high degree of conservation of HVR-I residues T-2, G-6 and G-23 in our patients. Contrary to recent findings, our analysis based on multiple clones per patient analysis did not reveal any particular motif associated with BCLD.

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.

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.

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.

International audience; OBJECTIVE:To assess the prevalence of TT virus (TMV) infection in a series of patients with chronic hepatitis C virus (HCV) infection, with or without benign (mixed cryoglobulinemia) or malignant (B-cell non-Hodgkin lymphoma (B-NHL)) lymphoproliferative disease.METHODS:Sixty-six HCV patients were studied, including patients with mixed cryoglobulinemia (n=30), B-NHL (n=15), and no mixed cryoglobulinemia or B-NHL (n=21). All HCV patients had increased transaminase levels and were HCV RNA positive. Patients were considered to have mixed cryoglobulinemia if two successive determinations of their serum cryoglobulin level were above 0.05 g/L. Mixed cryoglobulinemia-negative patients never had mixed cryoglobulins in their serum on multiple determinations. Subjects without HCV infection included 79 patients with histologically proven B-NHL, and 50 healthy blood donors. Serum samples were analyzed for TTV DNA by nested polymerase chain reaction, with two couples of primers in different regions of the genome, in two independent laboratories.RESULTS:In the group of HCV-positive patients, TTV DNA was found in one of 15 (6.7%) patients with B-NHL, and in nine of 51 (17.6%, P = 0.43) of those without B-NHL. Among HCV-positive patients without B-NHL, TTV DNA was more frequently found in those with type II mixed cryoglobulinemia vasculitis than in those without it (six of 16 (37.5%) versus two of 21 (9.5%), P = 0.05). In subjects without HCV infection, TTV DNA was present in 10 of 79 (12.7%) patients with B-NHL and in seven of 50 (14.0%, P = 0.82) blood donors.CONCLUSION:In patients chronically infected with HCV, TTV co-infection: (1) is not associated with the presence of B-NHL; and (2) is more frequently found in patients presenting a type II mixed cryoglobulinemia vasculitis.

Whether the host's immune response genes influence the severity of hepatitis C virus (HCV) liver disease is controversial. Human leukocyte antigen (HLA) class II alleles were analyzed in 233 HCV RNA-positive patients with chronic active hepatitis (197 patients with Knodell index of fibrosis F0-F3 and 36 patients with index of F4). The 2 groups did not differ by sex, duration of infection, mode of contamination, alcohol consumption, or HCV genotype. Patients with cirrhosis were older than those without (56+/-12 vs. 46+/-14 years; P10-4) and had a lower DRB1*11 allele frequency (5.6% vs. 14.5%; P=.037), whereas DRB1*03 and DQB1*0201 frequencies appeared to be higher (DRB1*03, 18.1% vs. 9.6%; DQB1*0201, 37.5% vs. 23.4%; P=.04, corrected P value is not significant). Mean index of fibrosis was higher in DR3-positive than in DR11-positive patients (2.14 vs. 1.58; P=.05). By multivariate analysis, cirrhosis was associated with male sex and age50 years. HLA class II alleles may weakly contribute to the severity of HCV liver disease. Of persons infected with HCV, only 15%-20% spontaneously clear the virus, and the rest become chronically infected.

International audience; BackgroundBehçet's disease (BD) significantly increases morbidity and mortality. BD mainly affects young adults with a peculiar geographical distribution. It has been suggested that BD varies in its phenotypic expression in different ethnic groups.MethodsWe investigated potential ethnicity-related differences relative to phenotype and prognosis of BD patients in a French multiethnic country. We included 769 consecutive patients fulfilling the international criteria of classification for BD, in the 3 largest ethnic groups of our cohort [European (n = 369), North African (n = 350) and sub Saharan African (n = 50)]. Factors that affect prognosis were assessed by multivariate analysis.Results535 (69.6%) patients were male and the median (IQR) age at diagnosis was of 30.9 (24.9-37.2) years. Sub Saharan African BD patients had a higher frequency of CNS involvement (48% vs 32.3% vs 29.5%, p = 0 .035), a higher rate of death (12% vs 6% vs 3.5%, p = 0.029) and a lower frequency of HLA B51 allele (29.4% vs 49.2% vs 55.8%, p = 0.009) compared to those from North Africa and Europe, respectively. Multivariate analysis showed that male gender (HR: 5.01, CI: 1.51-16.65), cardiovascular involvement (HR: 2.24, CI: 1.15-4.36), and sub Saharan African origin (HR 2.62 (0.98-6.97) were independently associated with mortality. The 15-year mortality rate was of 19%, 9% and 6% in sub Saharan African, North African and European BD patients, respectively (p = 0.015).ConclusionWe reported ethnicity-related differences with respect to phenotype of BD. Sub Saharan Africans patients exhibited a worse prognosis.

OBJECTIVE—To study maternal and fetal outcome in women with past or present histologically proven systemic lupus erythematosus (SLE) nephritis. METHOD—Retrospective study of 32 pregnancies in 22 women with past or present histologically proven SLE nephritis in a single French centre. RESULTS—Pregnancy (25 planned and 7 not planned) occurred in a mean (SD) of 8 (5) years after SLE diagnosis and 6 (4) years after renal disease onset. Seven occurred in women with antiphospholipid syndrome. At pregnancy onset, all but one woman had creatininaemia below 100 µmol/l, five had proteinuria >0.5 g/day, none had hypertension. Twelve pregnancies occurred in women previously treated with immunosuppressant drugs. Treatment comprised prednisone (n=31), hydroxychloroquine (n=11), aspirin (n=22), heparin (n=12), and azathioprine in one patient with steroid resistant nephrotic syndrome disclosing SLE. No therapeutic abortion was done. During pregnancy or the postpartum period, or both, proteinuria >0.5 g/day occurred in 10 women (five related to pre-eclampsia, four to renal flare, one to stable nephrotic syndrome). One flare consisted of mild arthralgias. Pregnancy outcome comprised one feto-maternal death in SLE disclosed by pregnancy, five embryonic losses, two fetal deaths, and 18 premature (one neonatal death) and six full term births. No criterion appeared to influence fetal survival significantly. At long term, one patient died during an SLE flare, three women had renal relapses. At the last visit, all had creatininaemia below 100 µmol/l except one woman with creatinine level 115 µmol/l, nine had proteinuria >0.5 g/day, and one was treated for hypertension. CONCLUSION—Pregnancy need not be discouraged in women with a history of SLE nephritis with normal or mildly impaired renal function. Deterioration of renal function rarely occurs. However, these pregnancies are at high risk of pre-eclampsia and prematurity.

A 50-kDa protein was purified as a potential receptor, using an affinity matrix containing biotinylated F14.6 or H9.3 anti-DNA mAbs derived from autoimmune (New Zealand Black × New Zealand White)F1 mouse and membrane extracts from cells. This protein was identified as calreticulin (CRT) by microsequencing. Confocal microscopy and FACS analysis showed that CRT was present on the surface of various cells. CRT protein was recognized by a panel of anti-DNA mAbs in ELISA. The binding of F14.6 to lymphocytes and Chinese hamster ovary cells was inhibited by soluble CRT or SPA-600. Thus, the anti-DNA mAbs used in this study bound to CRT, suggesting that CRT may mediate their penetration into the cells and play an important role in lupus pathogenesis.

Evidence for a genetic susceptibility to systemic lupus erythematosus (SLE) in humans is based on the high concordance rate observed in identical twins and on the relatively high incidence of familial cases. Although recent genetic studies have lead to significant advances in the identification of new susceptibility genes in SLE, no large clinico-pathologic study of familial SLE has been reported to date. In the present study, we describe the main clinical and immunologic features of 125 lupus multiplex families including at least 2 cases of SLE and/or discoid lupus erythematosus (DLE), recruited through a French national survey starting in July 1997. Medical records of all affected members were reviewed by the same investigator, all available family members were interviewed using the same standardized procedure, and blood was drawn for autoantibodies typing. Clinical and immunologic features of 90 probands from multiplex SLE families were compared with those of 100 sporadic SLE patients sharing the same French Caucasian origin. The 125 lupus multiplex families included 282 affected members (2.3 patients per family); of the 125 families, 96 were of French Caucasian origin. One hundred multiplex families included 2 affected relatives, while 25 included 3 or more affected individuals. The relationship between affected members was sibs (45%), parent-offspring (31%), and second-degree (24%). An autosomal dominant mode of inheritance was strongly suggested in 1 extended pedigree with 6 clinically affected members, and a recessive pattern was suspected in 5 other families. No obvious mode of inheritance could be suspected in most of the remainder. Among French Caucasians, sex ratio, mean age at onset, and clinical and biologic SLE-related manifestations were not significantly different in multiplex compared with sporadic SLE cases. The analysis of these 125 multiplex families suggests a genetic heterogeneity that should be considered for ongoing genomic screening.

Acquired C1 inhibitor (C1-INH) deficiency with consequent angioedema is a rare condition that may indicate an underlying lymphoproliferative disorder. The defect is caused by increased catabolism, which is often associated with the presence of serum autoantibodies to C1-INH. The present report describes 3 patients with systemic lupus erythematosus who developed typical symptoms of acquired angioedema, characterized by recurrent swelling of subcutaneous and mucous tissues. The 3 patients demonstrated a major classical pathway-mediated complement consumption, with very low levels of C3 antigen and decreased levels of C1-INH antigen. Neither antibodies to C1-INH nor associated lymphoproliferative disease was found. No patient had clinical and biologic signs of lupus activity at the time the angioedema occurred. All patients were treated with steroids and exhibited a good response, without relapse of angioedema and with normalization of plasma levels of C1-INH. In lupus patients who present with an angioedema syndrome, acquired or hereditary angioedema must be sought by examining parameters of the classical pathway and levels of C1-INH. Our observations suggest the existence of a new form of acquired C1-INH deficiency associated with a major classical pathway-mediated complement consumption and systemic autoimmunity.

The putative role of hepatitis C virus (HCV) infection in the pathophysiology of lymphoproliferative diseases (LPD) is supported by North American and southern European studies reporting high HCV seroprevalence in patients with B-cell-non-Hodgkin lymphoma (NHL). In order to evaluate the situation in France, we conducted a retrospective national study about the association of chronic HCV infection and LPD. 72 Internal Medicine and Infectious Diseases departments were contacted. Response rate was 51.4%. We recorded 43 LPD (19 males, 24 females): 31 B-cell-NHL, 4 Waldenstrom's macroglobulinemia, 3 chronic lymphocytic leukemia, 2 multiple myeloma, 2 lymphomas of the mucosa-associated lymphoid tissue, and 1 Hodgkin's disease. Mean age at HCV diagnosis was 62 years (range 33-84). In 16 cases, LPD occurred in patients known to be HCV-infected. For 11 patients, LPD diagnosis preceded the diagnosis of HCV infection, whereas diagnosis was done simultaneously in 11 patients. For those with accurate infection date, mean interval between both events was 15.2 years. Fourteen patients had HCV extrahepatic manifestations: 9 mixed cryoglobulinemia, including 7 with NHL, 5 sicca syndrome (5 NHL), and both in one patient. Cohort of HCV-infected patients could be accurately determined for 16 departments, totaling 1,485 patients and 37 cases. Thus, from our data the frequency of LPD among HCV-infected patients approximates 2. 49%. Despite possible bias inherent to this retrospective study, our data support the hypothesis of HCV-associated LPD and particularly B-cell-NHL. In France, this association is much lower than in Italy. Further studies are needed to assess the precise role of HCV in the multistep process leading to monoclonal proliferation.

Objective To assess the prevalence of clinical and biologic extrahepatic manifestations of hepatitis C virus (HCV) infection and to identify associations between clinical and biologic manifestations. Methods To analyze the natural history of extrahepatic manifestations of HCV infection, we reviewed only the data recorded prospectively during the first visit of 1,614 patients with chronic HCV infection, coming from a single monocenter cohort. Exclusion criteria were positivity for hepatitis B surface antigen or human immunodeficiency virus. The prevalence of dermatologic, rheumatologic, neurologic, and nephrologic manifestations; diabetes; arterial hypertension; autoantibodies; and cryoglobulins were assessed. Then, using multivariate analysis, we identified demographic, biochemical, immunologic, virologic, and liver histologic factors associated with the presence of extrahepatic manifestations. Results At least 1 clinical extrahepatic manifestation was observed in each of 1,202 patients (74%). Five manifestations had a prevalence >10%: arthralgia (23%), paresthesia (17%), myalgia (15%), pruritus (15%), and sicca syndrome (11%). Four biologic abnormalities had a prevalence >5%: cryoglobulins (40%), antinuclear antibodies (10%), low thyroxine level (10%), and anti–smooth muscle antibodies (7%). Only vasculitis, arterial hypertension, purpura, lichen planus, arthralgia, and low thyroxine level were associated with cryoglobulin positivity. By univariate and multivariate analyses, the most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations were age, female sex, and extensive liver fibrosis. Conclusion Extrahepatic clinical manifestations are frequently observed in HCV patients and involve primarily the joints, muscles, and skin. The most frequent immunologic abnormalities include mixed cryoglobulins, antinuclear antibodies, and anti–smooth muscle antibodies. The most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations are advanced age, female sex, and extensive liver fibrosis.

Objective To investigate the putative involvement of poly(ADP-ribose) polymerase (PARP) alleles in systemic lupus erythematosus (SLE) and primary anti- phospholipid syndrome (APS). Methods This study of French Caucasians included 171 unrelated patients with SLE, 88 unrelated patients with primary APS, and 193 ethnically matched healthy controls. The SLE group comprised 89 patients with sporadic SLE and 82 patients with familial SLE. Patients' and controls' DNA were genotyped for the various alleles of a polymorphic CA dinucleotide repeat located within the promoter region of PARP. Results No statistically significant difference was observed for the distribution of PARP alleles between the healthy control group and each patient group or the pooled SLE patient group. Conclusion The study findings strongly suggest that these alleles do not influence susceptibility to SLE or primary APS in French Caucasians.

Objective The antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases (CTDs). A high incidence of heart conduction disorders, including bundle-branch block and incomplete or complete atrioventricular block, has been observed among patients treated with CQ. Since no data were available for HCQ, we studied electrocardiograms (ECGs) in 85 unselected patients with CTD treated with HCQ as the sole antimalarial. Methods Eighty-five unselected out-patients treated with HCQ for a minimum of 1 yr, and without established cardiac diseases had standard 12-lead ECGs. Results Two incomplete right bundle-branch blocks and one left bundle-branch block were observed. No atrioventricular block was observed. The mean PR interval was 137 +/- 20 ms (range 99-188). The mean QTc interval was 410 ms (range 349-464). The mean heart rate was 73 beats/min (range 53-102). Conclusion PR interval, QTc interval and heart rate were not different from normal values. The rate of heart conduction disorders was similar to what is expected in the general population, and contrasted with prior results in CQ-treated patients. Our results add further evidence on the safety of HCQ compared with CQ.

We conducted a prospective study in order to determine planned pregnancy outcome in systemic lupus erythematosus followed in a tertiary referral centre. Pregnancy was authorized if disease was inactive on 20 mg/day prednisone or less for at least 1 yr. Upon the diagnosis of pregnancy, systematic corticosteroids consisting of 10 mg/day prednisone or more were started. In the case of antiphospholipid antibodies, 100 mg/day aspirin was added, replaced by heparin in the pre-partum period. In the case of antiphospholipid syndrome complicated by previous thrombotic events or fetal losses despite aspirin, heparin was prescribed. One woman with a history of atrioventricular block was treated with dexamethasone. Patients were monitored by medical and obstetrical examination, and laboratory tests carried out at least monthly and a quarterly echography. Among 62 pregnancies in 38 women, lupus flare was observed in 27% of the cases, 6% of which occurred in the post-partum period. Flares were moderate except in one renal involvement in a woman with prior diffuse proliferative glomerulonephritis. Therapy was not modified in half of the cases. Pregnancy ended in early spontaneous abortion not related to lupus flare (n = 10), stillbirth (n = 2). induced abortion (n = 2), preterm birth (n = 29) and full-term birth (n = 19). Caesarean section was performed in nine cases. A severe infection occurred in two premature neonates. Another premature neonate was growth retarded. Two children had cutaneous neonatal lupus. No child died, neither had atrioventricular block. Stillbirth and severe prematurity were more common in mothers with antiphospholipid syndrome. After exclusion of early spontaneous and induced abortions, the live birth rate was 96%, that is close to the French general population. The main problem remains a high rate of prematurity, but without maternal or neonatal death.

This report describes the case of woman who was admitted to the hospital for highly destructive axial and peripheral arthropathy in association with acute malignant hypertension and skin purpura. Type I IgGkappa serum cryoglobulinemia was identified and was classified as a monoclonal gammopathy of unknown significance. Cryoglobulin was shown to crystallize in the serum and synovium fluid and was responsible for both granulomatous microcrystalline synovial inflammation and occlusive vasculopathy in the kidneys and skin. Cryocrystalglobulinemia pathogenicity and therapeutic implications are discussed.

OBJECTIVE--To determine the factors associated with the occurrence of Pneumocystis carinii pneumonia (PCP) in Wegener's granulomatosis (WG). METHODS--We retrospectively compared a group of 12 patients with WG and PCP (PCP group), with 32 WG patients without PCP followed over the same period in the same centres (control group). RESULTS--The mean delay of onset of PCP after the start of the immunosuppressive therapy was 127 (SD 128) days. Before treatment, the clinical and biological features of the two groups were similar, except for the mean lymphocyte count which was lower in the PCP group than in the control group (1060/mm3 v 1426/mm3; p = 0.04). During treatment, both groups were lymphopenic. There was a significant difference between the lowest absolute lymphocyte count in each group (244/mm3 in the PCP group v 738/mm3 in the control group; p = 0.001). During the first three months of treatment, the lymphocyte count was less than 600/mm3 at least once in 10 of the 12 patients in the PCP group and in 11 of the 32 patients in the control group (p < 0.01). The mean cumulative dose of cyclophosphamide was greater in the PCP group than in the control group at the end of both the second (1.55 mg/kg/day v 0.99 mg/kg/day; p = 0.05) and the third (1.67 mg/kg/day v 0.97 mg/kg/day; p = 0.03) months. However, in multivariate analysis, the only two factors independently and significantly associated with the occurrence of PCP were the pretreatment lymphocyte count (p = 0.018) and the lymphocyte count three months after the start of the immunosuppressive treatment (p = 0.014). CONCLUSIONS--The severity of lymphocytopenia before and during immunosuppressive treatment is the factor best associated with PCP in WG.

Objective To investigate and describe the long-term outcome of venous thrombosis in patients with Behcet's disease (BD). Methods In a retrospective cohort of 807 BD patients, a reported 296 patients (36.7%) (73.3% male, median age 30 years [interquartile range 24–36 years]) met the international classification criteria for BD and had venous thrombosis. We assessed factors associated with thrombosis relapse and mortality. Results There were a total of 586 venous thrombosis events, including 560 cases of deep thrombosis and 26 cases of superficial thrombosis. Deep venous thrombosis events included 323 cases of limb thrombosis (55.1%), 77 cases of cerebral venous thrombosis (13.1%), 57 cases of pulmonary embolism (9.7%), 63 cases of vena cava lesions (10.7%), 14 cases of Budd-Chiari syndrome (2.4%), and 13 cases of cervical vein thrombosis (2.2%). One hundred of 296 patients (33.8%) experienced at least 1 venous thrombosis relapse. The mortality rate was 6.4% (19 of 296 patients) after a median followup of 4.75 years (interquartile range 2–7 years). In univariate analysis, death was associated with cardiac involvement (P = 0.026) and Budd-Chiari syndrome (P = 0.004). In multivariate analysis, the use of immunosuppressive agents was found to prevent relapse of venous thrombosis (hazard ratio 0.27 [95% confidence interval 0.14–0.52], P = 0.00021), and there was a trend toward prevention of relapse with the use of glucocorticoids (hazard ratio 0.62 [95% confidence interval 0.40–0.97], P = 0.058). Conclusion Immunosuppressive agents significantly reduce venous thrombosis relapse in BD.

Objective To retrospectively study the incidence of chronic cutaneous lupus erythematosus (CCLE) in French Guiana (FG), South America, during the period 1995–1999. Methods Private and public physicians specializing in dermatology, rheumatology, and internal medicine were asked during the year 2000 about lupus cases. We reviewed hospitals' files in data-processing departments. Results Twenty new cases of CCLE, mostly discoid form, were identified during this 5-year period in this population of predominantly African descent. The average annual incidence of the disease was 2.59 per 100,000 inhabitants (95% confidence interval 1.5–4). However, our methodology could introduce underestimation of the incidence of the disease. Conclusion The average annual incidence of CCLE in FG appears to be low in this retrospective study, but is very similar to the only previously published data in the US.

Objective To analyze the clinical findings, treatment, outcome, and prevalence of cerebral venous thrombosis (CVT) in a large cohort of patients with Behcet'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.

Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as mixed cryoglobulinemia (MC). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of peripheral blood B- and T-cell subsets, the clonal VH1–69 cells, as well as the cytokine profile following rituximab therapy. The study involved 21 patients with hepatitis C–related MC who received rituximab, of whom 14 achieved a complete response. Compared with healthy and hepatitis C virus (HCV) controls, pretreatment abnormalities in MC patients included a decreased percentage of naive B cells (P < .05) and CD4+CD25+FoxP3+ regulatory T cells (P = .02) with an increase in memory B cells (P = .03) and plasmablasts (P < .05). These abnormalities were reverted at 12 months after rituximab. Clonal VH1–69+ B cells dramatically decreased following treatment (32% ± 6% versus 8% ± 2%, P = .01). Complete responders of rituximab exhibited an expansion of regulatory T cells (P < .01) accompanied with a decrease in CD8+ T-cell activation (P < .01) and decreased production of interleukin 12 (IL-12; P = .02) and interferon-γ (IFN-γ; P = .01). Our findings indicate that in patients with MC, response to B-cell depletion induced by rituximab effectively normalizes many of the disturbances in peripheral B- and T-lymphocyte homeostasis.

Objective: Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE.Methods: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using 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: Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10.Conclusion: Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.