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We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

Riassunto La sindrome da anticorpi antifosfolipidi (APS) e una malattia autoimmune cronica identificata come l’associazione tra trombosi e/o una morbilita ostetrica e la presenza duratura di anticorpi (Ab) diretti contro i fosfolipidi (aPL) e/o i loro cofattori proteici. La APS e una malattia rara. I progressi compiuti hanno permesso di stratificare meglio il rischio trombotico individuale. Il trattamento della APS si basa sui farmaci antitrombotici.

International audience; Background: Hydroxychloroquine (HCQ), a useful treatment for chronic dermatologic or rheumatologic diseases, has recently gathered widespread attention as a possible treatment for COVID-19 infection. However, its rare et severe neuropsychiatric side effects (NSE), such as psychosis and suicidal tendencies, are poorly documented, especially in youths.Case presentation: We present the first case on a 17-yearold girl of severe acute psychosis with a suicide attempt during HCQ treatment in association with thalidomide for chronic and refractory discoid lupus erythematosus. Drug causality was evaluated using the updated French causality assessment method. We performed a literature review and a worldwide pharmacovigilance database search on psychotic features after HCQ and thalidomide treatment. We found six cases in the literature and 53 cases (psychotic disorder: N=45, 3.7% and acute psychosis: N=8, 0.7%) in the pharmacovigilance database reporting the occurrence of psychotic symptoms under HCQ and none under thalidomide. The intrinsic and extrinsic imputability scores support the hypothesis that HCQ induced psychosis and suicide attempt in our patient. Withdrawing HCQ resulted in a dramatically improved situation, which remained perfectly stable after 3 years of follow-up.Conclusion: In HCQ-induced psychosis, recovery may be obtained with HCQ withdrawal, no future HCQ reintroduction, and, for the most serious manifestations, a short period of antipsychotic medication. Clinicians need to be aware of the NSE of HCQ and the appropriate interventions to be carried out.

ObjectivesTo compare the efficacy to prevent flares of maintenance versus withdrawal of 5 mg/day prednisone in systemic lupus erythematosus (SLE) patients with clinically quiescent disease.MethodsA monocentric, 12-month, superiority, open-label, randomised (1:1) controlled trial was conducted with 61 patients continuing 5 mg/day prednisone and 63 stopping it. Eligibility criteria were SLE patients who, during the year preceding the inclusion, had a clinically inactive disease and a stable SLE treatment including 5 mg/day prednisone. The primary endpoint was the proportion of patient experiencing a flare defined with the SELENA-SLEDAI flare index (SFI) at 52 weeks. Secondary endpoints included time to flare, flare severity according to SFI and British Isles Lupus Assessment Group (BILAG) index and increase in the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI).ResultsProportion of patients experiencing a flare was significantly lower in the maintenance group as compared with the withdrawal group (4 patients vs 17; RR 0.2 (95% CI 0.1 to 0.7), p=0.003). Maintenance of 5 mg prednisone was superior with respect to time to first flare (HR 0.2; 95% CI 0.1 to 0.6, p=0.002), occurrence of mild/moderate flares using the SFI (3 patients vs 12; RR 0.2 (95% CI 0.1 to 0.8), p=0.012) and occurrence of moderate/severe flares using the BILAG index (1 patient vs 8; RR 0.1 (95% CI 0.1 to 0.9), p=0.013). SDI increase and adverse events were similar in the two treatment groups. Subgroup analyses of the primary endpoint by predefined baseline characteristics did not show evidence of a different clinical response.ConclusionMaintenance of long term 5 mg prednisone in SLE patients with inactive disease prevents relapse.Trial registration numberNCT02558517; Results

BackgroundRenal biopsy is the cornerstone of systemic lupus erythematosus (SLE) nephritis and antiphospholipid syndrome (APS) nephropathy management. However, transcutaneous renal biopsy (TCRB) is hampered by the antithrombotic treatment frequently prescribed for those diseases. Transjugular renal biopsy (TJRB) offers an attractive alternative for patients at increased risk of bleeding. The primary objective of the study was to describe the safety profile and diagnostic performance of TJRB in SLE and APS patients.MethodsAll SLE and/or APS patients who underwent a renal biopsy in our department (between January 2004 and October 2016) were retrospectively reviewed. Major complications were death, haemostasis nephrectomy, renal artery embolization, red blood cell transfusion, sepsis and vascular thrombosis; macroscopic haematuria, symptomatic perirenal/retroperitoneal bleeding and renal arteriovenous fistula without artery embolization were considered as minor complications.ResultsTwo hundred and fifty-six TJRBs—119 without antithrombotics (untreated), 69 under aspirin and 68 on anticoagulants and 54 TCRBs without antithrombotics—were analysed. Their major and minor complication rates, respectively, did not differ significantly for the four groups: 0 and 8% for untreated TJRBs, 1 and 6% for aspirin-treated, 6 and 10% for anticoagulant-treated and 2 and 2% for TCRBs. The number of glomeruli sampled and the biopsy contribution to establishing a histological diagnosis was similar for the four groups.ConclusionsTJRBs obtained from SLE and APS patients taking antithrombotics had diagnostic yields and safety profiles similar to those of untreated TCRBs. Thus, TJRB should be considered for SLE and APS patients at risk of bleeding.

No simple or standardized assay is available to quantify interferon-α (IFNα) in routine clinical practice. Single-molecule array (Simoa) digital enzyme-linked immunosorbent assay (ELISA) technology enables direct IFNα quantification at attomolar (femtogram per milliliter [fg/ml]) concentrations. This study was undertaken to assess IFNα digital ELISA diagnostic performances to monitor systemic lupus erythematosus (SLE) activity.IFNα concentrations in serum samples from 150 consecutive SLE patients in a cross-sectional study were determined with digital ELISA and a functional biologic activity assay (bioassay). According to their Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) flare composite scores, patients were divided into groups with inactive SLE (SLEDAI score of4 or clinical SLEDAI score of 0) or active SLE (SLEDAI score of ≥4 or clinical SLEDAI score of0), and into groups with no flare or mild/moderate flare or severe flare.Based on serum samples from healthy blood donors, the abnormal serum IFNα level threshold value was 136 fg/ml. Next, using receiver operating characteristic curves for an SLE patient series that was widely heterogeneous in terms of disease activity and organ involvement, the threshold IFNα value associated with active disease was determined to be 266 fg/ml. The digital ELISA-assessed serum IFNα level was a better biomarker of disease activity than the Farr assay because its specificity, likelihood ratio for positive results, and positive predictive value better discerned active SLE or flare from inactive disease. The digital ELISA was more sensitive than the bioassay for detecting low-abnormal serum IFNα concentrations and identifying patients with low disease activity.Direct serum IFNα determination with a highly sensitive assay might improve monitoring of clinical SLE activity and selection of the best candidates for anti-IFNα treatment.

International audience; OBJECTIVES:Infliximab is increasingly used to treat neurosarcoidosis. We aimed to determine the efficacy and tolerance of an infliximab biosimilar for treating neurosarcoidosis.METHODS:We conducted a retrospective single-center study to describe the efficacy, safety and immunogenicity of an infliximab biosimilar in neurosarcoidosis patients. We compared the survival time without relapse while receiving the biosimilar or previous originator-infliximab treatment.RESULTS:Twenty patients with histologically documented neurosarcoidosis were treated with an infliximab biosimilar (initiation of treatment in 12 and switch from the originator drug in 8) between February 2016 and August 2018. All patients presenting with neurological involvement of one or more areas, including meningeal (n = 15), cerebral (n = 10), spinal cord (n = 9), and/or cranial nerves (n = 5); epilepsy (n = 3); and/or intracranial hypertension (n = 3) were enrolled. Eighteen patients received glucocorticoids during infliximab treatment, and 16 had methotrexate or azathioprine concomitant treatment. The median duration of follow-up was 25 months (19-28). Six patients relapsed during biosimilar treatment. Relapse rates and time-to-relapse did not differ between the infliximab originator previously received and biosimilar treatment groups (p = 0.40 and 0.51, respectively). Nine patients experienced 11 adverse events with the infliximab biosimilar, including infections (n = 5), urticaria (n = 4), headache (n = 1), and diarrhea (n = 1). All side effects were grade 2 or less using the WHO classification.CONCLUSIONS:In this retrospective study, the infliximab biosimilar was efficacious and safe for treating neurosarcoidosis.

Context The management of systemic auto-immune diseases (SAID) -associated thrombotic microangiopathies (TMA) [SAID-TMA] remains debated. Objectives To provide a demographic, clinical and therapeutic picture of SAID-TMA. Methods A cross-sectional analysis was conducted on adult patients presenting with SAID and TMA from the French National TMA Registry over a 20-year period. Clinical features were extracted and compared to those from a historical cohort of atypical haemolytic and uremic syndrome (aHUS) patients. Results Forty-one patients with SAID-TMA were compared to 78 patients with aHUS from a historical cohort. Connective tissue diseases (CTD) were systemic lupus erythematosus (n=18), primary Sjogren's syndrome (n=7), systemic sclerosis (n=11), mixed CTD (n=2) and 2 cases of vasculitides, including 7 overlapping forms and 8 cases of primary antiphospholipid syndromes (APLS). Patients with SAID-TMA generally had pre-existing chronic kidney failure (OR= 3.17, 95%CI: 1.204 to 7.923; p= 0.016) compared to aHUS patients, though creatinine levels were significantly lower (216 [IQR, 108-334] µmol/L vs. 368 [IQR, 170-722] µmol/L; p= 0.002). Patients were less likely to recover if renal replacement therapy was needed at onset (OR= 0.07; 0.02 to 0.34; p 0.05). Conclusion The management of SAID-TMA implies an early initiation of immunosuppressive drugs for flares of the associated SAID, whereas TPE seem ineffective. Key messages • Systemic auto-immune diseases (SAID) in thrombotic microangiopathies (TMA) [SAID-TMA] include mainly systemic lupus erythematosus, systemic sclerosis and primary Sjogren's syndrome. • SAID-TMA improves with the treatment of the underlying SAID • Therapeutic plasma exchange does not seem to have an early effect on TMA features at Day-7 nor Day-15

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

The anti–von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

Patients with interstitial lung disease have been considered at high risk of complications of COVID-19 because of their underlying lung disease and use of immunosuppressive agents.1 However, data on COVID-19 in patients with sarcoidosis are scarce.2–4 Several reasons for an increased risk of severe forms of COVID-19 among sarcoidosis patients have been hypothesised: the involvement of the lung in almost 90% of patients with COVID-19, some of whom have reduced pulmonary function and comorbidities such as diabetes or hypertension, which are largely associated with the use of glucocorticosteroids for treating sarcoidosis; and the use of immunosuppressive agents in a subset of these patients.5 Recently, Gyorfi et al 6 described the case of a patient with sarcoidosis who experienced a symptomatic SARS-CoV-2 infection with spontaneous clinical improvement, and a virological relapse after steroids treatment. This case illustrated the fact that immunosuppression with glucocorticoids may induce relapse of COVID-19 in patients with sarcoidosis. However, we lack data on the outcomes of patients with sarcoidosis affected by COVID-19. We retrospectively collected data for all patients with sarcoidosis and SARS-CoV-2 infection seen among 15 French centres between 1 March and 20 May 2020. The inclusion criteria were a sarcoidosis diagnosis based on the American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis and other granulomatous diseases …

Cancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent.We describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor.CR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients' evolution, the persistence of TMA may reflect an uncontrolled malignancy.

Background Cancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent. Cases presentation We describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor. Conclusions CR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients’ evolution, the persistence of TMA may reflect an uncontrolled malignancy.

Background Bullous systemic lupus erythematosus (BSLE) is a rare blistering condition associated with systemic lupus erythematosus (SLE). Patients and Methods We conducted a multi-center retrospective study in order to describe the clinical, immunological, and histological presentations and outcomes of BSLE. The skin biopsies were centrally reviewed, and sera obtained during a flare of BSLE were analyzed for identification of circulating anti-basement membrane zone antibodies. Results Ten patients (all women, median age at SLE diagnosis of 22 years) were included, as well as 118 cases from a systematic review of the literature. Lupus nephritis was associated in 50% of the cases. BSLE presented as tensed bullae on normal or erythematous skin, predominantly localized on the trunk, arms, head and neck. Urticarial lesions were associated in 31% of the cases, and mucous membrane involvement was seen in 51%. Histological analyses displayed sub-epidermal detachment, dermal infiltration of polynuclear neutrophils, alignment of these cells at the basal membrane zone and leukocytoclasis. The direct immunofluorescence was polymorphic, showing linear and/or granular deposits of IgG, IgA, IgM and/or C3. Anti-type VII collagen antibodies were detected in 69% of cases. Dapsone was efficacious in 90% of cases. Conclusion BSLE is an autoimmune neutrophilic blistering disease associated with SLE; it is not a cutaneous manifestation of lupus but may be associated with active extra-cutaneous manifestations of SLE. Dapsone is the first-choice option.

Objectives The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. Methods This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Results We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Conclusion Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.

Background: Remission and relapses prevention are the main objectives of the treatment of Systemic Lupus Erythematosus (SLE). Interferon alpha (IFNα) is a key cytokine in SLE, but its usefulness for the definition of remission and for the prediction of flare has not been validated in clinical practice. Objectives: To study the association between serum IFNα level, remission and risk of relapse. Methods: 502 SLE patients were assessed for serum IFNα level using a biological functional assay(1). Remission was defined by the absence of clinical manifestation of lupus activity (clinical SELENA-SLEDAI = 0) and a prednisone intake ≤ 5 mg/day(2). Patients in remission were subsequently followed for one year. The SELENA-SLEDAI Flare Index was used to identify SLE flare. Uni- and multivariable analyses were performed to define disease parameters associated with serum IFNα positivity in patients in remission at baseline. Survival curve analysis, log-rank tests and Hazard Ratios (HR) were calculated to evaluate the risk of flare depending on IFNα, dsDNA Abs and C3 levels at baseline. Results: 345 samples were obtained from patients in remission. 28.6% of the patients in clinical remission on treatment (requiring clinical SELENA-SLEDAI = 0, positive anti-dsDNA antibodies and/or C3 decrease and prednisone intake 1 – 5 mg/day) had an abnormal serum IFNα level, compared to 6.5% of the patients in complete remission on treatment (requiring clinical SELENA-SLEDAI = 0, no anti-dsDNA antibodies nor C3 decrease and prednisone intake 1 – 5 mg/day). In patients in remission, high serum IFNα levels at baseline were associated in multivariable analysis with the positivity of anti-dsDNA Abs (HR 3.4 [95%CI 1.6-7.2], p=0.0001) and anti-RNP Abs (HR 3.2 [95%CI 1.5-6.8], p=0.0002). In patients in remission, high serum IFNα level at baseline was a significant and independent risk factor of lupus flare (HR=4.8 [95%CI 2.3-9.7], p Conclusion: A large number of SLE patients in remission display abnormal levels of serum IFNα. Abnormal levels of serum IFNα in patients in remission were significantly associated with positive anti-dsDNA and anti-RNP Abs and were an independent predictive biomarker of lupus flare in the following year. Adding serum IFNα to the routine laboratory assessments perform in patient in remission could help clinicians to identify a subgroup of SLE patient clinically in remission but serologically active and at higher risk of relapse. References: [1] Mathian A, et al. Monitoring disease activity in systemic lupus erythematosus with single-molecule array digital ELISA quantification of serum interferon-α. Arthritis Rheumatol Hoboken NJ.2018Dec3; [2] Vollenhoven R, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis. 2017Mar1;76(3):554–61. Disclosure of Interests: None declared

Background Glucocorticoids (GCs) are a mainstay of treatment for patients with SLE but are associated with significant adverse effects. Some SLE patients are maintained for a long-term under a low dose of prednisone to prevent relapse. There is no scientific data to sustain this therapeutic strategy. Objectives We hypothesized that maintaining a daily dose of 5 mg prednisone in patients with an inactive SLE for at least a year would prevent the risk of relapse. Methods The CORTICOLUP study (NCT02558517) was a prospective randomized, open-labeled, controlled, monocentric study sought to compare maintenance vs withdrawing of low-dose of prednisone (5mg) to reduce SLE flares, conducted from January 2014 to March 2017. Inclusion criteria were SLE patients who during the year preceding the inclusion had 1/an inactive SLE defined by a SLEDAI-2K score ≤ 4, a BILAG-2004 index C, D or E in all systems and a PGA =0 and 2/a stable SLE treatment including prednisone 5 mg daily. The primary end point was the number of patients with flares during 12 months of follow-up defined by the revised-SELENA SLEDAI Flare Index (rSFI). Secondary outcomes were occurrence of a BILAG scores A or B ≥1, clinical SLEDAI-2k >0, PGA ≥0.5 and increase of the SLICC damage index (SDI). All patients were included in the intention-to-treat analysis. Results A total of 124 patients (61 in the maintenance group and 63 in the withdrawal group) were included. No patients were lost to follow up. At baseline There were no significant differences between the maintenance and the withdrawal group with respect to: duration of SLE [mean (±standard deviation) duration of 11.8 (±0.9) versus 13.1 (±1.0) years], duration of remission [55.7 (±5.8) vs 67.5 (±6.8) months], HCQ treatment [98.2% vs 100.0%], immunosuppressive drugs [27.9% vs 25.4%], previous renal involvement [34.4% vs 41.3%], low C3 [16.4% vs 15.9%], positive Farr test [47.5% vs 46.0%], and SDI [mean index of 0.5 (±0.1) vs 0.7 (±0.2)]. There were significantly more flares in the withdrawal group compared to the maintenance group (17 flares versus 4, p=0.0034 using the Fisher’s exact test). Mild or moderate flares were more frequent in the withdrawal group compared to the maintenance group (12 vs 3, p=0.029). The occurrence of severe flare was not significantly different between the two groups (5 vs 1, p = 0.208). More than two-thirds of the flares in the withdrawal group occurred within the first six months. Within the withdrawal group, using forest plot analysis, no significant association was found between the occurrence of a flare and age, sex, duration of SLE, duration of SLE remission, duration of GCs treatment, immunosuppressants and serological SLE activity at randomization. Four patients in the withdrawal group and none in the maintenance group experienced damage: 2 osteoporosis bone fractures, 1 hydroxychloroquine retinopathy and 1 cataract. Conclusion Withdrawal of low dose of steroids in patients with inactive SLE and stable therapeutic regimen for more than a year is associated with a high risk of relapse. Disclosure of Interests None declared

ObjectivesMaintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has been poorly studied as yet. To study its expression in remission and its prognostic value in the prediction of a disease relapse, serum IFN-α levels were determined using an ultrasensitive single-molecule array digital immunoassay which enables the measurement of cytokines at physiological concentrations.MethodsA total of 254 SLE patients in remission, according to the Definition of Remission in SLE classification, were included in the study. Serum IFN-α concentrations were determined at baseline and patients were followed up for 1 year. Lupus flares were defined according to the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index Flare Index, whereas the Kaplan-Meier analysis and Cox regression analysis were used to estimate the time to relapse and to identify baseline factors associated with time to relapse, respectively.ResultsOf all patients in remission, 26% displayed abnormally high IFN-α serum levels that were associated with the presence of antibodies specific for ribonucleoprotein (RNP), double stranded (ds)DNA and Ro/SSA60, as well as young age. Importantly, elevated-baseline IFN-α serum levels and remission duration were associated in an independent fashion, with shorter time to relapse, while low serum levels of complement component 3 and anti-dsDNA Abs were not.ConclusionDirect serum IFN-α assessment with highly sensitive digital immunoassay permits clinicians to identify a subgroup of SLE patients, clinically in remission, but at higher risk of relapse.

Immunoglobulin G4-related diseases (IgG4-RD) are a group of chronic relapsing–remitting inflammatory conditions, characterised by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, fibrosis and a usually favourable response to steroids.In this narrative review, we summarise the results of a systematic literature research, which was performed as part of the European Reference Network ReCONNET, aimed at evaluating existing clinical practice guidelines (CPGs) and recommendations in IgG4-RD. From 167 publications initially obtained from a systematic literature search, only one was identified as a systematic multispecialist, evidence-based, consensus guidance statement on diagnosis and treatment of IgG4-RD, which may be recommended for use as CPG in IgG4-RD.With the recognition of a limited evidence based in this increasingly recognised disease, the group discussion has identified the following unmet needs: lack of shared classification criteria, absence of formal guidelines on diagnosis, no evidence-based therapeutic recommendations and lack of activity and damage indices. Areas of unmet needs include the difficulties in diagnosis, management and monitoring and the scarcity of expert centres.

Objective: To compare the efficacy of methotrexate (MTX) and mycophenolate mofetil (MMF) in the prevention of relapses in neurosarcoidosis. Methods: We conducted a retrospective multicenter study including patients who received MTX or MMF for the treatment of histologically proven neurosarcoidosis. The efficacy of the immunosuppressive drug was assessed by determining the time to relapse. Results: Forty patients with a diagnosis of neurosarcoidosis (24 men, 16 women, median age at diagnosis 43.5 years) who received at least 3 months of MTX (n = 32) or MMF (n = 14) were included. The immunosuppressive drug was always associated with steroids. The rate of relapse was 47% in the MTX group (0.2 relapses per year of exposure) and 79% in the MMF group (0.6 relapses per year of exposure) (p = 0.058). The median time to relapse was significantly shorter in the MMF group (11 months) compared with the MTX group (28 months) (p = 0.049). Adverse events occurred in 11 patients during MTX therapy and in 1 patient during MMF therapy (p = 0.12). Conclusions: Relapses of neurosarcoidosis occur frequently, despite the use of an immunosuppressive drug in addition to corticosteroids. MTX significantly increases the survival time without relapse compared to MMF and should be preferred over MMF for the treatment of neurosarcoidosis. This study provides Class IV evidence that for patients with neurosarcoidosis taking steroids, MTX is superior to MMF in reducing the risk of relapse.

Objective.Cardiac involvement during systemic lupus erythematosus (SLE) may include the pericardium, myocardium, valvular tissue, and coronary arteries. The aim of this study was to describe the clinical, biological, and radiological presentation of lupus myocarditis (LM) as well as the treatment response and longterm outcomes.Methods.We conducted a multicentric retrospective study of LM from January 2000 to May 2014.Results.Twenty-nine patients (3 men and 26 women) fulfilled the inclusion criteria (median age at the diagnosis of SLE: 30 yrs, range 16–57). Myocarditis was the first sign of SLE in 17/29 cases (58.6%). Troponin was elevated in 20/25 cases. Electrocardiogram results were abnormal in 25/28 cases. Echocardiography revealed low (≤ 45%) left ventricular ejection fraction (LVEF; 19/29, 66%) and pericardium effusion (20/29, 69%). Cardiac magnetic resonance imaging revealed delayed gadolinium enhancement in 9/13 patients (69%). Patients were treated with corticosteroids (n = 28), cyclophosphamide (CYC; n = 16), intravenous immunoglobulins (n = 8), and/or mycophenolate mofetil (n = 2). The median followup was 37 months. One month after the beginning of the treatment, 10/23 patients (43%) who had undergone echocardiography had an LVEF ≥ 55%. At the end of followup, 21/26 patients (81%) exhibited an LVEF ≥ 55%. Three patients died during followup, and 2 died from LM.Conclusion.LM is a severe manifestation of SLE. It can be the first manifestation of the disease or it can occur during followup, in particular in untreated patients. However, the longterm prognosis is typically positive. Patients with less severe disease exhibited good LVEF recovery without CYC.

Background:A role for Epstein Barr Virus (EBV) infection in Systemic Lupus Erythematosus (SLE) pathogenesis is highly suspected. The frequency of EBV seroprevalence and DNA detection in peripheral blood mononuclear cells are increased in SLE patients compared to healthy controls.Objectives:To analyse the relationship between EBV blood replication and SLE disease activity.Methods:Monocentric, observational and retrospective study of SLE patients (ACR or SLICC criteria) who have had a blood EBV DNA assessment using Polymerase Chain Reaction (artus® EBV Virus QS-RGQ assay) between 2012 and 2018. Exclusion criteria were: organ or bone marrow transplant, absence of EBV seroconversion and insufficient data. SLE clinical features, the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) flare index (SFI) and therapeutic regimen on the day of EBV DNA load assessment were recorded. A SELENA-SLEDAI score > 4 defined an active SLE. A blood EBV DNA load ≥125 IU/mL was defined as elevated.Results:A total of 105 patients (98 women and 7 men) were included in the study. At inclusion, median (quartiles) age and SLE duration were 34 (23.5-43) and 7 (2-14) years old, respectively. Treatment were hydroxychloroquine (HCQ) (n = 67; 64%), prednisone (n = 66; 63%) with an average (±Standard Deviation) dose of 11.3 (±16) mg/day and an immunosuppressant (n = 42; 40%). According to SFI, 57 SLE patients were experiencing a flare at the time of EBV assessment; flares were classified as severe and mild/moderate in 38 (36%) and 19 (18%) SLE patients, respectively. According to the SELENA-SLEDAI score, 60 patients (57%) were deemed active and 45 (43%) inactive. Main clinical manifestations were arthritis in 32 (30%) patients, constitutional symptoms (fever, weight loss, anorexia or lymphadenopathy) in 31 (30%), cutaneous involvement in 23 (22%), glomerulonephritis in 19 (18%), cytopenia in 14 (13%), neuropsychiatric involvement in 13 (12%) and serositis in 10 (16%). Blood EBV DNA was elevated in 54 (90%) of the 60 patients with active lupus versus 6 (13%) of the 45 patients with inactive SLE (p -4). It was increased in 34 (89%) of the 38 patients with severe flare, in 17 (89%) of the 19 patients with a mild/moderate flare (p = 1) and in 8 (17%) of the 48 patients without flare (p -4vs severe flare and p -4vs mild/moderate flare). EBV DNA load correlated with SELENA-SLEDAI score (r=0.58; p-4in paired analysis).Conclusion:Blood EBV viral load is dramatically increased in active phase of SLE, independently of the treatment. We were unable to demonstrate whether the replication of EBV was the cause or the consequence or just an epiphenomenon of the disease activity. Further studies are needed to study whether EBV viral load is linked with Interferons secretion or B lymphocyte activation.Disclosure of Interests:None declared

Preemptive rituximab infusions prevent relapses in immune thrombotic thrombocytopenic purpura (iTTP) by maintaining normal ADAMTS13 activity. However, the long-term outcome of these patients and the potential adverse events of this strategy need to be determined. We report the long-term outcome of 92 patients with iTTP in clinical remission who received preemptive rituximab after identification of severe ADAMTS13 deficiency (activity 1 iTTP episode, and the median cumulative relapse incidence before preemptive rituximab was 0.33 episode per year (interquartile range [IQR], 0.23-0.66). After preemptive rituximab, the median cumulative relapse incidence in the whole population decreased to 0 episodes per year (IQR, 0-1.32; P < .001). After preemptive rituximab, ADAMTS13 activity recovery was sustained in 34 patients (37%) during a follow-up of 31.5 months (IQR, 18-65), and severe ADAMTS13 deficiency recurred in 45 patients (49%) after the initial improvement. ADAMTS13 activity usually improved with additional courses of preemptive rituximab. In 13 patients (14%), ADAMTS13 activity remained undetectable after the first rituximab course, but retreatment was efficient in 6 of 10 cases. In total, 14 patients (15%) clinically relapsed, and 19 patients (20.7%) experienced benign adverse effects. Preemptive rituximab treatment was associated with a change in ADAMTS13 conformation in respondent patients. Finally, in the group of 23 historical patients with iTTP and persistently undetectable ADAMTS13 activity, 74% clinically relapsed after a 7-year follow-up (IQR, 5-11). In conclusion, persistently undetectable ADAMTS13 activity in iTTP during remission is associated with a higher relapse rate. Preemptive rituximab reduces clinical relapses by maintaining a detectable ADAMTS13 activity with an advantageous risk-benefit balance. ispartof: Blood vol:132 issue:20 pages:2143-2153 ispartof: location:United States status: published

Background— The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis. Methods and Results— This was a retrospective, multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years [20–55 years] treated by tumor necrosis factor-α antagonists [80%] or tocilizumab [20%]) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 [1–5]). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L [10–46 mg/L] versus 58 mg/L [26–76 mg/L]; P =0.006) and a trend toward fewer immunosuppressants drugs used before biologics ( P =0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L [ P P P =0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2–95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases. Conclusion— This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown aetiology that can be debilitating and life threatening. As new insights are gained into the underlying pathology of SLE, there have been an unprecedented number of new agents under development to treat the disease via a diverse range of targets. One such class of emerging agents target interferon (IFN) signalling. In this article, we review the preclinical evidence that the inhibition of the secretion and downstream effectors of both IFN-α and IFN-γ may be effective for the treatment of SLE. The primary agents that are currently in clinical development to treat SLE via the targeting of interferon pathways are monoclonal neutralising antibodies (Mab) that bind to and neutralise IFN-γ (AMG 811), IFN-α (sifalimumab, rontalizumab and AGS-009) or its receptor (anifrolumab), and IFN-α kinoid, which is a drug composed of inactivated IFN-α molecules coupled to the keyhole limpet haemocyanin protein. Phase I and II trials have demonstrated acceptable short-term safety with no increase in severe viral infections or reactivation, favourable pharmacokinetic profiles and an inhibition of IFN-associated gene overexpression; however, the impact of these drugs on disease activity must still be assessed in phase III clinical trials. This review concludes with a summary of the challenges that are inherent to this approach to managing SLE.

The aim of the study was to assess the efficacy and safety of rituximab (RTX) for treating systemic lupus erythematosus (SLE)-associated immune cytopenias. This multicenter retrospective cohort study of adults from French referral centers and networks for adult immune cytopenias and SLE involved patients ≥18 years old with a definite diagnosis of SLE treated with RTX specifically for SLE-associated immune cytopenia from 2005 to 2015. Response assessment was based on standard definitions. In total, 71 patients, 61 women (85.9%), with median age 36 years [interquartile range 31-48], were included. The median duration of SLE at the time of the first RTX administration was 6.1 years [2.6-11.6] and the reason for using RTX was immune thrombocytopenia (ITP) for 44 patients (62.0%), autoimmune hemolytic anemia (AIHA) for 16 (22.5%), Evans syndrome for 10 (14.1%), and pure red cell aplasia for one patient. Before receiving RTX, patients had received a mean of 3.1 ± 1.3 treatments that included corticosteroids (100%), and hydroxychloroquine (88.5%). The overall initial response rate to RTX was 86% (91% with ITP, 87.5% with AIHA, and 60% with Evans syndrome), including 60.5% with complete response. Median follow-up after the first injection of RTX was 26.4 months [14.3-71.2]. Among 61 initial responders, relapse occurred in 24 (39.3%); for 18, RTX retreatment was successful in 16 (88.8%). Severe infections occurred after RTX in three patients, with no fatal outcome. No cases of RTX-induced neutropenia were observed. In conclusion, RTX seems effective and relatively safe for treating SLE-associated immune cytopenias.

Multiple mononeuropathy (MM) occurs rarely during systemic lupus erythematosus (SLE) but may lead to major disability. The aim of this study was to investigate the clinic-pathological presentations of MM during SLE, as well as long-term outcomes. We conducted a multicentric retrospective study that included patients receiving a diagnosis of MM during SLE. Ten patients were included (8 women and 2 men, median age at MM diagnosis: 40.4 years). SLE was diagnosed before MM in 9/10 patients (median time 8.2 years). When MM occurred, the SLEDAI score was ≥6 for 6/9 patients. Presenting symptoms consisted of sensory deficits (n = 10), neuropathic pain (n = 9), and/or motor deficits (n = 9), sometimes symmetrical, affecting the lower limbs (10/10) and occasionally the upper limbs (5/10). All patients presented with uni- or bilateral damage of the common fibular nerve, with less frequent involvement of the tibial nerve. Serum cryoglobulinemia was positive in 5/9 patients. Electrophysiological studies confirmed the non-symmetrical involvement of multiple nerve trunks in all patients. Neuromuscular biopsy (performed in five patients) showed histological signs of vasculitis in two patients and perivascular lymphocytic inflammatory infiltrates in two others. All patients were treated with glucocorticosteroids combined with cyclophosphamide (n = 6), rituximab (n = 3), or mycophenolate-mofetil (n = 1). The median follow-up was 5 years. Two patients relapsed during follow-up. All patients had motor and/or sensory sequelae upon follow-up. MM associated with SLE is frequently caused by a vasculitis mechanism. Patients improve with steroids and immunosuppressive drugs. Long-term outcomes include frequent clinical sequelae and possible relapses.

The pulmonary-renal syndrome is a rare and life-threatening condition. It is defined as the association of a diffuse alveolar hemorrhage and a rapidly progressive glomerulonephritis. The characteristic histological lesion common to all underlying diseases is a necrotizing and crescentic glomerulonephritis. The pulmonary-renal syndrome is a diagnostic and therapeutic emergency: any delay in its management will lead to death or serious functional damage as pulmonary and renal impairment. ANCA-associated vasculitis and Goodpasture's disease are the main disorders associated to pulmonary-renal syndrome. More rarely systemic lupus, cryoglobulinaemia, Henoch-Schonlein purpura or subacute endocarditis may induce a pulmonary-renal syndrome. Differential diagnosis can sometimes be difficult, highlighting some ambiguity in the definition of the syndrome. Initial treatment usually associates systemic corticosteroid, cyclophosphamide and plasma exchange. The role of biotherapy as first line therapy remains to be determined.

International audience; Background: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome.Methods: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months.Results: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality.Conclusions: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.

Despite a significant improvement of thrombotic thrombocytopenic purpura (TTP) prognosis since the use of plasma exchange, morbidity and mortality remained significant because of poor response to standard treatment or exacerbations and relapses. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte CD20 antigen, has shown a particular interest in this indication. Recent studies also reported strong evidence for its efficiency in the prevention of relapses. This review addresses these recent progresses and still opened questions in this topic: should rituximab be proposed in all patients at the acute phase? Should all patients benefit from a preemptive treatment? Is the infectious risk acceptable in this context?

In acquired thrombotic thrombocytopenic purpura (TTP), the persistence of severe ADAMTS13 deficiency (

Conflicting data have been published regarding the risk of cervical lesions among women with systemic lupus erythematosus (SLE). We systematically reviewed the evidence for an association of SLE with cervical precancerous lesions (high-grade squamous intraepithelial lesions, HSIL), and performed a meta-analysis to determine the risk of HSIL in SLE patients. Observational studies identified up to February 2013 from the Medline, Embase and Cochrane databases were selected if they assessed the prevalence of HSIL in female SLE patients versus healthy female controls and included in a meta-analysis with pooled effect estimates obtained using a random-effects model. Of 235 citations retrieved, 7 studies met inclusion criteria. The pooled odds ratio for the risk of HSIL in SLE patients (n=416) versus female controls (n=11,408) was 8.66 (95% CI: 3.75-20.00), without significant heterogeneity across studies. Cumulative meta-analysis according to year of study publication revealed a slight increase in the risk of HSIL in the 2001-2011 period and then a stabilization afterwards. This meta-analysis shows that the risk of HSIL is significantly increased in SLE patients, compared to healthy female controls. This suggests that women with SLE may benefit from HPV vaccines and specific cervical cancer screening.

Lupus enteritis is a rare and poorly understood cause of abdominal pain in patients with systemic lupus erythematosus (SLE). In this study, we report a series of 7 new patients with this rare condition who were referred to French tertiary care centers and perform a systematic literature review of SLE cases fulfilling the revised ACR criteria, with evidence for small bowel involvement, excluding those with infectious enteritis. We describe the characteristics of 143 previously published and 7 new cases. Clinical symptoms mostly included abdominal pain (97%), vomiting (42%), diarrhea (32%) and fever (20%). Laboratory features mostly reflected lupus activity: low complement levels (88%), anemia (52%), leukocytopenia or lymphocytopenia (40%) and thrombocytopenia (21%). Median CRP level was 2.0 mg/dL (range 0–8.2 mg/dL). Proteinuria was present in 47% of cases. Imaging studies revealed bowel wall edema (95%), ascites (78%), the characteristic target sign (71%), mesenteric abnormalities (71%) and bowel dilatation (24%). Only 9 patients (6%) had histologically confirmed vasculitis. All patients received corticosteroids as a first-line therapy, with additional immunosuppressants administered either from the initial episode or only in case of relapse (recurrence rate: 25%). Seven percent developed intestinal necrosis or perforation, yielding a mortality rate of 2.7%. Altogether, lupus enteritis is a poorly known cause of abdominal pain in SLE patients, with distinct clinical and therapeutic features. The disease may evolve to intestinal necrosis and perforation if untreated. Adding with this an excellent steroid responsiveness, timely diagnosis becomes primordial for the adequate management of this rare entity.

Introduction Systemic Lupus Erythematosus (SLE) is associated with thrombocytopenia in approximately 20 % of cases. Management of such cases has been similar to that of Immune ThrombocytoPenia (ITP) as an immune-mediated mechanism is inferred in the pathogenesis of SLE-associated thrombocytopenia. First line treatment is similar to primary ITP (corticosteroids, intravenous immunoglobulin), with the use of hydroxychloroquin in addition. Immunosuppressive agents, rituximab or splenectomy can be used as second line treatment. However, a significant number of patients will not respond to these treatments and will relapse afterward. More recently, Romiplostim and Eltrombopag, 2 agonists of thrombopoietin receptor (TPO-RA) have been approved for ITP as second line therapy resulting in sustained increment in platelet count in about 70-80 % of cases with reduction in bleeding. However, the experience with this class of agents in SLE is only anecdotal. Their effectiveness and side effects in SLE related ITP is unknown. Patients and Method This was a multicenter retrospective cohort study of patients with SLE related ITP diagnosed from 1998 to 2015 and treated with TPO-RA. All participating centers (n=13) were secondary or tertiary care hospitals belonging to the French national network for adult ITP. Clinical data were retrospectively collected from medical charts for each patient and completed by telephone interviews with patients and physicians by using a standardized questionnaire. ITP was defined according to the international working group definitions. SLE was defined according to the international guidelines (American College of Rheumatology for systemic lupus erythematosus, revised Sapporo criteria for antiphospholipid syndrome). Response (R) and complete response (CR) were defined according to standardized international criteria: platelet count > 30 × 109/L with at least a doubling of the baseline value or >100 × 109/L.2 Non-response (NR) was defined as the absence of platelet count increase >30 × 109/L with at least a doubling of the baseline count or the need for rescue therapy (IVIg and/or corticosteroids). Patient's characteristics (table 1&2) PS: PitiŽ Salptrire, F: female, M: male, HCQ: hydroxychloroquin, MMF: Mycophenolate mofetil, CTC: corticosteroid, RTX : rituximab, CYC: cyclophosphamide, IVIG : intravenous immunoglobulin, AZA: azathioprine, spm: splenectomy, Toci: tocilizumab, Aba: abatacept, Csa: ciclosporine, TPO-RA : thrombopoietin-receptor agonist, Elt : eltrombopag, Romipl : romiplostim, NS :non specified, CR: complete remission, R :responder, NR :non responder APLS: antiphospholipid syndrome, APL : antiphospholipid (presence of antibody without clinical symptoms) Results and Discussion A total of 16 patients (12 F/ 4M) received TPO-RA (Romiplostim 36%, eltrombopag 28 %, both 36%). Patients had received a median of 5.5 treatment lines for ITP. All but one patient responded at least to one of TPO-RA (93%). No SLE flare has been observed with these treatments. Unexpectedly, 3 patients (18,5%) developed thrombotic events as a side effect. Two arterial thrombosis occurred in patients receiving eltrombopag (both of them with a previous history of APL or APLS), and two venous thrombosis in the same patient (without antiphospholipid) treated with romiplostim. The same strategy was used in the 3 patients: TPO-RA was stopped but rechallenged promptly to increase platelet level, given that they were receiving anticoagulant or anti-aggregant therapy. No reoccurrence has been observed. The other side effects were similar to that observed with primary ITP. This study has some limitations due to its retrospective design, including some potential selection bias but the rapid and sustained response observed raises the possibility that in certain refractory cases of thrombocytopenia associated with SLE, TPO-RA might be a second line therapy to be considered in this patient population. Given the high rate of thrombotic events, we suggest that TPO-RA should be used with caution in patient with APL. Prospective systematic studies would help define the role of this class of agents in SLE and other rheumatic disease that progress with immune mediated thrombocytopenia. Table 1 Table 1. Table 2 Table 2. Disclosures Terriou: amgen: Consultancy; Novartis: Consultancy. Bussel:Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; BiologicTx: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding.

Introduction: Autoimmune cytopenias and mostly immune thrombocytopenia (ITP) are common manifestations of systemic lupus erythematosus (SLE). Rituximab (RTX) is used off-label in many countries for treating primary ITP and warm autoimmune hemolytic anemia (AIHA). In SLE, the place of RTX is controversial and the aim of this study was to assess the efficacy and safety of RTX for treating SLE-associated immune cytopenias. Materials and methods: A multicentre retrospective study was performed throughout the French network of adult' immune cytopenias. Patients aged >18 years, with a definite diagnosis of SLE according to the usual criteria, treated by RTX from 2005 to 2015 specifically for a SLE-associated immune cytopenia could be included. SLE-associated ITP was defined as platelet count ≤ 50 x 109L after exclusion of any other cause of thrombocytopenia. AIHA was defined by a hemoglobin level (Hb) ≤100 g/l with markers of hemolysis and a positive direct antiglobulin test. To assess treatment efficacy, the following criteria were used: for ITP, complete response (CR) and response (R) were defined according to the consensus international criteria. For AIHA, a CR was defined by a normal Hb level in the absence of recent transfusion and without ongoing haemolysis, and a response (R) by a Hb level ≥100 g/l with an increase of at least 20 g/l from baseline. CR and PR could be retained only for patients who were treated with corticosteroids and/or other immunosuppressive agents at a stable or decreasing dose. Results: Sixty-two patients, 55 women (88.7%), with a median age of 36 years [range 31-49] were included. The median duration of SLE at time of first RTX administration was 6.7 years [3.4-11.4] and the reason for using RTX was ITP in 40 cases (64.5%), AIHA in 15 cases (24.2%) and Evan's syndrome in 6 cases (9.7%). One patient was treated for a SLE-associated pure red cell aplasia. Other SLE-related manifestations were: articular (54.8%), cutaneous (49.2%), serositis (14.5%), renal (11.1%) and/or neurological (14.5%). Patients had received an average of 3.1 ± 1.3 treatments prior to RTX including steroids (100%), and hydroxychloroquine (90.3%). The overall initial response rate to RTX was 82% (87% for ITP, 86% for AIHA, and 50% for Evan's syndrome) including 59% CR. Median follow-up after the first injection of RTX was 24.6 months [12.6-61.2]. Twenty-one (41%) of the initial responders relapsed and re-treatment with RTX was successful in 94%. Severe infections occurred after rituximab in three adults with no fatal outcome. No cases of of opportunistic infections of RTX-induced neutropenia were observed. Discussion: RTX appears to be an effective and relatively safe option for the treatment of SLE-associated immune cytopenias. Disclosures Michel: Roche: Research Funding.

Takayasu arteritis is a chronic inflammatory arteritis affecting large vessels, predominantly the aorta and its main branches. We report the case of a patient presenting with the rapid growth of a thoracic aortic aneurysm during pregnancy leading to the diagnosis of Takayasu disease and treated by a rapid delivery by cesarean section followed by an open aortic repair. One year after the operation the patient and her baby are alive and well.

Primary Sjogren syndrome (SS) is an autoimmune disease mainly affecting the exocrine glands causing a sicca syndrome. Neurological manifestations are rarely seen in SS although they are debilitating. Peripheral neuropathies namely sensory axonal neuropathy and painful small fiber neuropathy are the most frequent neurological manifestations. Sensory neuronopathy (SN) is less frequently seen although leading to more severe handicap.The aim of the study was to analyze the clinical presentation and treatment efficacy in a series of SS-related SN.We retrospectively studied patients with SS fulfilling the American-European Classification Criteria and SN according to recent criteria. Studied variables were neurological findings, associated autoimmune diseases, biological profiles, nerve conduction and sensory/motor amplitudes study, treatments received, and outcomes. Handicap scores were studied at beginning and end of each treatment using the modified Rankin Scale (mRS).Thirteen patients were included (12 women, 1 man; median age 55 years at SN diagnosis) presenting with SN with a median follow-up of 3 years (range 2-17). In 11 patients, SN preceded or coincided with SS diagnosis. Most common neurological findings were ataxia and areflexia followed by paresthesia and pain. Lower limbs were more affected than upper limbs, neurological deficits were often symmetric and cranial nerves were affected in 3 patients. Seven patients were treated with corticosteroids, 7 with mycophenolate mofetil, 6 with hydroxychloroquine, 5 with intravenous immunoglobulins, 4 with cyclophosphamide, and 2 patients received other immunosuppressive drugs. At the beginning and at the end of follow-up, average mRS was 2.15 (median 2) and 2.38 (median 2), respectively.SS-related SN progression is heterogeneous but tends to be chronic, insidious, and debilitating despite treatment. From these data concerning a small number of patients, treatment strategies with corticosteroids in association with immunosuppressive drugs, namely mycophenolate mofetil, had positive results. In contrast, intravenous immunoglobulins had disappointing results.

Objective Transforming growth factor-β is considered to play a key role in the process of fibrosis in systemic sclerosis (SSc) and in the development of regulatory T cells (Treg) and pro-inflammatory Th17 T cells producing interleukin 17 (IL-17) and IL-22. The authors therefore postulated that SSc could be characterised by a marked Treg/Th17 imbalance. Previous works did not distinguish between the different subsets of Treg and the non-regulatory FoxP3 + cells leading to inconsistent results. Methods Combined phenotypic and functional analysis of Th17 cells and FoxP3 + CD4 T cells, discriminating activated Tregs and resting Tregs from non-regulatory FoxP3 + T cells, in blood and skin of SSc patients. Results In early disease stages, there is a decreased proportion of activated Tregs. A concomitant resting Treg deficit becomes more apparent with disease progression. Active and diffuse forms of the disease are characterised by a relatively higher proportion of all FoxP3 + subsets, including non-regulatory T cells. No peripheral or local IL-17 amplification was observed. However, the authors found significantly increased IL-22 transcription levels in SSc lesional skin, as compared with healthy skin. Cytofluorometry confirmed the existence in SSc patients and controls of a distinct subset of T cells producing IL-22 in the absence of IL-17. Conclusion SSc pathogenesis does not appear to be linked to IL-17-, but rather to IL-22-producing cells with skin-homing potential and a concomitant quantitative Treg defect. Active and diffuse forms of the disease are associated with a FoxP3 signature. Altogether, our data depict a status of regulatory/pro-inflammatory T cell imbalance in SSc.

Dear Sir, Thirty to seventy per cent of patients with systemic lupus erythematosus (SLE) eventually develop lupus nephritis (LN), with increased risk for renal failure and cardiovascular events, conferring reduced survival. Current recommendations for first-line treatment of proliferative LN involve an induction therapy using a combination of high-dose intravenous steroids followed by oral steroids and either cyclophosphamide (CYC) or mycophenolate mofetil (MMF), then a maintenance phase with oral corticosteroids and either MMF or azathioprine.1 LN mandates long-term treatment and therefore exposes patients to corticosteroids adverse events. Recently, an observational study using no oral steroids has shown promising preliminary results.2 Therefore, the use of an alternative full steroid-free treatment regimen would be a major advance in LN. In 2001, a 37-year-old man was diagnosed with SLE based on the presence of arthritis, leucopenia, antinuclear antibodies (1:320) with positive search for anti-dsDNA and anti-Sm antibodies. He had a past medical history of gout and was treated with allopurinol. In 2003, treatment with hydroxychloroquine and intermittent oral prednisone (no more than 10 mg/day) was started for polyarthritis. In 2008, without any sign of active lupus, he …

A 44-year-old man was diagnosed with diabetes in our department in 2010, and after a short period on insulin, he was started on metformin. Autoantibodies consistent with type 1 diabetes were negative. In 2011, the patient developed hypoglycaemia, both while fasting and after physical activity, despite stopping metformin. He also developed widespread acanthosis nigricans (fi gure) and polyarthralgia, and had 10 kg weight loss. Despite recurrent hypoglycaemia, his HbA1c remained high (7·4% of total haemoglobin). After a 72 h fast, his glucose was 2·3 mmol/L, with inappropriately high serum insulin (26·3 pmol/L) and C peptide (0·1 nmol/L) concentrations. Despite fasting hypoglycaemia, 2 h after a 75 g oral glucose tolerance test (OGTT) his glucose was 12·6 mmol/L with serum insulin 1659·8 pmol/L and C peptide 2·1 nmol/L. A pancreatic endoscopic ultrasound, 111In-octreotide scintigraphy, and abdominal CT scan were normal. We also ruled out self-administration of hypoglycaemic drugs, adrenal or growth hormone defi ciency, hypothyroidism, and tumours secreting insulin-like growth factor-1 (IGF-1), IGF-2, or its precursors (big IGF-2). The patient had polyclonal hypergammaglobulinaemia, antinuclear and antiribonucleoprotein antibodies, antiextractable nuclear antigen, neutropenia, and decreased serum complement concentrations, suggestive of systemic lupus erythe matosus. Serum anti-insulin receptor antibodies (anti-IRAbs), which inhibit the binding of insulin to its receptor and exert insulin-like eff ects in vitro (appendix), led us to the diagnosis of type B insulin-resistance syndrome associated with systemic lupus erythematosus. Anti-insulin antibodies were negative. In August, 2012, we gave the patient two injections of rituximab (anti-CD 20 monoclonal antibodies) 15 days apart, with total disappearance of circulating B lymphocytes (CD19+). 3 months after treatment, the frequency of hypoglycaemia decreased and by June, 2013, his HbA1c was 5·6% and fasting test was normal (lowest glucose 3·8 mmol/L with serum insulin 4·9 pmol/L and C peptide 0·1 nmol/L). OGTT was normal, he had no episodes of hypoglycaemia during 5 days of continuous glucose monitoring, and anti-IRAbs were no longer detectable. His acanthosis nigricans decreased and he gained 4 kg of weight. Type B insulin resistance syndrome, caused by autoantibodies directed against the insulin receptor, is frequently associated with autoimmune diseases, most commonly systemic lupus erythematosus. Patients usually present with weight loss, hyperandrogenism, and widespread acanthosis nigricans, with insulin resistance, hyperadiponectinaemia, and hypo triglyceridaemia. Patients rarely develop initial or secondary hypoglycaemia, sometimes with unsuppressed insulinaemia, which might be due to defective degradation of insulin–insulin receptor complexes. Hypo glycaemia might be explained by variations in serum anti-IRAb concentration, with high antibody titres causing antagonist eff ects and low titres causing agonist eff ects. Alternatively, populations of both activating and blocking antibodies might coexist. In our patient, systemic lupus erythematosus associated anti-IRAbs were probably responsible for both hypoglycaemia and initial diabetes. After rituximab treatment, depletion of the anti-IRAbs-secreting B-cell population was associated with resolution of both hypoglycaemia and diabetes. Rituximab, which is an effi cient immunosuppressive treatment for hyperglycemia, might also be eff ective in hypoglycaemia linked to type B insulin resistance.

The current outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) represents a source of concern for the management of patients with systemic lupus erythematosus (SLE). Indeed patients with SLE have an increased risk of severe infections due to intrinsic perturbations of their immune response, the use of immunosuppressive drugs, as well as the potential presence of organ damage associated with their disease. In this context, hydroxychloroquine (HCQ), a drug that is currently part of the long-term, standard-of-care treatment for SLE, has been reported to possess antiviral activity in vitro, and recent results from a preliminary clinical trial might support its use in curative or even prophylactic treatment for COVID-19.1–3 During the first days of the COVID-19 outbreak in France, we launched an observational study with the aim to follow the clinical course of COVID-19 in patients with SLE who received long-term treatment with HCQ. To be eligible, patients with SLE had to (1) fulfil the 1997 criteria of the SLE classifications of the American College of Rheumatology or those of the 2019 European League Against Rheumatism/American College of Rheumatology4 5; (2) be on long-term treatment with HCQ; and (3) have SARS-CoV-2 carriage in their nasopharyngeal swab, as confirmed by real-time reverse transcription PCR analysis. Data …