Search

Not available.

Abstract Background Vinblastine is the standard treatment for children with Langerhans cell histiocytosis (LCH). Whether this treatment could be extended to adults with LCH is questionable. This retrospective multicenter study included 35 adult patients (median age 33 years; 23 men; 80% with multisystem LCH) who were treated with vinblastine + steroids as a first-line chemotherapy and followed for a median time of 83 months. The objectives were to determine the overall response rate (based on the Histiocyte Society criteria), disease reactivation rate, toxicity, permanent consequences, and survival rate corresponding to this treatment. The lung involvement outcome was based on serial lung function tests. The distribution of right-censored end points was estimated by the Kaplan-Meier method. Univariate Cox model with time-fixed and time-varying covariates was used for the predictive analysis of reactivation in the responders. Univariate analyses of risk factors for neurotoxicity were based on nonparametric Wilcoxon rank sum tests and exact Fisher tests. Results The median duration of the first course of vinblastine was 7.6 months, with a median cumulative dose of 160 mg [IQR 120–212]. Seventy percent of the patients were responders at the end of this treatment. Subsequently, LCH reactivation occurred with a 5-year cumulative incidence of 40%. During the study, 27 reactivations were observed in 17 patients, and half of these episodes were retreated with vinblastine. At the end of the last vinblastine treatment, 70% of the patients were responders. None of the patients with impaired lung function improved. No grade 3–4 peripheral neuropathy was observed. At the final vinblastine treatment, permanent LCH consequences, primarily pituitary stalk involvement, were present in 15 (43%) patients, and all were present at the time of vinblastine initiation. The 10-year survival rate was 86.2% (95CI, 71.8–100%), and the 2 patients who died from LCH had risk organ localizations. Conclusions Vinblastine is an effective and well-tolerated first-line treatment for adult LCH except in patients with lung involvement and impaired lung function. However, a significant portion of patients experienced LCH reactivation during long-term follow up. As in childhood LCH, the presence of risk organ involvement has a negative impact on patient prognosis.

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

IntroductionThis study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies.MethodsAmong a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up.ResultsAmong the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21–22], p

Abstract Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients’ association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Objectives We aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality.Methods We analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP).Results From 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia

Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.

Abstract Objectives Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder. Diagnosing AOSD can be challenging, as disease presentation and clinical course are highly heterogeneous. For unclear reasons, a few patients develop life-threatening complications. Our objective was to determine whether these cases resulted from therapeutic delay or could represent a peculiar AOSD subset. Methods We conducted a multicentre retrospective study of 20 AOSD patients with organ failure requiring intensive care unit admission and 41 control AOSD patients without organ failure. Clinico-biological data at hospital admission were explored using supervised analyses and unsupervised dimension reduction analysis (factor analysis of mixed data, FAMD). Results Disease duration before admission was shorter in patients with life-threatening AOSD (median, 10 vs 20 days, p = 0.007). Disease duration before AOSD therapy initiation also tended to be shorter (median, 24 vs 32 days, p = 0.068). Despite this shorter disease duration, FAMD, hierarchical clustering and univariate analyses showed that these patients exhibited distinctive characteristics at first presentation, including younger age; higher frequency of splenomegaly, liver, cardiac and/or lung involvement; less frequent arthralgia; and higher ferritin level. In multivariate analysis, 3 parameters predicted life-threatening complications: lack of arthralgia, younger age and shorter time between fever onset and hospitalisation. Conclusion This study suggests that life-threatening complications of AOSD occur very early, in a peculiar subset, which we propose to name catastrophic adult-onset Still’s disease (CAOSD). Its exact burden may be underestimated and remains to be clarified through large multicentre cohorts. Further studies are needed to identify red flags and define the optimal therapeutic strategy.

Abstract Background Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. Methods This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). Results Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P

Abstract Objective To report on the characteristics and long-term course of rheumatic manifestations in Schnitzler syndrome (SchS). Methods A retrospective cohort study of patients with SchS followed between 2000 and 2020. Inclusion criteria included a diagnosis of SchS (Strasbourg criteria). All available bone scans were reviewed and scored according to the intensity and number of pathological sites. The scintigraphic score was compared with the clinical activity score, CRP level, and treatments. Results Twenty-five patients were included. Median age at diagnosis was 68 years. Eighty patients (72%) had SchS-related rheumatic pain. Most patients had a long-standing isolated rash before constitutional and/or rheumatic symptoms appeared. The monoclonal component level was usually very low (IgMκ in 22/25). Rheumatic pain predominated around the knees. Bone scans revealed abnormal tracer uptake in 15/18 (85%). The scintigraphic score correlated with clinical activity (r = 0.4, p

Aims: To identify factors associated with vascular events in patients with giant cell arteritis (GCA). Methods: We performed a retrospective study of GCA patients diagnosed over a 20-year-period, who all underwent vascular imaging evaluation at diagnosis. Symptomatic vascular events were defined as the occurrence of any aortic event (aortic dissection or symptomatic aortic aneurysm), stroke, myocardial infarction, limb or mesenteric ischemia and de novo lower limbs arteritis stage 3 or 4. Patients with symptomatic vascular event (VE+) and without were compared, and risk factors were identified in a multivariable analysis. Results: Thirty-nine (15.4%) of the 254 included patients experienced at least one symptomatic vascular event during follow-up, with a median time of 21.5 months. Arterial hypertension, diabetes, lower limbs arteritis or vascular complication at diagnosis were more frequent in VE+ patients ( p

Background: Giant cell arteritis (GCA) is the most common systemic vasculitis. Relapses are frequent. The aim of this study was to identify relapse risk factors in patients with GCA with complete large-vessel imaging at diagnosis. Methods: Patients with GCA followed in our institution between April 1998 and April 2018 were included retrospectively. We included only patients who had undergone large vascular imaging investigations at diagnosis by computed tomography (CT)-scan and/or positron emission tomography (PET)-scan and/or angio-magnetic resonance imaging (MRI). Clinical, biological, and radiological data were collected. Relapse was defined as the reappearance of GCA symptoms, with concomitant increase in inflammatory markers, requiring treatment adjustment. Relapsing patients (R) and non-relapsing patients (NR) were compared. Relapse and multiple relapses (>2) risk factors were identified in multivariable Cox analyses. Results: This study included 254 patients (73.2% women), with a median age of 72 years at diagnosis and a median follow up of 32.5 months. At diagnosis, 160 patients (63%) had an inflammatory large-vessel involvement on imaging, 46.1% (117 patients) relapsed at least once, and 21.3% (54 patients) had multiple relapses. The median delay of first relapse after diagnosis was 9 months. The second relapse delay was 21.5 months. NR patients had more stroke at diagnosis than R ( p = 0.03) and the brachiocephalic trunk was involved more frequently on CT-scan ( p = 0.046), as carotids ( p = 0.02) in R patients. Multivariate Cox model identified male gender [hazard ratio (HR): 0.51, confidence interval (CI) (0.27–0.96), p = 0.04] as a relapse protective factor, and peripheral musculoskeletal manifestations [HR: 1.74 (1.03–2.94), p = 0.004] as a relapse risk factor. Peripheral musculoskeletal manifestations [HR: 2.78 (1.23–6.28), p = 0.014], negative temporal artery biopsy [HR: 2.29 (1.18–4.45), p = 0.015], large-vessel involvement like upper limb ischemia [HR: 8.84 (2.48–31.56), p = 0.001] and inflammation of arm arteries on CT-scan [HR: 2.39 (1.02–5.58), p = 0.04] at diagnosis were risk factors of multiple relapses. Conclusion: Male gender was a protective factor for GCA relapse and peripheral musculoskeletal manifestations appeared as a relapsing risk factor. Moreover, this study identified a particular clinical phenotype of multi-relapsing patients with GCA, characterized by peripheral musculoskeletal manifestations, negative temporal artery biopsy, and large-vessel involvement with upper limb ischemia or inflammation of arm arteries. Plain language Summary At giant cell arteritis diagnosis, large-vessel inflammatory involvement is predictive of multiple relapses 46.1% of patients with GCA relapse, and 21.3% undergo multiple relapses; Male gender appears as a protective factor for relapsing in GCA; Peripheral musculoskeletal manifestations are a relapse and multiple relapses risk factor; A negative temporal artery biopsy is predictive of multiple relapses; Large-vessel involvement is predictive of multiple relapses.

Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare life-threatening thrombotic microangiopathy requiring urgent therapeutic plasma exchange (TPE). However, the exact impact of a slight delay in TPE initiation on the subsequent patients’ outcome is still controversial. Aim We aimed to study the frequency, short-term neurological consequences, and determinants of diagnostic delay in iTTP. Methods We conducted a retrospective monocentric study including patients with a first acute episode of iTTP (2005–2020) classified into 2 groups: delayed (>24h from first hospital visit, group 1) and immediate diagnosis (≤24h, group 2). Results Among 42 evaluated patients, 38 were included. Eighteen cases (47%) had a delayed diagnosis (median: 5 days). The main misdiagnosis was immune thrombocytopenia (67%). The mortality rate was 5% (1 death in each group). Neurological events (stroke/TIA, seizure, altered mental status) occurred in 67% vs 30% patients in group 1 and 2, respectively (p = 0.04). Two patients in group 1 exhibited neurological sequelae. The hospital length of stay was longer in group 1 (p = 0.02). At the first hospital evaluation, potential alternative causes of thrombocytopenia were more prevalent in group 1 (33% vs 5%, p = 0.04). Anemia was less frequent in group 1 (67% vs 95%, p = 0.04). All patients had undetectable haptoglobin levels. By contrast, 26% of schistocytes counts were Conclusion Diagnostic delay is highly prevalent in iTTP, with a significant impact on short-term neurological outcome. In patients with profound thrombocytopenia, the thorough search for signs of incipient organ dysfunction, systematic hemolysis workup, and proper interpretation of schistocytes count are the key elements of early diagnosis of TTP.

BackgroundSchnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown.ObjectiveTo determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel.MethodsWe collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology.ResultsSpontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04).ConclusionOur data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.

Abstract Background Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course and phenotype of life-threatening AOSD, including response to therapy and long-term outcome. Methods A multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review. Results Twenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high (median: 29,110 ng/mL). Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effective. After ICU discharge, most patients required additional treatment. Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively. Conclusions AOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.

In this study, we aimed at evaluating the contribution of an extended myositis-related antibodies (Abs) determination by immunoblot to the diagnosis, classification, and prognosis of idiopathic inflammatory myositis (IIM). Medical records of all the patients (n = 237) with myositis-related Ab requests addressed to our department over a one-year period were retrospectively analyzed. Patients were classified as IIM, auto-immune disease (AID) other than IIM, and other diagnosis, and examined for their Ab profiles as determined by immunoblot. Ab positivity was qualified semi-quantitatively as low or strong according to the manufacturer’s recommendations. Among the 45 Ab-positive patients, 49% were diagnosed an IIM, 22% another AID, and 29% another diagnosis. The clinico-serological patterns of the myositis-related Ab+ patients fully recapitulated those described in the literature. Among non-IIM patients, anti-PM-Scl was the most frequently detected Ab (38%), followed by anti-Mi-2 (15%), and anti-OJ (12%). Importantly, strong Ab positivity was significantly more detected in IIM vs. non-IIM patients (82% vs. 35%; p = .002). This difference was further increased when comparing MSAs only (95% vs. 36%; p = .0004). Accordingly, strong Ab positivity associated with high specificity (96%) and positive likelihood ratio (pLR =12) for IIM. Our data suggest that while myositis-related Ab, including MSA, can be detected by immunoblot in non-IIM patients, strong positivity is nevertheless highly predictive of IIM. In conclusion, this work suggests that relevant clinical contribution to IIM is provided by the immunoblot determination of myositis-related Ab, more especially when considering strong positive detection of MSA.

BackgroundDendritic cells (DC) and regulatory cells (Treg) play pivotal roles in controlling both normal and autoimmune adaptive immune responses. DC are the main antigen-presenting cells to T cells, and they also control Treg functions. In this study, we examined the frequency and phenotype of DC subsets, and the frequency and function of Treg from patients with ANCA-associated vasculitis (AAV).Methodology/principal findingsBlood samples from 19 untreated patients with AAV during flares and before any immunosuppressive treatment were analyzed, along with 15 AAV patients in remission and 18 age-matched healthy controls. DC and Treg numbers, and phenotypes were assessed by flow cytometry, and in vitro suppressive function of Treg was determined by co-culture assay. When compared to healthy volunteers, absolute numbers of conventional and plasmacytoid DC were decreased in AAV patients. During the acute phase this decrease was significantly more pronounced and was associated with an increased DC expression of CD62L. Absolute numbers of Treg (CD4(+)CD25(high)CD127(low/-) Tcells) were moderately decreased in patients. FOXP3 and CD39 were expressed at similar levels on Treg from patients as compared to controls. The suppressive function of Treg from AAV patients was dramatically decreased as compared to controls, and this defect was more pronounced during flares than remission. This Treg functional deficiency occurred in the absence of obvious Th17 deviation.ConclusionIn conclusion, these data show that AAV flares are associated with both a decrease number and altered phenotype of circulating DC and point to a role for Treg functional deficiency in the pathogenesis of AAV.