Fostamatinib is available in France since October 2021 for the treatment of adult chronic immune thrombocytopenia (ITP). French health authorities requested a 3-year, prospective, multicenter registry to provide real-world evidence about the effectiveness and safety of fostamatinib. Patients' characteristics, treatment response (ongoing exposure to fostamatinib and a platelet count ≥ 30 × 10 9 /L with no rescue in the previous 4 weeks) after 3, 6, 12, and 24 months (M); bleeding; fostamatinib discontinuation; adverse drug reactions (ADRs) and other events of interest have been analyzed. In total, 164 patients were included (median age: 59 years; 55.5% women; 84.1% had previous bleeding; 30 had secondary ITP; 89.0% had chronic ITP). The median ITP duration was 7.2 years and the median number of previous ITP treatments was 6. The response rate was 44.0% (70/159) at M3, 41.9% (62/148) at M6, 32.4% (44/136) at M12 and 20.0% (21/105) at M24. Concomitant treatment (mostly TPO-RA) was used in > 60.0% of responders at each endpoint. The cumulative discontinuation rate at each endpoint was, respectively, 27.0%, 44.6%, 55.9%, and 76.2%. Seventy-one (43.3%) patients experienced at least one bleeding during fostamatinib exposure; none was fatal. One hundred adverse drug reactions (8 serious) were observed in 61 (36.7%) patients, including diarrhea in 28 (17.1%) patients, arterial hypertension in 17 (10.4%). Seven thrombosis (4.3%) and 40 infections (12 serious) were reported in 25 patients (15.2%), mostly in patients with known risk factors. In conclusion, fostamatinib in combination with TPO-RA should be considered in difficult-to-treat ITP patients. No new safety signal was observed.

Adult patients with immune thrombocytopenia (ITP) have an increased risk of venous thrombosis as compared to the general population. The management of ITP in the context of anticoagulation is challenging. We conducted an observational study in the prospective, multicenter, national CARMEN-France registry. Adult patients with newly diagnosed ITP between June 2013 and May 2022 were selected. We assessed the cumulative incidence of venous thrombosis during follow-up with death as a competing event, described these events, and assessed patient outcomes depending on management strategies, with a focus on thromboses that occurred during treatment with thrombopoietin receptor agonists (TPO-RA). Among the 1303 patients selected for this study, 53 experienced venous thrombosis. The cumulative incidence of venous thrombosis was 2.6% (95% CI: 1.8-3.7) at 1 year and 8.6% (95% CI: 5.8-12.0) at 5 years. In patients exposed to TPO-RA, the cumulative incidence was 9.3% (95% CI: 6.2-13.2) and 13.4% (95% CI: 8.6-19.2) at 1 and 5 years of exposure, respectively. Patients who experienced thrombosis were older, had more frequently a history of venous thrombosis and secondary ITP, a more severe ITP, and were more frequently treated with TPO-RAs. Twenty (37.7%) of the 53 events were atypical, including five cerebral venous thromboses. Four patients died, and seven experienced major bleeding. The analysis of different managements of ITP after the thrombotic event suggested that the safest strategy was to promptly control ITP to enable early anticoagulation, including using TPO-RAs. Long-term anticoagulation therapy should be considered in patients treated with TPO-RAs and persistent risk factors for thrombosis.

Autoimmune hemolytic anaemias (AIHAs) represent different subtypes of a rare autoimmune disease in which autoantibodies targeting autoantigens expressed on autologous red blood cells’ (RBCs) membrane are produced, leading to their accelerated destruction. In the presence of hemolytic anaemia, the direct antiglobulin test (DAT) is the cornerstone of AIHA diagnosis. AIHAs are classified according to the isotype and the thermal optimum of the autoantibody, into warm (wAIHAs), cold and mixed AIHAs. wAIHAs, by far the most frequent type of AIHAs, are associated with underlying conditions in ∼50% of cases. Among adults, cold AIHAs include cold agglutinin disease (CAD), and cold agglutinin syndrome (CAS) when there is an underlying condition. Both CAD and CAS are IgM cold-antibody driven AIHAs characterized by classical complement pathway-mediated hemolysis. The management of AIHAs which has has long been empirical is mostly based on corticosteroids±rituximab for wAIHAs and on rituximab±bendamustine for CAD requiring to be treated, complement inhibition with sutimlimab being a new therapeutic option for CAD. This article reporting the French guidelines focused on diagnosis and treatment of adult AIHAs is adapted from the last update of the Protocole National de Diagnostic et de Soins (French protocol for diagnosis and management). These guidelines have been set up and led by the French national center for adult’ immune cytopenias (CeReCAI).

In membranous lupus nephritis (LN), positivity for the target antigen exostosin 1/2 (EXT) is associated with a lower chronicity index (CI) at first biopsy and a lower risk of progression to end-stage kidney disease (ESKD) compared to EXT-negative patients. Repeat kidney biopsies (RKB) in LN may reveal increasing CI and class transition with prognostic significance. In a cohort of membranous LN with RKB, we assessed the variation in EXT and neural cell adhesion molecule 1 (NCAM1) expression and their association with class III/IV + V transition and renal outcomes. Thirty patients with 78 biopsies were enrolled. Index biopsies included 60

Mycoplasma pneumoniae (MP), primarily a respiratory pathogen, can cause extra-pulmonary manifestations including cold agglutinin syndrome (CAS). We conducted a national, multicenter, observational, ambispective study to describe the characteristics, risk factors, and outcomes of MP-associated CAS. Adult patients hospitalized for a MP-infection with CAS (hemolytic anemia with hemoglobin < 10 g/dL and C3 positive direct anti-globulin test) were included. Recovery was defined as hemoglobin > 10 g/dL off therapy. We also compared MP-infected patients with or without CAS. Sixty patients (51.7% of females; median age of 48.5 years) were included. CAS was diagnosed a median of 10 days after MP-infection symptoms onset. At diagnosis, the median hemoglobin level was 6.9 g/dL, and 71.7% of patients received red blood cell transfusions. Intensive care unit (ICU) admission was required in 45% of patients, and 16.7% experienced a venous thromboembolic event (VTE). Seventeen patients (28.3%) received glucocorticoids alone, while 40 (66.7%) did not receive any specific treatment for CAS. After a median follow-up of 56 (30-83) days, 90% of patients achieved recovery, while 2 patients (3.3%) died from sepsis and pulmonary embolism. Glucocorticoid use did not significantly impact the rate or timing of recovery. Compared with MP-infected patients from the MYCADO cohort study (n = 1267), CAS patients had significantly more VTE (p < 0.0001) and ICU admissions (p = 0.03). MP-associated CAS typically occurs 10 days after the first symptoms of MP infection and is associated with ICU admissions and VTE. Overall, the prognosis of CAS is good, and glucocorticoids do not appear to influence outcomes.

Introduction Despite the increasing number of therapeutic options for immune thrombocytopenia (ITP), refractory disease remains an unmet need in clinical practice. Anti-CD38 monoclonal antibodies such as daratumumab have recently been shown to be a promising treatment in ITP. The aim of this study was to assess safety and efficacy of daratumumab given for refractory ITP. Patients and methods We conducted an observational, retrospective, multicenter study throughout the network of the French reference center for adult' immune cytopenias including patients receiving compassionate off-label treatment by daratumumab for ITP (either primary or secondary) between 01/01/2020 and 01/06/2025. ITP was diagnosed according to international guidelines. Patients were excluded if daratumumab was given to treat plasma cell malignancy. Complete response (CR) was defined by platelet count >100x109/L and response (R) by platelet count 30 to 100x109/L with at least a 2-fold increase from baseline. Patients who required any other treatment including rescue therapy more than six weeks after first daratumumab infusion were considered non-responders regardless of platelet counts. All patients were informed and gave consent to ‘off-label’ use of daratumumab. The study received institutional review board approval (00011558, UPEC University, AP-HP). Results Twenty-one patients (43% females) with a median age at first daratumumab infusion of 67 years [range 21-88] were included in the study. Eight had secondary ITP (38%; Evans syndrome, n=6, and/or antiphospholipid syndrome (APLS), n=2, or rheumatoid arthritis, n=1). In addition, 2 patients had antibodies against GPIIb-IIIa (acquired Glanzmann syndrome, n=1) and GPVI (n=1) responsible for chronic bleeding symptoms. Median ITP duration was 78 months [range 4-594], and patients had previously received a median number of 8 [range, 3-12] treatment lines for ITP, including corticosteroids (100%), rituximab (100%), intravenous immunoglobulin (95%), thrombopoietin receptor agonists (95%; including eltrombopag [90%] and romiplostim [86%]), mycophenolate mofetil (81%), splenectomy (71%), fostamatinib (48%), and one or more other immunosuppressive drug (43%). Fifteen patients (71%) had bleeding symptoms despite treatment in the previous month. Patients received a median number of 6 [range 3-20] infusions of daratumumab either at 16mg/kg of body weight intravenously (n=10) or at a fixed dose of 1800 mg subcutaneously (n=11) with dexamethasone premedication. Daratumumab was given with other ITP treatments in 15 patients (71%). Median follow up after daratumumab was 16 months [range 1-60]. Ten (48%) patients had adverse events imputable to daratumumab, including 5 patients (24%) with infectious events requiring hospitalization (sepsis, n=2, bacterial pneumonia, n=2, acute tonsillitis, n=1), 2 patients with transient neutropenia (but without infection), and 3 patients with immediate reaction after infusion. During follow-up, 4 patients (19%) died (1 splenectomized patient had campylobacter sepsis 1 month after daratumumab initiation, 1 patient with stroke and APLS had sepsis 23 months after daratumumab, 1 patient died from refractory ITP, and 1 patient with metastatic cancer died from cardiac failure). In the 6 months following daratumumab, among the 10 patients with available gammaglobulin assessment without intravenous immunoglobulin administration, 8 (80%) had concentrations below 6g/L. Overall response (CR+PR) was achieved in 11 patients (52%), including 9 CR (43%), and 2 PR (10%), with a median time to response of 35 days [range 7-84]. Relapses occurred in 3/7 (43%) of responders that had a follow-up >6 months after daratumumab. Four patients had long-lasting CR without any other ITP treatment, with relapses in 2 (50%) after 10 and 32 months, respectively. Two patients with initial CR and experiencing a relapse had a second course of daratumumab, resulting in 2 new initial CR but eventually with relapses in both patients. Discussion Overall, these results suggest that daratumumab has the potential to induce durable remissions even in multirefractory ITP patients, although response appears transient in most responders. However, this came at the cost of a high rate of severe infections in this particular group of heavily treated, frequently splenectomized, immunocompromised and fragile patients. Careful assessment of benefit/risk balance is therefore warranted before daratumumab administration.

To assess efficacy and safety of dapsone in adult immune thrombocytopenia (ITP), a multicenter randomized controlled trial (RCT) and a real-word study cohort were performed. Participants were adults with primary ITP, transient response to corticosteroids ± intravenous immunoglobulin, and a platelet count ≤ 30x109/L (or ≤ 50x109/L with bleeding). Patients in the RCT were randomized in arm A (prednisone x3weeks+dapsone for 12 months) or arm B (prednisone alone). The observational study involved dapsone initiation at 100 mg/d with standard follow-up. The primary endpoint was the response rate (platelet count >30x109/L and ≥2×baseline) at 52 weeks, with the response rate at 24 weeks and adverse events as secondary endpoints. The RCT enrolled 93 patients (54.8% female), median age 48.5 years (46 in arm A, 47 in arm B). In the intention-to-treat analysis, 78.3% of patients in group A discontinued dapsone after a median of 4.6 weeks due to adverse events (66.7%) or lack of efficacy (33.3%). The response rate at week 52 was 21.7% (95% CI:10.9%-36.4%) in group A versus 8.5% (95% CI:2.7%-18.6%) in group B (p=0.17). The observational study, which was conducted after the end of the RCT, included 46 patients (52.2% female), median age 50.7 years. Adverse events occurred in 30.4%, leading to discontinuation of dapsone in 23.9%, and 13.6% (95% CI: 5.2%-27.4%) met the primary efficacy endpoint. Results from both studies showed an unfavorable risk-benefit ratio for the use of dapsone in adult primary ITP and suggest that, whenever available, second-line options should be used. NCT02627417, NCT02877706

INTRODUCTION:Mixed connective tissue disease (MCTD) is a rare systemic disorder that belongs to connective tissue diseases (CTD). Few studies are available on MCTD treatment. METHODS:We conducted an observational study within the French MCTD cohort. Data were collected at diagnosis, during follow-up, and at the last follow-up (LFU). We studied three treatment groups i) no treatment, ii) hydroxychloroquine (HCQ) and/or glucocorticoids (GC) and iii) disease-modifying antirheumatic drugs (DMARDs)/immunosuppressant (IS). RESULTS:Three hundred and fifteen patients were included and followed for 96 [40-156] months. At MCTD diagnosis, 52 (16.5 %) patients were treatment-free, while 224 (71.1 %) received GC and/or HCQ and 39 (12.4 %) received DMARDs and/or IS. During follow-up, 10 (3.2 %) patients remained treatment-free, and 77 (24.4 %) were GC-free. Most patients (n = 271; 85.8 %) received HCQ, and 161 (51.1 %) were treated with DMARDs and/or IS. DMARDs and/or IS, including anti-B cell therapeutics, were more frequently prescribed in patients with musculoskeletal involvement (p < 0.0001), interstitial lung disease (ILD, p < 0.0001) and/or pulmonary arterial hypertension (PAH, p < 0.01). Patients in clinical remission and those who did not evolve to a differentiated CTD (MCTD-dCTD) received significantly less frequently DMARDs and/or IS (including anti-B cell therapeutics; p < 0.0001 for both). Patients who received HCQ at MCTD diagnosis appeared to develop less frequently ILD or PAH (p < 0.05). CONCLUSION:HCQ and GC were the cornerstones of MCTD treatment and were sufficient to control disease manifestations in nearly half of the patients, reflecting the good prognosis of this disease. DMARDs and IS were used for musculoskeletal involvement, PAH/ILD, and in MCTD-dCTD patients.

Durable responses with front-line rituximab in autoimmune cytopenias associated with indolent B-Cell clones.

Only few data are available regarding the efficacy and safety of thrombopoietin receptor agonists (TPO-RAs) for treating systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS)-associated immune thrombocytopenia (ITP). We retrospectively assessed the efficacy and safety of TPO-RAs in 80 adults with ITP in three subgroups: (1) 37 patients with definite or incomplete SLE and no antiphospholipid antibodies (APAs), (2) 27 patients with definite or incomplete SLE associated with APAs and no history of arterial or venous thrombotic events (TEs) and (3) 16 patients with APS. In total, 39 (48.8%) patients received eltrombopag, 14 (17.5%) romiplostim and 27 (33.8%) both TPO-RAs sequentially. The overall response of ITP was 78.8%. In total, 17 (21.3%) patients had 21 TEs (7 venous and 14 arterials, including 3 catastrophic APS); 3 were fatal. The rate of TEs was 8.1% in the SLE or lupus without APAs group, 22.2% in the SLE or lupus with APAs group and 50% in the APS group. In 12 patients, TPO-RAs were continued after TE onset, combined with an anticoagulant (n = 12) and/or an antiplatelet agent (n = 3). Only one TE relapse occurred in the nine patients with TPO-RAs maintained and combined with an anticoagulant after TE. TPO-RAs may be effective safe in ITP associated with SLE and no APAs. Their use should be carefully considered in the presence of thrombotic risk factors and/or APA positivity and should be avoided in patients with definite APS. When a TE occurs, risk of relapse is low with maintenance of the TPO-RA combined with anticoagulation.

Autoimmune hemolytic anemias (AIHA) encompass with three main different subtypes based on the properties of the autoantibody: warm AIHA (wAIHA), cold agglutinin disease/syndrome (CAD/CAS; i.e., primary/secondary AIHA with exclusively cold antibodies, respectively), and mixed AIHA (mAIHA). The epidemiology of AIHA has been assessed using retrospective cohort studies including up to 308 patients, or cohorts based on claims databases that often lack detailed clinical and biological data. This study aimed to describe the clinical and biological characteristics at diagnosis of AIHA by subtypes, in a multicenter, prospective cohort in France. The data source was the Carmen-France Registry, that includes prospectively all adults with AIHA in the 50 participating centers. We selected the patients included between January 2015 and February 2025. AIHA diagnosis was based on international consensus criteria. The clinical and biological characteristics of patients at AIHA onset were described, as well as the causes of secondary AIHA, and the treatments used within the first week following the diagnosis. During the study period, 413 AIHA patients were included in the registry: 283 (68.5%) had wAIHA, 64 had CAD/CAS (15.5%), and 66 (16.0%) had mAIHA. The median age at diagnosis was 69 years (Q1-Q3: 56-79) and was similar between AIHA subtypes. There was a slight male predominance among wAIHA patients (148 males, 52.3%), and a female predominance among CAD/CAS (42 females, 65.6%) and mAIHA patients (38 females, 57.6%). A Charlson Comorbidity Index median score ≥1 was more frequent among the patients with wAIHA and mAIHA than CAD/CAS (respectively, 49.8%, 60.6% and 39.1%). Before AIHA diagnosis, 225 (54.5%) patients had cardiovascular risk factors: 150 (36.3%) had hypertension, 66 (16.0%) had dyslipidemia, 58 (14.0%) had diabetes, and 45 (10.9%) patients had active or recent cessation of smoking. In total, 51 (12.3%) patients had a history of arterial thrombosis, and 42 (10.2%) of venous thrombosis. At AIHA onset, 40 (62.5%) patients had symptoms of anemia in CAD/CAS versus 212 (74.9%) and 48 (72.7%) in wAIHA and mAIHA, respectively. In wAIHA, 123 (43.5%) had jaundice versus 18 (28.1%) and 19 (28.8%) in CAD/CAS and mAIHA, respectively. Clinical splenomegaly was present in 21.2% of wAIHA (primary: 14.0%; secondary: 30.2%) and 22.7% of mAIHA. Cardiac failure was present in 3.9% of patients and coronary insufficiency in 1.2%. The hemoglobin level was 71 g/L (Q1-Q3: 59-85) in wAIHA, 77 g/L (Q1-Q3: 66-94) in mAIHA, and 87 g/L (Q1-Q3: 76-99) in CAD/CAS. The levels of hemolytic markers were similar between groups. In the overall population, the lactate dehydrogenase level was 450 U/L (Q1-Q3: 338-666), the total bilirubinemia level was 38 µmol/L (Q1-Q3: 22-60), and the total haptoglobin level was 0.08 g/L (Q1-Q3: 0.00-0.10). We identified 126 secondary wAIHA (44.5% of wAIHA), 27 CAS (42.2% in CAD/CAS group), and 20 secondary mAIHA (30.3% of mAIHA). B cell clonal lymphoproliferative diseases were predominant in all AIHA subtypes (wAIHA: 55.6%; CAS: 44.4%; mAIHA 70.0%). In secondary wAIHA, the most frequent cause was chronic lymphocytic leukemia (23.0%) followed by marginal zone lymphoma (12.7%). Other autoimmune diseases were found in up to 25.4 % of wAIHA. Infections were the second causes of CAS (33.3%) including 5 (18.5%) patients with Mycoplasma pneumoniae infection. In secondary wAIHA, 10.3% of patients had systemic lupus erythematosus and 6.3% had antiphospholipid syndrome. Drug-induced wAIHA concerned 12 patients (n=5 immune checkpoint inhibitors; n=3 antibiotics). During the first week after AIHA diagnosis, wAIHA patients mostly received corticosteroids: 226 (80.0%) versus 28 (42.4%) and 10 (15.6%) in mAIHA and CAD/CAS, respectively. Red blood cell transfusion was required in 99 (35.0%) wAIHA patients, 20 (31.3%) CAD/CAS patients, and 16 (24.2%) mAIHA patients. During this early period, rituximab was introduced in 34 (12.0%) wAIHA patients, 6 (9.1%) mAIHA patients, and 3 (4.7%) CAD/CAS patients. Erythropoietin was scarcely used in all subtypes (wAIHA: 6.0%; CAD/CAS: 7.8%; mAIHA: 9.1%).In conclusion, age at AIHA diagnosis was similar between subtypes. AIHA was a severe disease with red blood cell transfusion requested at diagnosis in one quarter to one third of patients. The hemoglobin level was higher in cAIHA than in wAIHA and mAIHA. Rituximab was used early after wAIHA diagnosis in 12% of patients.