Matthieu Mahévas

Current treatments for immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA), rare autoimmune diseases in which autoreactive B cells play a major role, can lead to high response rates; however, for many patients these responses are not durable or maintained after treatment discontinuation. Binding of B‐cell‐activating factor (BAFF) to its receptor (BAFF‐R) has been shown to lead to B‐cell differentiation, proliferation, and survival, with BAFF levels shown to be elevated in patients with ITP and wAIHA. Targeting the BAFF/BAFF‐R pathway could address unmet needs that remain for patients with ITP and wAIHA despite available treatments.

Immune imprinting profoundly shapes antibody responses to breakthrough infections and vaccination against evolving endemic viruses. Current vaccine design primarily focuses on antigen sequence and variant mutations but rarely consider the structural context in which these antigens are being recognized. In this study, we make use of the longitudinal analysis of memory B cell (MBC) responses in boosted individuals enrolled in the COVIBOOST clinical trial to provide a proof of principle that variant-specific conformational dynamics can impact MBC recruitment and protective antibody responses, independently of epitope conservation. Combining functional characterization of MBC-derived monoclonal antibodies, repertoire analysis, epitope mapping and in silico structural modeling of epitope accessibility, we found that the adjuvanted B.1.351 spike vaccine preferentially recalled MBCs targeting exposed receptor-binding domain neutralizing epitopes. This preferential recruitment arises from the more restricted conformational dynamics of the B.1.351 spike compared to the ancestral Hu-1 spike, leading to increased masking of class 4 and 5 cryptic RBD epitopes. These findings demonstrate that antigen conformational dynamics can be leveraged to redirect pre-existing immunity toward neutralizing epitopes upon boost immunization.

Les plasmocytes à longue durée de vie responsables de la production d’anticorps sont majoritairement retrouvés dans la moelle osseuse (Manz, et al 1997). D’autres sites de résidence ont été décrits, comme la rate ou les lieux de réactions immunes inflammatoires. Au cours de ce travail, nous nous sommes attachés à décrire les caractéristiques des cellules plasmocytaires responsables de la sécrétion d’anticorps pathogéniques, dans une maladie auto-immune, le purpura thrombopénique immunologique (PTI). Le PTI est une maladie caractérisée par une thrombopénie d’intensité variable associée à la présence d’anticorps anti-plaquettes à l’origine d’une destruction des plaquettes par les macrophages spléniques.Nous avons étudié la rate de ces patients dans différentes conditions pathologiques, splénectomisés en seconde ligne thérapeutique, ou après traitement par un anticorps anti-CD20 déplétant les lymphocytes B. En étudiant les tissus spléniques des patients en échec primaire du traitement par anti-CD20, nous avons mis en évidence une population plasmocytaire résiduelle splénique constituée principalement de plasmocytes, qui en l’absence de lymphocytes B proliférant, préexistaient à la déplétion B. L’analyse du transcriptome de ces plasmocytes, a révélé un profil comparable aux plasmocytes de la moelle osseuse, avec un programme à longue durée de vie. A l’inverse, les plasmocytes des donneurs sains, ainsi que les plasmocytes des patients non traités par les anti-CD20 présentaient un profil intermédiaire entre les plasmocytes à longue durée de vie et les plasmablastes. Une analyse plus fine en cellule unique a confirmée qu’il s’agissait d’une population intermédiaire. Ainsi, la déplétion lymphocytaire B (par l’anticorps anti-CD20) dans le PTI semble favoriser la différenciation en plasmocytes à longue durée de vie dans la rate de ces patients, expliquant ainsi pour certain d’entre eux l’absence de réponse thérapeutique. Nos résultats suggèrent ainsi que les modifications de l’environnement splénique par la déplétion B, pourraient promouvoir la différenciation et l’établissement de plasmocytes « normaux » en plasmocytes à longue durée de vie dans la rate, notamment par le biais de BAFF (B-cell activating factor), ouvrant la perspective à des travaux fondamentaux, et surtout à des applications cliniques qui permettraient en modulant l’environnement splénique lors du traitement anti-CD20 d’empêcher la formation des plasmocytes à longue durée de vie et donc la splénectomie.

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.

Resistance to B-cell–targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38+ long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase 2 study evaluated safety and efficacy of daratumumab in 21 patients with previously treated ITP. Following a safety run-in, 2 dosing cohorts received 8 and 10 subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary end points were safety and response (2 consecutive platelet counts ≥50 × 109/L at week 12 for the safety run-in/cohort 1, and at week 16 for cohort 2). At baseline, median platelet count was 17 × 109/L, median number of prior therapies was 4. Most treatment-emergent adverse events were transient grade 1 to 2, most commonly infections (38%). Two patients (4.7%) experienced grade 3 adverse events, 1 infusion-related reaction, and 1 severe acute respiratory syndrome coronavirus 2 infection with acute renal failure. Ten patients (48%) met the primary efficacy end point. Sustained response (2 consecutive platelet counts ≥50 × 109/L at week 24) was achieved in 8 patients (38%), of whom 2 later relapsed. Response and relapse rates did not differ between cohorts. Patient-reported quality of life measured by 36-Item Short-Form Health Survey improved in responding patients. Daratumumab decreased immunoglobulin levels in all patients, and substantially reduced CD38+ cells in peripheral blood and bone marrow. There was no significant difference in antiplatelet antibodies between responders and nonresponders. This study confirms CD38 as an important target in ITP. This trial was registered at clinicaltrials.gov as #NCT04703621, and at the European Clinical Trial Register (EudraCT #2019-004683-22).

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.

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.