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Etienne Crickx,1,2 Matthieu Mahévas,1,3,4 Marc Michel,1 Bertrand Godeau1 1Service de Médecine Interne, Centre national de référence des cytopénies auto-immunes de l’adulte, Hôpital Henri Mondor, Fédération Hospitalo-Universitaire TRUE InnovaTive theRapy for immUne disordErs, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris Est Créteil, Créteil, France; 2Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Paris, F-75015, France; 3Institut Necker Enfants Malades (INEM), INSERM U1151/CNRS UMS 8253, ATIP-Avenir Team AI2B, Université de Paris, Université Paris-Est-Créteil, Paris, France; 4INSERM U955, équipe 2, Université Paris-Est Créteil (UPEC), Créteil, FranceCorrespondence: Bertrand Godeau, Service de Médecine Interne, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris (AP-HP), 51 avenue du maréchal de Lattre de Tassigny, Créteil, 94000, France, Tel +331 49 81 29 05, Fax +331 49 81 29 02, Email bertrand.godeau@aphp.frAbstract: Many epidemiological studies have shown that the incidence of immune thrombocytopenia (ITP) increases after age 60 years and peaks in patients over age 80 years. Therefore, ITP is a concern for physicians taking care of older patients, especially regarding its diagnosis and management. The diagnostic work-up should exclude other causes of thrombocytopenia and secondary ITP, including myelodysplastic syndrome and drug-induced ITP. The treatment decision is influenced by an increased risk of bleeding, infectious diseases and thrombosis in this population and should take into account comorbidities and concomitant medications such as anticoagulant drugs. First-line treatment is based on short corticosteroids courses and intravenous immunoglobulin, which should be reserved for patients with more severe bleeding complications, with their higher risk of toxic effects as compared with younger patients. Second-line treatment should be tailored to the patient’s history, comorbidities and preferences. Preferred second-line treatments are thrombopoietin receptor agonists for most groups and guidelines given their good efficacy/tolerance ratio, but the thrombotic risk is increased in older people. Other second-line options that can be good alternatives depending on the clinical context include rituximab, dapsone, fostamatinib or immunosuppressive drugs. Splenectomy is less often performed but remains an option for fit patients with chronic refractory disease. Emerging treatments such as Syk or Bruton tyrosine kinase inhibitors and FcRn antagonists are becoming available for ITP and may modify the treatment algorithm in the near future. The aim of this review is to describe the particularities of the diagnosis and treatment of ITP in older people, including the response and tolerance to the currently available drugs. We also discuss some situations related to co-morbidities that can frequently lead to adapt the management strategy in older patients.Keywords: immune thrombocytopenia, ITP, elderly, intravenous immunoglobulin, IVIg, thrombopoietin receptor agonists, splenectomy, rituximab

Le purpura thrombopénique immunologique (PTI) multiréfractaire se définit comme l'échec successif des deux agonistes du récepteur de la thrombopoïétine (ARTPO), du rituximab, de la splénectomie (ou contre-indication ou refus) et la nécessité de poursuivre un traitement. La démarche devant un PTI multiréfractaire doit être systématique et implique en premier lieu de reconsidérer le diagnostic. Les thrombopénies constitutionnelles, les hémopathies lymphoïdes et myélodysplasies sont les principales causes à évoquer. Le PTI multiréfractaire est souvent associé à un PTI secondaire avec des signes d'auto-immunité cliniques ou biologiques, une gammapathie monoclonale de signification indéterminée et une moindre réponse à la corticothérapie. La prise en charge thérapeutique est complexe et repose sur l'association de traitements. De nouvelles thérapeutiques sont en cours de développement. Multirefractory immune thrombocytopenia (ITP) is defined by the absence of response to TPO receptor agonists, rituximab and splenectomy (or contraindicated or refused) and the need of treatment. The approach to multirefractory ITP must be systematic and firstly involves reconsidering the diagnosis. Inherited thrombocytopenia, lymphoid hemopathies and myelodysplastic syndrome are the main causes to be mentioned. Multirefractory ITP is often associated with secondary ITP with signs of clinical or biological autoimmunity, monoclonal gammopathy of undetermined significance and a poor response to corticosteroids. Therapeutic management is complex and is based on the combination of treatments. New treatments are being developed. [ABSTRACT FROM AUTHOR]

Rituximab has been used for immune thrombocytopenia (ITP) for almost 20 years and is now considered a valid off-label second-line treatment. About 60% to 70% of patients with ITP show initial response to rituximab, but in half of these patients, the disease will eventually relapse. Therefore, in 30% of patients with persistent or chronic ITP, one course of rituximab at 375 mg/m2/week for 4 weeks or 2 fixed 1000-mg rituximab infusions allows for a sustained response rate at 5 years. Unfortunately, to date, no robust predictor of long-term sustained response has been found to assist the physician in deciding to treat with rituximab on an individual basis, and the choice of rituximab or another second-line treatment must be individualized and shared with the patient. Retreatment with rituximab has been found efficient, with a similar or higher magnitude and duration of response in most patients. Rituximab is usually well tolerated, with mainly mild and easily manageable infusion-related adverse events. Severe infections are uncommon, including in the long-term, and occur in patients with at least another contributing factor in more than two thirds. Several issues remain to be resolved. Indeed, head-to-head comparisons with other and new treatments in ITP and robust predictors of long-term response are urgently needed to better determine the position of rituximab in the therapeutic armamentarium for adult ITP. Additionally, the place of combination therapies, maintenance therapy with rituximab and rituximab in newly-diagnosed ITP deserve additional studies. [ABSTRACT FROM AUTHOR]

Le syndrome d'activation lympho-histiocytaire (SALH) est un syndrome rare, souvent secondaire à des pathologies infectieuses, notamment chez les immunodéprimés. Nous décrivons ici un cas rare de SALH secondaire à une nocardiose disséminée et une infection pulmonaire à Streptomyces spp. Une femme de 69 ans notait l'apparition progressive de nodules sous-cutanés des avant-bras et des lombes, associée à une neuropathie périphérique et un nodule pulmonaire du lobe supérieur droit. La biopsie cutanée retrouvait un granulome. Les lésions cutanées s'aggravaient et la patiente présentait un SALH avec probable atteinte cardiaque et neurologique, associé à une granulomatose cutanée et une prolifération lymphocytaire polyclonale diffuse. La PCR spécifique Nocardia était positive sur la biopsie cutanée et les prélèvements respiratoires revenaient positifs à Streptomyces spp en culture et Nocardia en PCR. L'évolution sous traitement antibiotique était favorable. La découverte d'un SALH doit toujours faire rechercher une étiologie infectieuse. Devant l'absence d'étiologie évidente d'un SALH, l'hypothèse d'une infection à germe à croissance exigeante tels que Nocardia ou Streptomyces doit être évoquée. Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome frequently secondary to infectious disease, especially in immuno-compromised patients. We report a HLH secondary to disseminated nocardiosis and Streptomyces spp pulmonary infection. A 69-years-old women had recent subcutaneous nodules of the forearms and loins associated with peripheral neuropathy and pulmonary nodule of the right upper lobe. Cutaneous biopsy revealed granuloma. Cutaneous lesions worsened and the patient developed a HLH with probable cardiac and neurological involvement, associated with cutaneous granulomatosis and diffuse polyclonal lymphocyte proliferation. Nocardia PCR was positive in cutaneous biopsy. Pulmonary samples revealed Streptomyces in culture and Nocardia in PCR. The evolution under antibiotic treatment was favorable. Recent diagnosis of HLH without obvious etiology should lead to etiological investigation, including the search for infections with slow-growing bacteria such as Nocardia or Streptomyces spp. [ABSTRACT FROM AUTHOR]

L'incidence du purpura thrombopénique immunologique (PTI) augmente avec l'âge. Si les études observationnelles ont montré qu'un âge ≥ 65 ans modifiait la présentation et la prise en charge du PTI, peu de données sont disponibles concernant les patients très âgés. L'objectif de cette étude était de décrire la présentation et la prise en charge des PTI primaires survenant chez les patients très âgés (≥ 80 ans ; groupe 1) en comparaison avec celui des patients âgés (≥ 65–79 ans ; groupe 2). La source de donnée était le registre CARMEN-France. Le registre Cytopénies Auto-immunes : Registre Midi-PyréneEN (CARMEN) a pour but le suivi prospectif de tous les PTI incidents de l'adulte (≥ 18 ans) dans la région Midi-Pyrénées depuis juin 2013. Ce registre a été étendu en premier lieu au centre national de référence du PTI (Créteil) depuis octobre 2015, prenant alors le nom de CARMEN-France. Les critères d'inclusion dans la présente étude étaient : inclusion dans le registre CARMEN-France entre juin 2013 et décembre 2018 ; âge 365 ans au diagnostic du PTI ; PTI primaire défini selon les critères internationaux (plaquettes < 100 × 109/Litre et exclusion des autres causes de thrombopénie) et un myélogramme normal. Les patients étaient en groupes 1 et 2 selon l'âge au diagnostic de PTI. Nous avons comparé les caractéristiques des patients, la présentation du PTI et l'exposition aux traitements de première et seconde ligne. Nous avons également recherché les facteurs associés aux saignements et aux saignements graves (hématurie, saignement gastro-intestinal ou intracrânien) au diagnostic du PTI dans le groupe 1 en utilisant des modèles de régression logistique. Parmi les 541 patients inclus dans le registre CARMEN-France, 184 remplissaient les critères d'inclusion : 87 dans le groupe 1 et 97 dans le groupe 2. L'âge moyen était de 85,7 ans dans le groupe 1 versus 71,8 dans le groupe 2. Le sex-ratio était similaire (63,2 % vs 60,8 % d'hommes). Les patients dans le groupe 1 avaient plus de comorbidités (score de Charlson ≥ 1 : 67,4 % versus 47,9 %) et de polymédication (34 médicaments : 63,3 % vs 45,4 %) ; ils étaient plus fréquemment exposés aux antiagrégants plaquettaires et aux anticoagulants (37,9 % versus 23,7 %). La numération de plaquettaire moyenne au diagnostic était similaire (22,0 versus 18,0 × 109/L). Les fréquences de saignement au diagnostic était similaire (58,6 % versus 54,6 %) tout comme celles des saignements muqueux (25,3 % versus 26,8 %) mais les saignements sévères étaient plus fréquents dans le groupe 1 (10,3 % versus 4,1 %). La fréquence de tous les saignements et des saignements muqueux était plus importante dans les deux groupes si la numération plaquettaire était < 20 × 109/L. Les saignements sévères survenaient toujours lorsque la numération plaquettaire était < 20 × 109/L dans le groupe 2, alors qu'ils survenaient pour n'importe quelle numération plaquettaire dans le groupe 1. La fréquence de traitement était similaire (85,1 % dans le groupe 1 et 80,4 % dans le groupe 2). Les patients du groupe 1 étaient plus fréquemment exposés aux en première ligne (58,1 % versus 48,7 %). Des traitements de seconde ligne étaient prescrits chez 39,1 % et 37,5 % des patients, respectivement, avec une répartition similaire (préférentiellement des agonistes du récepteur de la thrombopoïétine ; 13,8 % vs 13,4 %). En analyse multivariée, les principaux facteurs associés à la présence d'un saignement dans le groupe 1 étaient le sexe féminin (odds ratio [OR] : 4,75 ; intervalle de confiance à 95 % [IC95 %] : 1,31–17,32) et une numération plaquettaire < 20 × 109/L (OR : 10,05 ; IC95 % : 4,83–67,39). En analyse univariée, le principal facteur associé à la présence d'un saignement grave dans le groupe 1 était l'exposition aux anticoagulants (OR : 7,61 ; IC95 % 1,77–32,83). En comparaison aux patients âgés, les patients très âgés atteints de PTI ont présenté plus de saignements graves malgré une numération plaquettaire moyenne semblable ; ils avaient plus de comorbidités, de polymédication et d'exposition aux antithombotiques. L'âge ≥ 80 ans n'affectait pas la fréquence du traitement du PTI ni le choix du traitement de deuxième ligne. Chez les patients de 80 ans et plus, le sexe féminin et une numération plaquettaire < 20 × 109/L étaient les principaux facteurs associés au saignement, et l'exposition aux anticoagulants (et non la numération plaquettaire) était fortement associée aux saignements graves. [ABSTRACT FROM AUTHOR]

The choice between thrombopoietin receptor agonists (TPO-RAs) and anti-CD20 as the preferred second-line therapies for immune thrombocytopenia remains in the eye of the beholders. Each has major advantages and certain weaknesses. Stolz et al. describe a single-centre experience that whets our appetite for a large randomized controlled trial comparing a TPO agonist and an anti-CD20 agent. Commentary on: Stolz et al. Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia - A single center retrospective analysis. Br J Haematol 2024; 205:1121-1125., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we profiled circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-reactive CD3 + CD4 + CD154 + T cells in children and adults before infection, during infection, and 11 months after infection, stratifying children into separate age groups and adults according to disease severity. During SARS-CoV-2 infection, children younger than 5 years old displayed a lower antiviral CD4 + T cell response, whereas children older than 5 years and adults with mild disease had, quantitatively and phenotypically, comparable virus-reactive CD4 + T cell responses. Adults with severe disease mounted a response characterized by higher frequencies of virus-reactive proinflammatory and cytotoxic T cells. After SARS-CoV-2 infection, preschool-age children not only maintained neutralizing SARS-CoV-2-reactive antibodies postinfection comparable to adults but also had phenotypically distinct memory T cells displaying high inflammatory features and properties associated with migration toward inflamed sites. Moreover, preschool-age children had markedly fewer circulating virus-reactive memory B cells compared with the other cohorts. Collectively, our results reveal unique facets of antiviral immunity in humans at a young age and indicate that the maturation of adaptive responses against SARS-CoV-2 toward an adult-like profile occurs in a progressive manner.

Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.

The aim of this study was to assess the prevalence and the burden of difficult-to-treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. Adult patients were selected in the prospective, real-world CARMEN-France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult-to-treat ITP (3.5%; 95% confidence interval [CI]: 2.3%-4.8% in total; 7.6%; 95% CI: 4.9%-10.2% of patients needing ≥2nd line treatment). The 3-year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow-up: 30.3 months)., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Deficiency in regulatory B cells has been suggested in immune thrombocytopenia. In this study, Stimpson et al. emphasize the importance of considering the treatments received for immunological analyses. Commentary on: Stimpson et al. Systemic immunosuppression depletes peripheral blood regulatory B cells in patients with immune thrombocytopenia. Br J Haematol 2024;204:644-648., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Immune thrombocytopenia (ITP) is an acquired bleeding disorder mediated by pathogenic autoantibodies secreted by plasma cells (PCs) in many patients. In refractory ITP patients, the persistence of splenic and bone marrow autoreactive long-lived PCs (LLPCs) may explain primary failure of rituximab and splenectomy respectively. The reactivation of autoreactive memory B cells generating new autoreactive PCs contributes to relapses after initial response to rituximab. Emerging strategies targeting B cells and PCs aim to prevent the settlement of splenic LLPCs with the combination of anti-BAFF and rituximab, to deplete autoreactive PCs with anti-CD38 antibodies, and to induce deeper B-cell depletion in tissues with novel anti-CD20 monoclonal antibodies and anti-CD19 therapies. Alternative strategies, focused on controlling autoantibody mediated effects, have also been developed, including SYK and BTK inhibitors, complement inhibitors, FcRn blockers and inhibitors of platelet desialylation., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reactions, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with a marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies., Competing Interests: Declaration of interests Outside of the submitted work, M. Mahévas received research funds from GSK and personal fees from LFB and Amgen. J.-C.W. received consulting fees from Institut Mérieux. P.B. received consulting fees from Regeneron Pharmaceuticals., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Combining drugs could be an effective option for treating multirefractory ITP, that is, patients not responding to rituximab, thrombopoietin receptor agonists (TPO-RA) and splenectomy. We conducted a retrospective, multicenter, observational study including multirefractory ITP patients who received a combination of a TPO-RA and an immunosuppressive drug. We included 39 patients (67% women, median age 59 years [range 21-96]), with a median ITP duration of 57 months [3-393] and a median platelet count at initiation of 10 × 10 9 /L [1-35]. The combination regimen was given for a median duration of 12 months [1-103] and included eltrombopag (51%) or romiplostim (49%), associated with mycophenolate mofetil (54%), azathioprine (36%), cyclophosphamide (5%), cyclosporin (3%) or everolimus (3%). Overall, 30 patients (77%) achieved at least a response (platelet count ≥30 × 10 9 /L and at least doubling baseline during at least 3 months), including 24 complete responses (platelet count >100 × 10 9 /L during at least 3 months) with a median time to response of 30 days [7-270] and a median duration of response of 15 months [4-63]. Severe adverse event related to ITP treatment was observed in 31%. In conclusion, this study confirms that some patients with multirefractory ITP can achieve long lasting response with this combination., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here, we qualitatively investigated the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain (RBD) in cohorts of BNT162b2-vaccinated naive and COVID-19-recovered individuals. Using a droplet microfluidic and imaging approach, we analyzed more than 4,000 single IgG-secreting cells, revealing high interindividual variability in affinity for RBD, with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented more than 65% of the plasmablast response at all time points. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.

Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974., (© 2023 by The American Society of Hematology.)

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines., (© 2022 Sokal et al.)

Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering., (© 2022 New York Academy of Sciences.)

Memory B cells (MBCs) can persist for a lifetime, but the mechanisms that allow their long-term survival remain poorly understood. Here, we isolated and analyzed human splenic smallpox/vaccinia protein B5-specific MBCs in individuals who were vaccinated more than 40 years ago. Only a handful of clones persisted over such an extended period, and they displayed limited intra-clonal diversity with signs of extensive affinity-based selection. These long-lived MBCs appeared enriched in a CD21 hi CD20 hi IgG + splenic B cell subset displaying a marginal-zone-like NOTCH/MYC-driven signature, but they did not harbor a unique longevity-associated transcriptional or metabolic profile. Finally, the telomeres of B5-specific, long-lived MBCs were longer than those in patient-paired naive B cells in all the samples analyzed. Overall, these results imply that separate mechanisms such as early telomere elongation, affinity selection during the contraction phase, and access to a specific niche contribute to ensuring the functional longevity of MBCs., Competing Interests: Declaration of interests M.M. received research funds from GSK and personal fees from LFB and Amgen, and J.-C.W. received consulting fees from Institut Mérieux, all outside of the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: After two doses of mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients on dialysis show a defective humoral response, but a third dose could increase anti-SARS-CoV-2 spike IgG titers. Responses could be different in virus-naive and SARS-CoV-2-recovered patients on dialysis. However, characterization of memory B cell response after three doses is lacking., Design, Setting, Participants, & Measurements: We evaluated the dynamics of antireceptor binding domain IgG titers and antireceptor binding domain memory B cells until 6 months after two and three doses (administered within 6 months after the second dose) of mRNA vaccine in SARS-CoV-2-recovered and virus-naive dialysis populations. Results were analyzed by ordinary one-way ANOVA, the Kruskal-Wallis test, or the Wilcoxon matched-pairs test as appropriate., Results: In total, 108 individuals (59 patients on dialysis and 49 controls) were included. In virus-naive patients on dialysis, antireceptor binding domain IgG response was quantitatively lower after two doses compared with healthy controls, but IgG titers increased by three-fold after three doses ( P =0.008). In SARS-CoV-2-recovered patients on dialysis, antireceptor binding domain IgG titers after two doses were significantly higher compared with virus-naive patients on dialysis but did not significantly increase after a third dose. Regarding memory B cell response, we detected receptor binding domain-specific memory B cells at similar proportions in virus-naive patients on dialysis and vaccinated controls after two doses. Moreover, a strong receptor binding domain-specific memory B cell expansion was observed after the third dose in virus-naive patients on dialysis (5.5-fold; P <0.001). However, in SARS-CoV-2-recovered patients on dialysis, antireceptor binding domain memory B cells remained unchanged after the third dose., Conclusions: The third dose of mRNA vaccine given within 6 months after the second dose boosts serologic and memory response in virus-naive patients but not in SARS-CoV-2-recovered patients on dialysis., Clinical Trial Registry Name and Registration Number: COVID-19: SARS-CoV-2 Specific Memory B and T-CD4+ Cells (MEMO-COV2), NCT04402892., (Copyright © 2022 by the American Society of Nephrology.)

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals., Competing Interests: Declaration of interests Outside of the submitted work, M. Mahévas received research funds from GSK and personal fees from LFB and Amgen. J.-C.W. received consulting fees from Institut Mérieux. P.B. received consulting fees from Regeneron Pharmaceuticals. J.-M.P. received personal fees from Abbvie, Gilead, Merck, and Siemens Healthcare. F.A.R. is a member of the board of MELETIOS Therapeutics and of the Scientific Advisory Board of eureKARE., (Copyright © 2022. Published by Elsevier Inc.)

Data about the presentation and the management of primary immune thrombocytopenia (ITP) in very elderly patients (VEPs; aged ≥80 years) are lacking. The aim of the present study was to describe ITP in this subgroup. The data source was the prospective CARMEN-France registry. Patients included between 2013 and 2018 were selected. ITP presentation and management in VEPs was compared to elderly patients (EPs; aged 65-79 years). We assessed factors associated with bleeding at ITP onset in VEPs. Of 541 patients, 184 were included: 87 in the VEP group and 97 in the EP group. The mean age was 85·7 years in the VEP group. Comorbidities were more frequent in the VEP group (67·4% vs. 47·9%). The median platelet count at ITP onset was similar but severe bleeding tended to be more frequent in VEPs (10·3% vs. 4·1%, P = 0·1) as well as mortality. Exposure to ITP drugs, response to first-line treatment, need of second-line treatment, evolution towards persistency, occurrence of bleeding, infection and thrombosis did not differ between groups. In VEPs, factors associated to bleeding were female sex [odds ratio (OR) 4·75, 95% confidence interval (CI) 1·31-17·32] and platelet count of <20 × 10 9 /l (OR 10·05, 95% CI 4·83-67·39). Exposure to anticoagulants was strongly associated with severe bleeding (OR 7·61, 95% CI 1·77-32·83)., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: To characterize the clinical and biological course, management and response to treatment in SLE-associated pure red cell aplasia (PRCA)., Methods: This was a nationwide, multicentre, retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection., Results: We enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level, and reticulocyte and differential erythroblast count were 39.2 (13.2) years, 62 ( 20) g/l, 9.1 (7.6) × 109/l and 2.8 ( 2.5)%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range 2-11). CS therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, 5 (21%) partial response and 2 (8%) treatment failure. In total, 21 (87%) patients required red blood cell transfusion; 5 had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization., Conclusion: SLE-associated PRCA is a severe condition. Repeated red blood cell transfusions and several lines of immunosuppressant therapy are mostly required, with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs., Competing Interests: Declaration of interests Outside of the submitted work, M. Mahévas. received research funds from GSK and personal fees from LFB and Amgen. J.-C.W. received consulting fees from Institut Mérieux. P.B. received consulting fees from Regeneron Pharmaceuticals. J.-M.P. received personal fees from Abbvie, Gilead, Merck, and Siemens Healthcare. F.R. is a member of the board of MELETIOS Therapeutics and of the Scientific Advisory Board of eureKARE., (Copyright © 2021. Published by Elsevier Inc.)

Background: Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS)., Objectives: To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome., Methods: A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML., Results: Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS., Conclusions: Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.

B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP. The primary endpoint was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition. In total, 15 non-splenectomized adults, nine (60%) with persistent IPT and six (40%) with chronic ITP, were included. No severe adverse event, infection, or severe hypogammaglobulinemia was observed. Thirteen patients achieved an initial overall response. At W52, 12 (80%) patients achieved an overall response, including ten (66.7%) with complete response. When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell repopulation appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy. Combining rituximab and belimumab seems a promising strategy in ITP, with high efficacy and acceptable safety.

Objective: This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy., Methods: We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long-lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow-up during induction therapy., Results: The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long-lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure., Conclusion: Our results suggest potential for ASC-directed therapy in refractory lupus nephritis., (© 2021, American College of Rheumatology.)

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. Although the primary triggering factors of ITP remain unknown, a loss of immune tolerance-mostly represented by a regulatory T-cell defect-allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcγRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcγR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. The better understanding of ITP pathogenesis has provided important therapeutic advances. B cell-targeting therapies and thrombopoietin-receptor agonists (TPO-RAs) have been used for years. New emerging therapeutic strategies that inhibit FcγR signaling, the neonatal Fc receptor or the classical complement pathway, will deeply modify the management of ITP in the near future., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia. By analyzing the B and plasma cell immunoglobulin gene repertoire at bulk and antigen-specific single-cell level, we demonstrate that relapses are associated with two responses coexisting in germinal centers and involving preexisting mutated memory B cells that survived RTX treatment and naive B cells generated upon reconstitution of the B cell compartment. To identify distinctive characteristics of the memory B cells that escaped RTX-mediated depletion, we analyzed RTX refractory patients who did not respond to treatment at the time of B cell depletion. We identified, by single-cell RNA sequencing (scRNA-seq) analysis, a population of quiescent splenic memory B cells that present a unique, yet reversible, RTX-shaped phenotype characterized by down-modulation of B cell-specific factors and expression of prosurvival genes. Our results clearly demonstrate that these RTX-resistant autoreactive memory B cells reactivate as RTX is cleared and give rise to plasma cells and further germinal center reactions. Their continued surface expression of CD19 makes them efficient targets for current anti-CD19 therapies. This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: To report four cases of life-threatening COVID-19 pneumonia in patients with high blood concentrations of neutralizing autoantibodies against type I interferons (IFNs), who were treated with plasma exchange (PE) as a rescue therapy., Methods: Prospective case series, which included patients, diagnosed with RT-PCR-confirmed SARS-CoV-2 infection and positive autoantibodies against type I IFNs in two French intensive care units (ICUs) between October 8 and November 14, 2020. Six critically ill COVID-19 patients with no anti-IFN antibodies were used as controls. Anti-IFN autoantibodies and IFN concentrations, together with the levels of anti-SARS-CoV-2 antibodies, were measured sequentially in serum. Viral load was determined in the upper and lower respiratory tract. Patients were followed during hospital stay., Results: Three men and one woman were included. Three of the patients had four PE sessions each, while another had three PE sessions. PE decreased the concentrations of autoantibodies against type I IFN in all four patients, whereas anti-SARS-CoV-2 antibody levels remained stable. Autoantibodies against type I IFN levels were high in tracheal aspirates of one patient and decreased after three PE sessions. By contrast, anti-IFN autoantibodies were not detected in tracheal aspirates from five control patients without detectable anti-IFN autoantibodies in serum. During PE, serum IFN-α levels slightly increased in three out of four patients, and upper respiratory tract viral load decreased in all patients. All patients were alive at day 28 of ICU admission. Two patients eventually died in the ICU, while the two survivors were discharged from the ICU at days 50 and 66., Conclusions: PE efficiently removes autoantibodies against type I IFNs, including those detected in tracheal aspirates, without affecting anti-SARS-CoV-2 antibody levels, in patients with life-threatening COVID-19 pneumonia. The clinical benefit of PE in patients with autoantibodies against type I IFNs should be tested in a larger study.

Objective: To assess the effectiveness of corticosteroids on outcomes of patients with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen without mechanical ventilation., Methods: We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) versus standard of care (no-CTC group) among adults 18-80 years old with confirmed COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death by day 28. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting., Results: Among the 891 patients included in the analysis, 203 were assigned to the CTC group. Use of corticosteroids was not significantly associated with risk of intubation or death by day 28 (weighted hazard ratio (wHR) 0.92, 95%CI 0.61-1.39) nor cumulative death rate (wHR 1.03, 95%CI 0.54-1.98). However, use of corticosteroids was associated with reduced risk of intubation or death by day 28 in the prespecified subgroups of patients requiring oxygen ≥3 L/min (wHR 0.50, 95%CI 0.30-0.85) or C-reactive protein level ≥100 mg/L (wHR 0.44, 95%CI 0.23-0.85). The number of hyperglycaemia events was higher for patients with corticosteroids than for those without, but the number of infections was similar., Conclusions: We found no association between the use of corticosteroids and intubation or death in the broad population of patients 18-80 years old, with COVID-19, hospitalized in settings non intensive care units. However, the treatment was associated with a reduced risk of intubation or death for patients with ≥3 L/min oxygen or C-reactive protein level ≥100 mg/L at baseline. Further research is needed to confirm the right timing for corticosteroids in patients with COVID-19 requiring oxygen only., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis., Methods: We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN)., Results: Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively)., Conclusions: An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection., Competing Interests: Declaration of interests M. Mahévas received research funds from GlaxoSmithKline, outside of the submitted work, and personal fees from LFB and Amgen, outside of the submitted work. J.-C.W. received consulting fees from Institut Mérieux, outside of the submitted work. J.-M.P. received personal fees from Abbvie, Gilead, Merck, and Siemens Healthcare, outside of the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hepatic sarcoidosis is a relatively common manifestation of extrapulmonary sarcoidosis. It occurs in 20 to 30% of cases and is rarely severe. However, a cluster of patients may develop severe complications such as cirrhosis and portal hypertension. In this review, we describe the current knowledge of clinical, biological, pathological, and radiological features of liver involvement in sarcoidosis and discuss essential clues for management and treatment., Competing Interests: None declared., (Thieme. All rights reserved.)

B-cell depletion with anti-CD20 monoclonal antibodies is widely used for the treatment of autoimmune diseases. This review will discuss mechanisms contributing to success or failure of B-cell depletion therapy in antibody-mediated autoimmune diseases. It will also explain how key information about disease pathogeny can be provided by the different outcomes observed after B-cell depletion therapy. These findings provide the basis for future innovative therapeutic strategies aiming at an optimized B cell and/or plasma cell depletion to increase long-term disease remission., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Rituximab is a second-line option in adults with immune thrombocytopenia (ITP), but the estimated 5-year response rate, only based on pooled retrospective data, is about 20%, and no studies have focused on long-term safety. We conducted a prospective multicenter registry of 248 adults with ITP treated with rituximab with 5 years of follow-up to assess its long-term safety and efficacy. The median follow-up was 68.4 [53.7-78.5] months. The incidence of severe infections was only 2/100 patient-years. Profound hypogammaglobulinemia (<5 g/L) developed in five patients at 15 to 31 months after the last rituximab infusion. In total, 25 patients died at a median age of 80 [69.5-83.9] years, corresponding to a mortality rate of 2.3/100 patient-years. Only three deaths related to infection that occurred 12 to 14 months after rituximab infusions could be due in part to rituximab. At 60 months of follow-up, 73 (29.4%) patients had a sustained response. On univariate and multivariate analysis, the only factor significantly associated with sustained response was a previous transient response to corticosteroids (P = .022). Overall, 24 patients with an initial response and then relapse received retreatment with rituximab, which gave a response in 92%, with a higher duration of response in 54%. As a result of its safety profile and its sustained response rate, rituximab remains an important option in the current therapeutic armamentarium for adult ITP. Retreatment could be an effective and safe option., (© 2019 Wiley Periodicals, Inc.)

Objective: To describe a new autoinflammatory syndrome with recurrent fever and monoclonal gammopathy that differs from Schnitzler syndrome., Methods: We conducted a retrospective study of patients with monoclonal gammopathy and recurrent fever of unknown origin., Results: Five patients were studied; median age at onset of symptoms was 44 years. Median frequency of fever attacks was 6 episodes per year. In the absence of treatment, the median duration of fevers was 3 days., Conclusion: This new autoinflammatory syndrome is defined by an association among monoclonal gammopathy, arthralgias, and recurrent fever.