Autoimmune cytopenias (AICs) arise from pathogenic autoantibody-mediated destruction of blood cells. Current treatments often fail to achieve durable remission, necessitating long-term treatment including immunosuppression and exposure to treatment-related toxicities. Insights into B cell biology demonstrate the central role of autoreactive B cells and plasma cells in sustaining disease activity and relapse, providing a rationale to achieve sustained, treatment-free remissions through "immune reset". This review summarizes the current understanding of immune reset in AICs and examines clinical data for depletion strategies targeting distinct stages of B cell maturation. We compare therapeutic modalities across monoclonal antibodies, bispecific T cell engagers (TCE), and chimeric antigen receptor (CAR) T cells. The depth and breadth of depletion, kinetics of immune reconstitution, and treatment-related risks are critical determinants of long-term outcome potential and individualized risk-benefit assessment. Collectively, these advances support a potential paradigm shift from chronic immunosuppression towards durable remissions off therapy with time-limited therapeutic interventions.

Limited data exist on how patients and physicians perceive immune thrombocytopenia (ITP) symptoms and treatment-related burden. I-WISh (ITP World Impact Survey) 2.0 surveyed 1018 patients and 431 physicians in 15 countries to characterize the impact of ITP and its treatments on patients. Approximately one-third of patients reported that ITP had a high impact on daily activities and family/social life, and 54% reported that it had a high impact on emotional wellbeing. Patients and physicians generally aligned on symptoms and treatment goals, but more patients (48%) than physicians (29%) reported fatigue as common and problematic. Ninety-seven percent of patients reported that they had received treatment for ITP, most commonly corticosteroids. Most patients and 54% of physicians were satisfied with available treatments, although patients reported treatment-related burdens. Twenty-eight percent confirmed they would have chosen a different treatment. Two-thirds of patients were in a stable, sustained remission, and most had never paused treatment (67%). Nevertheless, two-thirds of patients preferred limiting time on treatment and/or not being on lifelong treatment. I-WISh 2.0 emphasizes the extensive disease and treatment burden faced by patients living with ITP, especially the impact of fatigue. It also reminds us that shared decision-making is needed to ensure treatment goals are aligned with patient expectations, including health-related quality of life.

OBJECTIVES:To determine the safety and efficacy of ruxolitinib (RUX) and fostamatinib (FOS) compared with standard of care (SOC) in patients requiring hospital admission for the treatment of COVID-19 pneumonia. DESIGN:Adaptive multiarm, multistage, randomised, open-label trial (three arm, two stage). SETTING:Five hospitals in England between October 2020 and September 2022. PARTICIPANTS:Hospitalised patients (≥18 years) with COVID-19 pneumonia defined by a modified WHO COVID-19 severity grade of 3 or 4. INTERVENTIONS:Participants were randomly assigned 1:1:1 to receive RUX (10 mg two times per day for 7 days then 5 mg two times per day for 7 days), FOS (150 mg two times per day for 7 days then 100 mg two times per day for 7 days) or SOC. MAIN OUTCOME MEASURES:Primary outcome was development of severe COVID-19 pneumonia (modified WHO severity grade≥5) within 14 days of randomisation. Secondary outcomes included mortality, invasive and non-invasive ventilation, venous thromboembolism, duration of hospital stay, readmissions, inflammatory markers and serious adverse events (SAEs). RESULTS:At stage 1, 181 patients were randomised, with 4 assessed as ineligible post randomisation. FOS was stopped early for futility with 16 participants (27.6%, n=58) developing severe COVID-19 pneumonia compared with 15 (25.0%, n=60) in the SOC arm (adjusted odds ratio (aOR) compared with SOC: 1.12; 95% CI 0.49 to 2.58; p=0.608). RUX progressed to stage 2 but the trial was stopped early due to slow recruitment. At the final analysis, 10 participants (16.1%, n=62) developed severe COVID-19 pneumonia in the RUX arm compared with 15 (24.6%, n=61) in the SOC arm (aOR: 0.63; 95% CI 0.25 to 1.57; p=0.161). Four (7.4%) participants in the FOS arm, none in the RUX arm and three (5.5%) in the SOC arm died within 14 days of randomisation. Infections were the most frequently reported SAE and were numerically higher in the FOS (10, 17.2%) and RUX (10, 16.1%) arms compared with SOC (7, 11.5%). Two unexpected serious adverse reactions occurred in the RUX arm only. CONCLUSIONS:We found no evidence that FOS was superior to SOC for the treatment of COVID-19 pneumonia in patients requiring hospital admission. Due to early stopping, the trial was underpowered to establish RUX's effect in this population. Further study is needed. TRIAL REGISTRATION NUMBER:NCT04581954; EUDRA-CT: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001750-22/GB.

The anti-CD52 monoclonal antibody, alemtuzumab, is used as induction therapy for renal transplantation. Its use has been associated with autoimmune manifestations, particularly autoimmune cytopenias (AICs). Here, we report a single-center, retrospective analysis of patients who developed AICs after an alemtuzumab-induced renal transplant. Over a period of 8 years, 40 renal transplant patients developed immune thrombocytopenia (ITP) (n=28), autoimmune hemolytic anemia (AIHA) (n=7) or Evans syndrome (ES) (n=5), with two peaks of incidence, at 18 and 36 months after alemtuzumab. Response and relapse rates to standard first-line ITP and AIHA therapy were comparable to primary forms, with two thirds requiring second-line agents. Most patients with ITP who failed to go into remission after steroids or IVIG received either rituximab or a thrombopoietin receptor agonist (TPO-RA). Compared to primary ITP, a higher response rate (91.6%) and median duration of response (56 months) were achieved with rituximab; and a higher proportion of patients were able to discontinue TPO-RAs and maintain remission (50%). Most patients experienced one or more adverse events, most commonly, infections (62.5%), cardiovascular diseases (27.5%) and deep vein thrombosis (25%). In conclusion, AICs are a significant complication following alemtuzumab-induced renal transplantation, typically occurring within the 5-year period of immune reconstitution. Both rituximab and TPO-RAs show good efficacy, a few patients develop multi refractory disease, and the majority go into sustained remission off-treatment. Given that treatment is complicated by high rates of infections and thrombosis, supportive measures using antimicrobials as well as quick re-introduction of antiplatelet or anticoagulants in ITP and addition of anticoagulation in AIHA is recommended.

Abstract Introduction: Immune thrombocytopenia (ITP) is a rare autoimmune disorder characterised antibody-mediated platelet and megakaryocyte destruction. The UK Childhood ITP Registry (UKCITP) opened in January 2007 and closed to recruitment in January 2024 and final data entry in March 2024. It includes 2271 cases from 139 UK centres (Research ethics reference: 06/MRE03/09). This analysis aimed to describe the patient (pt), and disease characteristics of UK children diagnosed with primary ITP. Methods: For this analysis, pt were excluded if they had platelet count >100 x 109/L (plt x 109/L), had secondary ITP as defined by the international working party consensus, or an alternative cause of thrombocytopaenia identified. Data was analysed in different age groups: <2 years (y), 2-5y, 6-11y and 12 to <18y. Results: 499 pts were excluded from analysis: 22 for secondary ITP, 2 for alternative causes of low plt, and 475 due to insufficient data or plt>100 at diagnosis. Data from 1772 children (52.9% male, 84.4% white) were analysed. Age at presentation varied, peaking ay 2-5y (<2y = 368, 2-5y = 784, 6-11y = 393 and 12-17y = 227). The male-to-female (M:F) ratios at diagnosis shifted from male predominance in the younger cohorts to female predominance in the older cohorts (age <2 1.6:1, age 2 to 5 1.22:1, age 6 to 11 1:1.1 and age 12 to 17 1:1.5). The majority of this registry is of Caucasian origin with a gradual reduction of non-Caucasian presentation occurring with age (<2y = 82.1%, 2-5y = 83.9%, 6-11y = 84.7% and 12-17y = 89.0% white). Mean time of follow up (FU) for documented plt counts was 23.2 months (mo), however, pt were discharged from local follow up and the registry once counts remained >150, per routine practice, but could re-enter the study at a later date. The rate of persistent ITP (plt <150) falls from 39.8% at 6mo to 23.4% at 12mo and 16.6% at 24mo FU. The rate of persistent disease is lowest in the <2y cohort at 25.0% at 6mo, 13.0% at 12mo and 6.8% 24mo; this contrast to the higher rate in the 12-17y cohort at 63.9%,45.8% and 31.7% at 6,12 and 24mo respectively. At presentation 81.7% had a plt<20 and 95.8% <50. The median plt was lowest in the <2y cohort (6.5%) and highest in the older cohort (9.0%). The proportions with persisting plt <20 drops from 14.5% at 6mo to 7.5% at 12mo and 4.4% at 24mo across all age groups. The rates are lowest in the <2 cohort at 7.3%, 2.7% and 1.6% at 6, 12 and 24mo; and highest in the older cohort at 14.5%, 7.5% and 4.4% at 6, 12 and 24mo. The proportions with plt<50 follows the above trend reducing from 21.8% at 6mo to 11.6% at 12mo and 7.2% at 24mo across all age groups. Again, rates are lowest in the <2y cohort at 7.1%, 4.1% and 1.9% at 6,12 and 24mo and highest rates in the 12-17y cohort at 18.5%, 12.8% and 6.2% at 6, 12 and 24mo. The most common factor associated with the onset of ITP was a preceding viral illness, reported in 58.2% of <2y, 58.0% of 2-5y, 45.3% of 6-11y and 41.0% of 12-17y. Vaccination preceded ITP significantly more often in the <2y cohort (57.6%), reflecting the UK paediatric vaccination schedule compared to 2-5, 6-11 and 12-17y (7.4, 2.5 and 9.7% respectively). Of the 284 bone marrow aspirations, the procedure was more common in the 6-11y and 12-17y cohorts (20.9% and 23.8% respectively). 744 pts were admitted to hospital at presentation for a median of 24 hours. 45.43% were between 2-5y, followed by 25.1% at <2y, 18.8% at 6-11y and 10.6% at 12-17y. Conclusion: This analysis offers unique insight into the paediatric primary ITP population; gathering data from both specialist and local centres across the UK. As such, this cohort reflects real-world data, including spontaneous remitters, though recruitment bias may reduce alignment with current UK census ethnicity statistics. These data indicate that, the shift to predominant female disease occurs in the 6-11y cohort, not in the adolescent group, which has been previously suggested. The rate of persistent disease is shown to increase with age reinforcing the need for plt supporting therapies across all ages but particularly in the older age group. Further analysis will assess the proportion of pts with persistent severe thrombocytopaenia receiving rescue and second line therapies and compare the UKCITP against adult and international paediatric counterparts.

Primary autoimmune thrombocytopenia (ITP) is characterized by thrombocytopenia, bleeding, and reduced health-related quality of life. In the Phase 3 ADVANCE IV study, intravenous efgartigimod induced significant platelet count responses versus placebo in patients with chronic ITP. ADVANCE SC, a Phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study, evaluated the efficacy and safety of subcutaneous efgartigimod PH20 in adults with primary ITP. Participants with platelet counts < 30 × 109/L who received more than one prior ITP therapy. Between December 16, 2020, and October 9, 2023, 207 participants were randomized (2:1) to receive 1000 mg efgartigimod PH20 SC (n = 137) or placebo (n = 70) once weekly (visits 1-4), weekly or biweekly (depending upon response; visits 5-16), and at a fixed dosing interval (visits 17-24). Most (92.8% [192/207]) had chronic ITP and 74.9% (155/207) received at least three previous ITP treatments. The median time since diagnosis was 7.0 years. Superior efficacy of efgartigimod PH20 SC versus placebo was not demonstrated for the primary or secondary endpoints, with a comparable proportion of efgartigimod PH20 SC and placebo-treated participants achieving the primary efficacy endpoint (platelet count ≥ 50 × 109/L for at least four of the six visits during weeks 19-24): -13.7% [17/124] versus 16.2% [11/68], respectively; p = 0.51; adjusted difference in proportions, -3.5% [95% CI, -14.7-7.0]. Efgartigimod PH20 SC was well tolerated: most adverse events were mild to moderate and comparable between treatment groups. Platelet count increases from baseline were higher than expected with placebo and lower than expected with efgartigimod PH20 SC. Clinical Trial Registration: The ADVANCE SC trial is registered on ClinicalTrials.gov (NCT04687072).

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.

BACKGROUND:Current second-line treatments for immune thrombocytopenia (ITP) require long-term administration. Ianalumab, a monoclonal antibody targeting B cells, is being assessed as a short-course second-line therapy in ITP. METHODS:In this phase 3, randomized, double-blind trial, we assigned, in a 1:1:1 ratio, adults with primary ITP and an insufficient response or a relapse after first-line glucocorticoid therapy to receive ianalumab at a dose of 9 mg or 3 mg per kilogram of body weight or placebo once monthly for 4 months. Eltrombopag, an oral thrombopoietin-receptor agonist, was administered once daily in each group according to local prescribing information; the dose was tapered until discontinuation by the end of week 24 in eligible patients. The primary end point was freedom from treatment failure, as determined in a time-to-event analysis, with treatment failure defined by a platelet count of less than 30×109 per liter more than 8 weeks after randomization, initiation of rescue therapy more than 8 weeks after randomization, initiation of new ITP therapy, inability to taper or discontinue eltrombopag because of an inadequate platelet count, or death from any cause, whichever occurred first. The key secondary end point was a stable response at 6 months, defined by a platelet count of at least 50×109 per liter in at least 75% of the measurements between weeks 19 and 25 without use of rescue therapy or new ITP therapy. Safety was assessed. RESULTS:A total of 152 patients underwent randomization: 50 to the 9-mg ianalumab group, 51 to the 3-mg ianalumab group, and 51 to the placebo group. The estimated probability of being free from treatment failure at 12 months was 54% (95% confidence interval [CI], 39 to 67) in the 9-mg group, 51% (95% CI, 36 to 64) in the 3-mg group, and 30% (95% CI, 18 to 43) in the placebo group. The time to treatment failure was significantly longer with ianalumab plus eltrombopag than with placebo plus eltrombopag; the estimated hazard ratio for treatment failure (ianalumab vs. placebo) was 0.55 (P = 0.04) in the 9-mg group and 0.58 (P = 0.045) in the 3-mg group. The percentage of patients with a stable response at 6 months was significantly higher in the 9-mg group than in the placebo group (62% vs. 39%; P = 0.045). The overall frequency of adverse events during the treatment period was generally similar in the three groups. The frequency of serious adverse events was 16% in the 9-mg group, 6% in the 3-mg group, and 4% in the placebo group. CONCLUSIONS:Ianalumab plus eltrombopag led to a longer time to treatment failure than placebo plus eltrombopag. (Funded by Novartis; VAYHIT2 ClinicalTrials.gov number, NCT05653219.).

Immune thrombocytopenia (ITP) is an autoimmune disease where premature destruction of platelets as well as inhibition of platelet production leads to thrombocytopenia and associated bleeding. It has long been considered a disease primarily caused by B cells, but the role of T lymphocytes in its pathogenesis is now better understood and deserves elucidation. Two types of T cells will be discussed: (1) splenic T follicular helper cells (TFH) that participate in differentiation of B cells within germinal centres (GC) and stimulate the production of antiplatelet antibodies, thus supporting the humoral autoimmune response; and (2) antibody-independent mechanisms of action of cytotoxic T lymphocytes (CTL) that may directly participate in platelet destruction as well as inhibit their production by targeting megakaryocytes. To date, most novel therapies target antibody-mediated disease, but targeting either TFH or CTL may provide new therapeutic opportunities.

OBJECTIVES:Ultrasound is the first-line imaging modality of the pelvis in the pediatric and adolescent gynecology (PAG) population. Ultrasound findings in pre- and postpubertal PAG patients differ from those in adults. Diagnostic models for adnexal pathology have not been validated in this cohort. The primary aim of this study was to evaluate normative findings and the incidence of pathology in this cohort. The secondary aim was to assess the performance of expert opinion alone, as well as using retrospective application of the International Ovarian Tumor Analysis (IOTA) simple rules (SRs) and benign descriptors (BDs) in those found to have an adnexal mass. METHODS:This was a retrospective review of pelvic ultrasound examinations performed in patients < 18 years of age from January 2017 to July 2021 in one expert center in the UK. Analysis was performed on three age groups: neonatal (aged < 1 year), premenarchal (aged ≥ 1 year) and postmenarchal. The study was locally approved as an audit (GRM_082). Expert review of images of ovarian masses was performed using retrospective application of the IOTA-SRs and IOTA-BDs. RESULTS:In total, data on 1429 pelvic ultrasound examinations were retrieved, of which 116 were excluded, resulting in the inclusion of 1313 ultrasound images (1145 patients). The median age at the first ultrasound scan was 2 days after birth in the neonatal group (n = 20), 8.8 years in the premenarchal group (n = 124) and 16.1 years in the postmenarchal group (n = 961). The status of menarche was unknown in a further 40 patients. Normative ultrasound findings were in keeping with those in the existing literature. Uterine anomalies were seen in 14 (1.2%) patients. Endometrial pathology was rare, with five cases of gestational trophoblastic disease. The most frequent indication for ultrasound scan for each group were a known medical condition in neonates (n = 11 (55.0%)), suspected precocious puberty in premenarchal girls (n = 38 (30.6%)) and abnormal vaginal bleeding in postmenarchal girls (n = 504 (52.4%)). Polycystic ovarian appearances were described in 150 (15.6%) postmenarchal girls. Adnexal pathology was identified in 102 (8.9%) participants on initial ultrasound: four neonates, three premenarchal and 95 postmenarchal patients. Benign cystadenomas and hemorrhagic cysts were the most common adnexal mass type in all groups. Final outcomes were available for 79/95 masses in the postmenarchal group, none of which were malignant. The IOTA-SRs, IOTA-BDs, expert opinion and standard ultrasound reporting could characterize as benign 96.2%, 87.3%, 98.7% and 77.2% of the masses, respectively, all with a specificity of 100%. Eleven patients underwent 12 surgeries overall (three oophorectomies, six cystectomies and three cyst aspirations), with 11 out of 12 masses classified as benign based on retrospective expert assessment. CONCLUSIONS:Ultrasound is effective for assessment of the female pelvis in the PAG population. Adnexal masses are common, but few require surgical intervention and most resolve expectantly. The IOTA-BDs and IOTA-SRs maintain their performance in this population. Larger studies are required for the prospective validation of diagnostic models which may aid a fertility-sparing approach to care. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Immune Thrombocytopenia (ITP) is a heterogenous autoimmune disorder diagnosed by excluding other conditions. Misdiagnosis of primary ITP occurs in patients with inherited thrombocytopenia and primary immunodeficiency syndromes. This study investigates whether genetic testing for inherited thrombocytopenia or primary immunodeficiency can enhance diagnostic accuracy in ITP, and guide treatment strategies. We performed whole genome sequencing or targeted panel sequencing on peripheral blood samples in a cohort of 80 participants with chronic ITP, utilising the ThromboGenomics (TG) Panel (n=72) and the Genomics of Rare Immune Disorders (GRID) panel (n=50) consisting of genes known to cause bleeding and platelet disorders (BPDG) or primary immunodeficiency syndromes (PIDG) respectively. A replication cohort of 73 patients underwent clinical genomics testing with either the R90 (BPDG, n=35) or R15 (PIDG, n=50) NHS Genomics panels. Known pathogenic or likely pathogenic, disease-causing, variants were identified in 9 patients in the first cohort (11% CI:5-20); 7 patients (10% CI:4-19) in BPDG and 2 patients (4% CI:1-14) in PIDG. Additionally, 26 patients (32.5%) carried variants of uncertain significance (VUS). In the replication cohort, 8% (CI:2-20) and 9% (CI:2- 23) of patients had a pathogenic variant identified on the R15 (PIDG) or R90 panel (BPDG) respectively. The findings impacted clinical management such as avoidance of immunosuppression (ANKRD26, GP1BB, ETV6, TUBB1, ITGB3) and eligibility for allogeneic stem cell transplantation (UNC13D). Our findings demonstrate that genomic sequencing identifies diagnostically relevant variants in patients with chronic ITP. Identification of these variants can guide treatment decisions and improve patient outcome.