Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

Healthcare resource utilization of patients with warm autoimmune hemolytic anemia initiating first line therapy of oral corticosteroids with or without rituximab.

This retrospective cohort study described real-world treatment patterns and healthcare resource utilization (HCRU) of patients with warm autoimmune hemolytic anemia (wAIHA) initiating treatment with first-line (1L) oral corticosteroids (OCS) + rituximab (R) compared to 1L OCS. Patients with a wAIHA diagnosis code (D59.11) between 8/2020-3/2022 were identified using US pharmacy and medical claims databases. Patients initiating 1L OCS ± R were identified (date of initiation = 'index date') with a 1-year pre-index period and a variable (minimum 1-year) follow-up period. The final sample comprised 77 1L OCS + R patients and 400 1L OCS patients (~ 60% female, mean age > 64 years). Over the 1-year follow-up, HCRU was higher in the OCS + R cohort with higher mean number of physician office visits (22.9 and 14.4; p < 0.01), including hematology/oncology office visits, and higher utilization of rescue therapy (59.7% and 33.3%; p < 0.01), driven by higher use of injectable corticosteroids. Patients in OCS + R and OCS groups completed 1L therapy after a similar mean duration of 103.5 and 134.6 days, respectively (p = 0.24). In the majority of patients, second-line (2L) therapy was initiated at a similar timepoint: 66.2% OCS + R and 72.0% OCS cohorts (p = 0.31) initiated 2L in a mean of 218.3 and 203.2 days (p = 0.76) after the end of 1L treatment, respectively. The addition of rituximab in 1L did not extend the remission period, with most patients in both cohorts initiating 2L therapy within less than 1 year of completing 1L treatment. 1L OCS + R patients also had substantial HCRU burden. More effective novel therapies are needed to address the high unmet need in wAIHA.

Obesity is associated with adverse outcomes in primary immune thrombocytopenia - a retrospective single-center study.

The pathophysiology of immune thrombocytopenia (ITP) involves immune-mediated platelet destruction. The presence of adipose tissue in obese individuals creates an inflammatory environment that could potentially impact the clinical course and outcomes of ITP. However the relationship between obesity and ITP outcomes has not been well described. We evaluated ITP outcomes in 275 patients diagnosed with primary ITP from 2012 to 2022. Patients were categorized into four groups based on their body mass index (BMI) at diagnosis. Female gender was associated with a lower platelet count at the time of diagnosis at any BMI. Patients with high BMI had lower platelet counts at diagnosis and at platelet nadir (p < 0.001), an increased likelihood of requiring therapy (p < 0.001) and requiring multiple lines of therapy (p = 0.032). Non-obese patients who required corticosteroid treatment experienced a longer remission duration compared to obese patients (p = 0.009) and were less likely to be steroid-dependent (p = 0.048). Our findings suggest that obesity may be a significant risk factor for developing ITP and for ITP prognosis. Future studies are needed to evaluate the role of weight loss intervention in improving ITP outcomes.

Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open-label study.

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.

The Role of Early Subspeciality Consultation in the Timing of Hemophagocytic Lymphohistiocytosis Diagnosis and Management.

OBJECTIVE: The aim of this study was to investigate the relation between timing of subspeciality consult and hemophagocytic lymphohistiocytosis (HLH) consideration, immunosuppression initiation, and in-hospital mortality in patients with HLH. METHODS: We conducted a medical records review study of patients 18 years or older with definite or probable HLH at Montefiore Medical Center between 2006 and 2019. Earlier subspeciality consultation (rheumatology, hematology, and infectious disease) was defined as consultation in less than or equal to 18 hours from time of admission. Demographic, clinical characteristics, and outcomes were compared between patients with early and later subspecialty consultation. RESULTS: A total of 28 patients were included. The median age was 40 years, and 61% of patients were male. Infection was identified as a cause of HLH in 13 patients (46%). Fifteen patients (54%) were classified as having an earlier subspeciality consultation with a median time (interquartile range) to HLH consideration of 1.0 day (0.3-4.2 days) compared with 7.9 days (3.1-9.9 days) for the later consultation group (p = 0.002). The median time (interquartile range) to immunosuppression initiation was 4.6 days (1.7-7.8 days) versus 10.9 days (5.1-13.4 days) (p = 0.01), respectively. Five patients (33%) had in-hospital deaths in the early consultation group compared with 7 patients (54%) in later consultation group (p = 0.27). Among the subset of patients who survived to discharge, the 90-day readmission rate was higher in the later consultation group (83% vs 30%, p = 0.12). CONCLUSIONS: In patients with HLH, earlier subspeciality consultation may play a role in earlier HLH consideration and treatment initiation.

Association between antiphospholipid antibodies and all-cause mortality among end-stage renal disease patients with and without SLE: a retrospective cohort study.

OBJECTIVE: To investigate the association between the presence of aPL and/or LA and all-cause mortality among end-stage renal disease (ESRD) patients with and without SLE. METHODS: We included ESRD patients >18 years old followed at an urban tertiary care centre between 1 January 2006 and 31 January 2014 who had aPL measured at least once after initiating haemodialysis. All SLE patients met ACR/SLICC criteria. APL/LA+ was defined as aCL IgG or IgM >40 IU, anti-ß2glycoprotein1 IgG or IgM >40 IU or LA+. Deaths as at 31 January 2014 were captured in the linked National Death Index data. Time to death was defined from the first aPL measurement. RESULTS: We included 34 SLE ESRD and 64 non-SLE ESRD patients; 30 patients died during the study period. SLE ESRD patients were younger [40.4 (12.5) vs 51.9 (18.1) years, P = 0.001] and more were women (88.2% vs 54.7%, P < 0.001) vs non-SLE ESRD patients. The frequency of aPL/LA+ was 24% in SLE and 13% in non-SLE ESRD (P = 0.16). Median (inter-quartile range) follow-up time was 1.6 (0.3-3.5) years in SLE and 1.4 (0.4-3.2) years in non-SLE, P = 0.74. The adjusted hazard ratio (HR) for all-cause mortality for SLE patients who were aPL/LA+ vs aPL/LA- was 9.93 (95% CI 1.33, 74.19); the adjusted HR for non-SLE aPL/LA+ vs aPL/LA- was 0.77 (95% CI 0.14, 4.29). CONCLUSION: SLE ESRD patients with aPL/LA+ had higher all-cause mortality risk than SLE ESRD patients without these antibodies, while the effects of aPL/LA on mortality were comparable among non-SLE ESRD patients.

Diagnosis and management of Evans syndrome in adults: first consensus recommendations.

Evans syndrome is a rare disease marked by a severe clinical course, high relapse rate, infectious and thrombotic complications, and sometimes fatal outcome. Management is highly heterogeneous. There are several case reports but few large retrospective studies and no prospective or randomised trials. Here, we report the results of the first consensus-based expert recommendations aimed at harmonising the diagnosis and management of Evans syndrome in adults. After reviewing the literature, we used a fuzzy Delphi consensus method, with two rounds of a 42-item questionnaire that were scored by a panel of 13 international experts from five countries using a 7-point Likert scale. Panellists were selected by the core panel on the basis of their personal experience and previous publications on Evans syndrome and immune cytopenias; they met virtually throughout 2023. The panellists recommended extensive clinical and laboratory diagnostic tests, including bone marrow evaluation and CT scan, and an aggressive front-line therapy with prednisone (with or without intravenous immunoglobulins), with different treatment durations and tapering for immune thrombocytopenia and autoimmune haemolytic anaemias (AIHAs). Rituximab was strongly recommended as first-line treatment in cold-type AIHA and as second-line treatment in warm-type AIHA and patients with immune thrombocytopenia and antiphospholipid antibodies, previous thrombotic events, or associated lymphoproliferative diseases. However, rituximab was discouraged for patients with immunodeficiency or severe infections, with the same applying to splenectomy. Thrombopoietin receptor agonists were recommended for chronic immune thrombocytopenia and in the case of previous grade 4 infection. Fostamatinib was recommended as third-line or further-line treatment and suggested as second-line therapy for patients with previous thrombotic events. Immunosuppressive agents have been moved to third-line or further-line treatment. The panellists recommended the use of recombinant erythropoietin in AIHA in the case of inadequate reticulocyte counts, use of the complement inhibitor sutimlimab for relapsed cold AIHA, and the combination of rituximab plus bendamustine in Evans syndrome secondary to lymphoproliferative disorders. Finally, recommendations were given for supportive therapy, platelet or red blood cell transfusions, and thrombotic and antibiotic prophylaxis. These consensus-based recommendations should facilitate best practice for diagnosis and management of Evans syndrome in clinical practice.

Rituximab resistance in ITP and beyond.

The pathophysiology of immune thrombocytopenia (ITP) is complex and encompasses innate and adaptive immune responses, as well as megakaryocyte dysfunction. Rituximab is administered in relapsed cases and has the added benefit of inducing treatment-free remission in over 50% of patients. Nevertheless, the responses to this therapy are not long-lasting, and resistance development is frequent. B cells, T cells, and plasma cells play a role in developing resistance. To overcome this resistance, targeting these pathways through splenectomy and novel therapies that target FcγR pathway, FcRn, complement, B cells, plasma cells, and T cells can be useful. This review will summarize the pathogenetic mechanisms implicated in rituximab resistance and examine the potential therapeutic interventions to overcome it. This review will explore the efficacy of established therapies, as well as novel therapeutic approaches and agents currently in development.

Development of New Drugs for Autoimmune Hemolytic Anemia.

Autoimmune hemolytic anemia (AIHA) is a rare disorder characterized by the autoantibody-mediated destruction of red blood cells, and treatments for it still remain challenging. Traditional first-line immunosuppressive therapy, which includes corticosteroids and rituximab, is associated with adverse effects as well as treatment failures, and relapses are common. Subsequent lines of therapy are associated with higher rates of toxicity, and some patients remain refractory to currently available treatments. Novel therapies have become promising for this vulnerable population. In this review, we will discuss the mechanism of action, existing data, and ongoing clinical trials of current novel therapies for AIHA, including B-cell-directed therapy, phagocytosis inhibition, plasma cell-directed therapy, and complement inhibition.

Maternal Hematologic Conditions and Fetal/Neonatal Outcomes of Pregnancy.

Hematologic conditions in reproductive-age women can complicate pregnancy and the neonatal period. Affected pregnancies have a higher risk of severe morbidity and mortality. Coagulation factor changes that occur in the normal state of pregnancy can delay detection and recognition of a bleeding disorder in cases without an apparent bleeding history, thus hindering the appropriate management during gestation and the neonatal period. In addition, unique maternal immunologic changes occur during pregnancy, which are meant to protect the fetus who shares paternal antigens. Rarely, derangement of the maternal immune system may result in alloimmunization against fetal platelet antigens, leading to the development of fetal and/or neonatal thrombocytopenia. Bleeding and platelet disorders pose significant risk of intracranial hemorrhage for the fetus and newborn that is associated with significant morbidity and mortality. We discuss contemporary diagnosis and management of rare bleeding and platelet disorders in pregnancy and their effect on the neonatal period.

Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia.

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia, less than 50% of patients remain in long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder that requires therapy in the majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first-line as well as relapsed settings. Rituximab is the preferred therapy for steroid refractory warm autoimmune hemolytic anemia (wAIHA) and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of rituximab and the current literature on its role in the management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease.

A rare combination of thrombotic thrombocytopenic purpura and antiphospholipid syndrome.

: Thrombocytopenia, in the setting of microangiopathic hemolytic anemia and thrombotic events, is characteristic of both thrombotic thrombocytopenic purpura and primary antiphospholipid syndrome. Clinically, it is difficult to distinguish between these two syndromes. We present a 41-year-old woman with chronic, relapsing thrombotic thrombocytopenic purpura in the presence of antiphospholipid antibodies. She had clinical manifestations of antiphospholipid syndrome without meeting laboratory criteria of the Sydney classification system. In the literature, there have only been nine cases of thrombotic thrombocytopenic purpura associated with primary antiphospholipid syndrome. Seven of the nine cases suffered from one or multiple strokes, a common feature in antiphospholipid syndrome, but an uncommon finding in thrombotic thrombocytopenic purpura. We introduce the possibility of an association between thrombotic thrombocytopenic purpura and the presence of antiphospholipid antibodies. Systematic testing of ADAMTS13 activity and anti-ADAMTS13 antibodies in patients who present with neurological symptoms and thrombocytopenia, in the presence of antiphospholipid antibodies, may help with the diagnosis of the rare thrombotic thrombocytopenic purpura-antiphospholipid syndrome combination.