Systemic loxoscelism leading to autoimmune haemolytic anaemia in a healthy young adult.

The brown recluse spider (Loxosceles reclusa) is endemic to the southcentral Midwest and the Southern United States. A bite from a brown recluse spider may result in symptoms that range from local skin necrosis to systemic complications such as acute haemolytic anaemia, disseminated intravascular coagulopathy, rhabdomyolysis and death. Although rare, systemic loxoscelism is a clinical diagnosis of exclusion that should be considered in a patient with acute autoimmune haemolytic anaemia. We describe a case of a young man with autoimmune haemolytic anaemia secondary to systemic loxoscelism successfully treated with intravenous immunoglobulin and steroids.

The evolving management algorithm for the patient with newly diagnosed cold agglutinin disease.

INTRODUCTION: Cold agglutinin disease (CAD) is driven by IgM autoantibodies reactive at <37°C and able to fix complement. The activation of the classical complement pathway leads to C3-mediated extravascular hemolysis in the liver and to intravascular hemolytic crises in case of complement amplifying conditions. C3 positivity at direct Coombs test along with high titer agglutins are required for the diagnosis. Treatment is less standardized. AREAS COVERED: This review recapitulates CAD diagnosis and then focus on the evolving management of the disease. Both current approach and novel targeted drugs are discussed. Literature search was conducted in PubMed and Scopus from 2000 to 2024 using 'CAD' and 'autoimmune hemolytic anemia' as keywords. EXPERT OPINION: Rituximab represents the frontline approach in patients with symptomatic anemia or disabling cold-induced peripheral symptoms and is effective in 50-60% of cases. Refractory/relapsing patients are an unmet need and may now benefit from complement inhibitors, particularly the anti-C1s sutimlimab, effective in controlling hemolysis thus improving anemia in >80% of patients, but not active on cold-induced peripheral symptoms. Novel drugs include long-acting complement inhibitors, plasma cells, and B-cell targeting agents (proteasome inhibitors, anti-CD38, BTKi, PI3Ki, anti-BAFF). Combination therapy may be the future answer to CAD unmet needs.

Case of autoimmune haemolytic anaemia, possibly secondary to vedolizumab in ulcerative colitis, successfully treated with rituximab.

Autoimmune haemolytic anaemia (AIHA), autoimmune destruction of erythrocytes is most commonly secondary to immunomodulated conditions. The association between AIHA and inflammatory bowel disease (IBD) has been poorly investigated. We aim to report a case of AIHA in a patient with ulcerative colitis (UC) treated with vedolizumab.A case of a woman in her 30s with UC that after the initiation of vedolizumab developed severe anaemia. Due to the absence of visible blood losses and a positive Coombs direct test, the diagnosis of AIHA was established. The patient initially initiated prednisolone with no response. Rituximab had to be introduced. After a few days with this therapy, there was a clinical and analytical improvement.AIHA must be taken into account as a possible cause of anaemia in patients with IBD. The differential diagnosis between IBD or drug-related (namely vedolizumab) as the cause of the AIHA is complex and almost impossible to establish.

Clinical Approach to Immune-Mediated Hemolytic Anemia and Thrombocytopenia.

Primary immune mediated hemolytic anemia (IMHA) and thrombocytopenia (IMTP) are rare in horses with the conditions more commonly occurring secondary to underlying disease. Several case reports have suggested a link between neoplasia and immune-mediated destruction of platelets and red blood cells. Diagnostic investigations should therefore focus on identifying possible underlying causes such as infections and neoplasia. Immunosuppressive therapy with corticosteroids and azathioprine is the mainstay of treatment but should be used cautiously in cases where underlying infection has not been excluded. Given the frequent association of secondary IMHA and IMTP cases with neoplasia, primary cases generally have a better prognosis.

Efficacy of rituximab-containing regimens used as first-line and rescue therapy for giant cell hepatitis with autoimmune hemolytic anemia a retrospective study.

OBJECTIVE: To evaluate the efficacy of rituximab (RTX)-containing therapy as first-line as well as rescue treatment for giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA). METHODS: This retrospective study recruited patients diagnosed with GCH-AHA and treated with conventional immunosuppressor regimens consisting of prednisone or RTX-containing regimes consisting of RTX and prednisone, with or without another immunosuppressor. The primary outcomes were the complete remission (CR) rate and time-period required for CR. The secondary outcomes included relapses and adverse events. RESULTS: Twenty patients (8 females and 12 males; age range 1-26 months), 15 receiving conventional regimens and 5 receiving RTX-containing regimens, were included. The CR rates were 73.3 % (11/15) and 100 % (5/5) in the conventional and RTX-containing groups, respectively. The time-period required for CR was significantly shorter in the RTX-containing group than in the conventional group (6 (3-8) versus 14 (5-25) months, P = 0.015). Relapses occurred in 30.8 % (4/13) of patients in the conventional group; all achieved CR after adding RTX. Relapses occurred in 40.0 % (2/5) of patients in the RTX-containing group; both achieved CR after adding intravenous immune globulins or tacrolimus. Transient low immunoglobulin and infections were recorded in both groups. Treatment withdrawal was achieved in 73.3 % (11/15) and 60.0 % (3/5) of patients receiving conventional and RTX-containing regimens after 36 (2-101) and 22 (4-41) months, respectively. Two patients in conventional group died of disease progression and infection. CONCLUSIONS: RTX-containing first-line therapy achieves CR of GCH-AHA more quickly than the conventional therapy. RTX is efficacious when added to rescue therapy.

Multiple autoimmune disorders refractory to glucocorticoids after allogeneic hematopoietic stem cell transplantation: a case report and review of the literature.

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy.

Cost-effectiveness of sutimlimab in cold agglutinin disease.

Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold-reactive antibodies that bind to red blood cells and lead to complement-mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard-of-care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis, was shown to reduce transfusion-dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2-year extension data. Using data from the transfusion-dependent patient population that led to sutimlimab's initial FDA approval, we performed the first-ever cost-effectiveness analysis in primary CAD. The projected incremental cost-effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper-end conventional US willingness-to-pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan-refractory SOC patient phenotype (i.e., treated sequentially with bendamustine-rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time-limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost-effective. The impact of sutimlimab on health system costs with longer term follow-up data merits future study and consideration through a distributional cost-effectiveness framework.

Sirolimus is effective and safe in childhood relapsed-refractory autoimmune cytopenias: A multicentre study.

Autoimmune cytopenias are a heterogeneous group of disorders characterized by immune-mediated destruction of haematopoietic cell lines. Effective and well-tolerated treatment options for relapsed-refractory immune cytopenias are limited. In this study, the aim was to evaluate the efficacy and safety of sirolimus in this disease group within the paediatric age group. The study enrolled patients in the paediatric age group who used sirolimus with a diagnosis of immune cytopenia between December 2010 and December 2020, followed at six centres in Turkey. Of the 17 patients, five (29.4%) were treated for autoimmune haemolytic anaemia (AIHA), six (35.2%) for immune thrombocytopenic purpura (ITP) and six (35.2%) for Evans syndrome (ES). The mean response time was 2.7 months (range, 0-9 months). Complete response (CR) and partial response (PR) were obtained in 13 of 17 patients (76.4%) and nonresponse (NR) in four patients (23.5%). Among the 13 patients who achieved CR, three of them were NR in the follow-up and two of them had remission with low-dose steroid and sirolimus. Thus, overall response rate (ORR) was achieved in 12 of 17 patients (70.5%). In conclusion, sirolimus may be an effective and safe option in paediatric patients with relapsed-refractory immune cytopenia.

Successful treatment of concurrent cold agglutinin disease and myelodysplastic syndrome.

Herein, we describe a case of severe anemia presenting with myelodysplastic syndrome with cold agglutinin disease that was successfully treated by a moderate dose of steroids followed by cyclosporine. In patients with myelodysplastic syndrome, autoimmunity in erythroid cells is occasionally demonstrated, and autoimmune hemolytic anemia is seen in some patients. However, hemolytic anemia with cold agglutinin in patients with myelodysplastic syndrome is less common, and the effect of corticosteroids for autoimmune hemolytic anemia caused by cold agglutinin is thought to be limited. Although the elevated levels of reticulocytes and LDH are usually caused by ineffective hematopoiesis in myelodysplastic syndrome, clinicians should be aware of latent cold agglutinin disease. In the present case, in addition to the improvement of erythroid dysplasia, the corticosteroid-sparing effect on cold agglutinin disease may have played a role in the mechanism underlying the effectiveness of cyclosporine.

Autoimmune hemolytic anemia and thrombocytopenia in a Chinese patient with heterozygous NBAS mutations: Case report.

RATIONALE: Neuroblastoma amplified sequence (NBAS)-associated disease is an autosomal recessive disorder and a broad spectrum of clinical symptoms has been reported. However, autoimmune mediated hemolytic anemia (AIHA) is rarely reported in NBAS disease. PATIENT CONCERNS: A now 21-year-old male harbors heterozygous variants of c.6840G>A and c.335 + 1G>A and was found had retarded growth, hypogammaglobulinemia, B lymphopenia, optic atrophy, horizontal nystagmus, slight splenomegaly and hepatomegaly since childhood. This case had normal hemoglobin level and platelet count in his childhood. He developed AIHA first in his adulthood and then thrombocytopenia during the treatment of AIHA. The mechanism underlying a case with pronounced hypogammaglobulinemia and B lymphopenia is elusive. In addition to biallelic NBAS mutations, a germline mutation in the ANKRD26 (c.2356C>T) gene was also detected. So either autoimmune or ANKRD26 mutation-mediated thrombocytopenia is possible in this case. INTERVENTION AND OUTCOME: He was initially managed with steroid and intermittent intravenous immunoglobulin supplement. After treatment, he responded well with a normalization of hemoglobin and serum bilirubin. But the patient subsequently experienced severe thrombocytopenia in addition to AIHA. He was then given daily avatrombopag in addition to steroid escalation. He responded again to new treatment, with the hemoglobin levels and platelet counts went back to the normal ranges. Now he was on de-escalated weekly avatrombopag and low-dose steroids maintenance. CONCLUSION: The phenotype of this case indicates that c.335 + 1G>A NBAS variant is probably a pathogenic one and c.2356C>T ANKRD26 variant is improbably a pathogenic one. AIHA may respond well to steroid even when happened in patients with NBAS disease.

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease.

ABSTRACT: Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.

Autoimmune cytopenias in children: When to think of primary immunodeficiency?

Autoimmune cytopenias are defined by autoantibodies' immune destruction of one or more blood elements. Most often it is autoimmune hemolytic anemia or immune thrombocytopenia or both that define Evans syndrome. It may be secondary to infection or to underlying pathology such as systemic autoimmune disease or primary immunodeficiency, especially when it becomes chronic over several years. Primary Immunodeficiencies or inborn errors of immunity (IEI) are no longer defined solely by infections: autoimmunity is part of the clinical features of several of these diseases. It is dominated by autoimmune cytopenias, in particular, immune thrombocytopenia (ITP) and autoimmune hemolytic anaemia (AIHA). The challenges for the clinician are the situations where autoimmune cytopenias are chronic, recurrent and/or refractory to the various long-term therapeutic options. Most of these therapies are similar in action and generally consist of non-mediated immune suppression or modulation. In these situations, primary Immunodeficiencies must be diagnosed as soon as possible to allow the initiation of a targeted treatment and to avoid several ineffective therapeutic lines.

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.

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections.

INTRODUCTION: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI. METHODS: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups. RESULTS: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups. CONCLUSION: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

Anemia hemolítica autoinmune después de la infección por Covid 19 / Autoimmune Haemolytic Anaemia After Covid 19 Infection

Since its emergence in Wuhan province in late 2019, SARS-CoV-2 infection has affected more than 520 million people and caused the death of more than 6.2 million individuals. Despite rare, several haematological disorders have been observed and associated with SARS-CoV-2 infection, in particular, autoimmune haemolytic anaemia (AIHA). We present the case of a 71-year-old man with recent SARS-CoV-2 infection, presenting with 5 weeks evolution of asthenia and loss of 10% of body weight. From the initial study, normochromic normocytic anaemia stands out with haptoglobin consumption. Direct Coombs test was positive, with positive direct antiglobulin test for IgG4. The patient was admitted and started corticosteroids therapy with prednisolone 1 mg / kg. Given that the extended etiologic study was negative, covid 19 was assumed to be the trigger of the current clinical picture. During hospitalization, the patient presented a favourable evolution with recovery of haemoglobin value and absence of haemolysis. (AU)

Desde su aparición en la provincia de Wuhan a finales de 2019, la infección por SARS-CoV-2 ha afectado a más de 520 millones de personas y ha causado la muerte de más de 6,2 millones de individuos. A pesar de ser poco frecuentes, se han observado varios trastornos hematológicos asociados a la infección por SARS-CoV-2, en particular la anemia hemolítica autoinmune (AIHA). Presentamos el caso de un varón de 71 años con infección reciente por SARS-CoV-2, que presenta astenia de 5 semanas de evolución y pérdida del 10% del peso corporal. Del estudio inicial destaca anemia normocítica normocrómica con consumo de haptoglobina. El test de Coombs directo fue positivo, con antiglobulina directa positiva para IgG4.El paciente fue ingresado y se inició tratamiento con corticosteroides con prednisolona 1 mg / kg. Dado que el estudio etiológico ampliado fue negativo, se asumió que el covid 19 era el desencadenante del cuadro clínico actual. Durante la hospitalización, el paciente presentó una evolución favorable con recuperación del valor de hemoglobina y ausencia de hemólisis. (AU)

Anemia hemolítica autoinmune / Autoimmune haemolytic anaemia

Las anemias hemolíticas autoinmunes (AHAI) son trastornos hematológicos adquiridos ocasionados por una destrucción periférica de eritrocitos incrementada, mediada por autoanticuerpos dirigidos frente a antígenos eritrocitarios. Se clasifican según etiología en primarias y secundarias, y según el tipo de anticuerpo detectado y temperatura de reacción en AHAI por anticuerpos calientes (AHAI-C) y AHAI por anticuerpos fríos (AHAI-F).El pilar del manejo en AHAI-C continúa siendo el tratamiento con glucocorticoides, y la adición precoz de rituximab ha demostrado buenos resultados en los últimos estudios. Las AHAI-F primarias se tratan principalmente con rituximab, solo o combinado con quimioterapia.En fase de desarrollo avanzado encontramos nuevos fármacos como los inhibidores de Syk, Ig anti-FcRn e inhibidores del complemento, que permitirán ampliar el arsenal terapéutico, especialmente en casos refractarios o recidivantes. (AU)

Autoimmune haemolytic anaemias (AIHA) are acquired haematological disorders caused by increased peripheral erythrocyte destruction mediated by autoantibodies against erythrocyte antigens. They classified according to aetiology into primary and secondary, and according to the type of antibody and reaction temperature into AIHA due to warm antibodies (w-AIHA) and AIHA due to cold antibodies (c-AIHA).The mainstay of management in w-AIHA remains glucocorticoid therapy, and the early addition of rituximab has shown good results in recent studies. Primary c-AIHA is mainly treated with rituximab, alone or in combination with chemotherapy.New drugs such as Syk inhibitors, anti-FcRn Ig and complement inhibitors are in advanced development and will expand the therapeutic arsenal, especially in refractory or relapsed cases. (AU)