Severe autoimmune hemolytic anemia; epidemiology, clinical management, outcomes and knowledge gaps.

Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder, mediated by auto-antibodies, and has a variable clinical course ranging from fully compensated low grade hemolysis to severe life-threatening cases. The rarity, heterogeneity and incomplete understanding of severe AIHA complicate the recognition and management of severe cases. In this review, we describe how severe AIHA can be defined and what is currently known of the severity and outcome of AIHA. There are no validated predictors for severe clinical course, but certain risk factors for poor outcomes (hospitalisation, transfusion need and mortality) can aid in recognizing severe cases. Some serological subtypes of AIHA (warm AIHA with complement positive DAT, mixed, atypical) are associated with lower hemoglobin levels, higher transfusion need and mortality. Currently, there is no evidence-based therapeutic approach for severe AIHA. We provide a general approach for the management of severe AIHA patients, incorporating monitoring, supportive measures and therapeutic options based on expert opinion. In cases where steroids fail, there is a lack of rapidly effective therapeutic options. In this era, numerous novel therapies are emerging for AIHA, including novel complement inhibitors, such as sutimlimab. Their potential in severe AIHA is discussed. Future research efforts are needed to gain a clearer picture of severe AIHA and develop prediction models for severe disease course. It is crucial to incorporate not only clinical characteristics but also biomarkers that are associated with pathophysiological differences and severity, to enhance the accuracy of prediction models and facilitate the selection of the optimal therapeutic approach. Future clinical trials should prioritize the inclusion of severe AIHA patients, particularly in the quest for rapidly acting novel agents.

The long-term effect of mTOR inhibition on lipid and glucose metabolism in tuberous sclerosis complex: data from the Dutch TSC registry.

BACKGROUND: MTOR inhibition is an effective treatment for many manifestations of tuberous sclerosis complex. Because mTOR inhibition is a disease modifying therapy, lifelong use will most likely be necessary. This study addresses the long-term effects of mTOR inhibitors on lipid and glucose metabolism and aims to provide better insight in the incidence and time course of these metabolic adverse effects in treated TSC patients. METHODS: All patients who gave informed consent for the nationwide TSC Registry and were ever treated with mTOR inhibitors (sirolimus and/or everolimus) were included. Lipid profiles, HbA1c and medication were analysed in all patients before and during mTOR inhibitor treatment. RESULTS: We included 141 patients, the median age was 36 years, median use of mTOR inhibitors 5.1 years (aimed serum levels 3.0-5.0 µg/l). Total cholesterol, LDL- and HDL-cholesterol levels at baseline were similar to healthy reference data. After start of mTOR inhibition therapy, total cholesterol, LDL-cholesterol and triglycerides increased significantly and were higher compared to healthy reference population. Mean total cholesterol levels increased by 1.0 mmol/L after 3-6 months of mTOR inhibition therapy but did not increase further during follow-up. In this study, 2.5% (3/118) of patients developed diabetes (defined as an HbA1c ≥ 48 mmol/mol) during a median follow-up of 5 years. CONCLUSIONS: Hypercholesterolemia is a frequent side effect of mTOR inhibition in TSC patients, and predominantly occurs within the first year of treatment. Although hyperglycemia is a frequent side effect in other indications for mTOR inhibition, incidence of diabetes mellitus in TSC patients was only 2.5%. This may reflect the difference of mTOR inhibition in patients with normal mTOR complex pathway function versus patients with overactive mTOR complex signaling due to a genetic defect (TSC patients).

Two-Year Outcome after Laparoscopic Fundoplication in Pediatric Patients with Gastroesophageal Reflux Disease.

Introduction: Many studies on short-term efficacy of laparoscopic antireflux surgery (LARS) have shown good to excellent results on reflux symptom control and health-related quality of life (HRQoL). Prospective studies on the long-term efficacy, however, are scarce and indicate that the efficacy of symptom control may decline over time. The aim of this study is to assess the 2-year outcome on reflux symptoms and HRQoL after LARS. Materials and Methods: Between 2011 and 2013, 25 children (12 males, median age 6 [2-18] years) with proton pump inhibitor-resistant gastroesophageal reflux disease were included in a prospective longitudinal cohort study. To assess reflux symptoms and HRQoL, patients and/or their caregivers were asked to fill out the validated age-appropriate gastroesophageal reflux symptom questionnaire and Pediatric Quality of Life Inventory™ before, 3 months, 1 year, and 2 years after LARS. Results: Two years after LARS, 29% of patients had moderate to severe reflux symptoms compared with 92% (P < .001) before operation and 12% 3-4 months after operation (P = .219). The significant increase in HRQoL shortly after fundoplication (80.0 compared with 69.5 (P = .004)) is not observed after 2 years (72.0 compared with 69.5, P = .312). Correlation between the impaired HRQoL scores and the recurrence of symptoms could not be verified. Conclusions: Although the efficacy of LARS tends to deteriorate after 2 years, LARS is still effective in controlling reflux symptoms in the majority of patients. The short-term improvement in HRQoL after LARS appears to be transient.