An 8-year-11-month-old girl with severe atopic dermatitis had previously received treatments including topical hydrocortisone butyrate, pimecrolimus, tacrolimus, hormone ointment encapsulation, and narrowband ultraviolet B (NB-UVB) phototherapy. She also took oral antihistamines such as cetirizine and loratadine, but these interventions provided limited relief, and her pruritus persisted. In August 2023, she began dupilumab therapy with a 400 mg subcutaneous loading dose, followed by 200 mg subcutaneous injections every two weeks. Vitiligo developed three months after dupilumab initiation in this child with severe atopic dermatitis and improved with combination therapy while dupilumab was continued. Together with previously published reports, this observation supports a possible temporal association between dupilumab exposure and vitiligo development; however, causality cannot be established from the currently available evidence.

Cold antibody-mediated autoimmune hemolytic anemia, or cold agglutinin syndrome (CAS), in pediatrics is typically transient, although it can often be severe and require transfusion support. Recurrence in children is rare, but those with underlying immune dysfunction can have a refractory course with limited options available. We report a 4-year-old girl with Evans syndrome and life-threatening CAS refractory to transfusions, plasmapheresis, steroids, and immunosuppression as well as a 12-month-old boy status post liver transplant with CAS refractory to steroids, rituximab, and tacrolimus cessation with transition to sirolimus, both of whom received sutimlimab, a C1s inhibitor, with rapid improvement in hemolysis, transfusion independence, and a sustained remission. To our knowledge, these are the first reported uses of sutimlimab in the pediatric population.

Calcineurin-nuclear factor of activated T cells (NFAT) signaling plays a central role in immune activation and represents a major therapeutic target for immunosuppression. Although calcineurin inhibitors such as tacrolimus are clinically effective, their long-term use is limited by severe systemic toxicities associated in part with broad inhibition of calcineurin catalytic activity. In this study, we investigated whether small-molecule inhibition of NFAT signaling could suppress NFAT activation while limiting direct inhibition of calcineurin catalytic activity. We designed and synthesized fourteen analogs (2-15) based on a small-molecule inhibitor previously identified and derived from the PxIxIT sequence. We assessed the inhibitory activities of structurally modified analogs against NFATc1 and NFATc2 and compared their isoform-specific inhibitory profiles. Our investigation revealed that analog 14 produced closely matched inhibition of NFATc1 and NFATc2, suppressed NFAT-dependent cytokine production, and showed cellular immunosuppressive activities. Importantly, 14 showed only limited inhibition of calcineurin catalytic activity at concentrations associated with its NFAT-inhibitory effects. At concentrations matched for IL-2 suppression, 14 modestly reduced Jurkat T-cell proliferation and activation. It also showed a favorable preliminary safety-related profile across the cellular and zebrafish models tested, including longer-term assessments of cell viability, oxidative stress, and renal injury. Collectively, these findings establish 14 as an early-stage lead compound for selective modulation of NFAT signaling while limiting calcineurin catalytic inhibition, providing a foundation for further pharmacological development.

GRAVITAS-119 (NCT03320642), a single-arm, open-label, phase 1, proof-of-concept study, assessed addition of itacitinib to standard-of-care graft-versus-host disease (GVHD) prophylaxis regimens in reduced-intensity conditioning peripheral blood allogeneic hematopoietic stem cell transplant. Day 28 hematologic recovery (percentage of patients demonstrating neutrophil recovery and platelet recovery) was the primary endpoint. Of 84 enrolled patients, 41 received itacitinib plus tacrolimus/methotrexate (nine with antithymocyte globulin [ATG]), 24 received itacitinib plus cyclosporine A/mycophenolate mofetil (16 with ATG), and 19 received itacitinib plus post-transplant cyclophosphamide/tacrolimus. Hematologic recovery was achieved by 51/55 (92.7%) evaluable patients (neutrophil recovery, 98.7%; platelet recovery, 94.6%). Estimated 1-year GVHD-free, relapse-free survival was 39.7%; estimated 1-year overall survival was 78.3%. Cumulative incidences for grade 2‒4 and grade 3‒4 acute GVHD at Day 180 were 13.2% and 4.8%, respectively; cumulative incidence of chronic GVHD at 1 year was 37.8%. Most common grade ≥3 adverse events were cytopenias; grade ≥3 infections occurred in 23 (27.4%) patients. Most patients receiving itacitinib plus standard-of-care GVHD prophylaxis achieved hematologic recovery, with any-grade GVHD and infection rates similar to previous reports with standard-of-care prophylaxis. Addition of itacitinib to GVHD prophylaxis permits timely hematologic recovery and does not increase GVHD or infection rates, although unmet need still remains for improved regimens.

Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been the backbone of graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation for more than four decades. Yet, the pharmacological framework governing their therapeutic drug monitoring has been significantly imported from solid organ transplantation. This critical narrative review argues that this extrapolation is scientifically unsound. The unique biological environment of allogeneic hematopoietic cell transplantation characterized by toxic conditioning regimens, profound hematologic changes, systemic inflammation, and an unparalleled drug interaction landscape creates pharmacokinetic and pharmacodynamic conditions for which solid organ transplant-derived targets are inadequate. We critically appraise the quality of evidence underpinning current therapeutic drug monitoring practices, examine the historical divide between cyclosporine and tacrolimus use, and propose a research agenda directed at developing hematopoietic transplant-specific precision immunosuppression strategies.

Children with congenital and acquired heart disease frequently require complex and prolonged pharmacotherapy, often involving off-label cardiovascular medications with narrow therapeutic ranges. Consequently, variability in drug response and medication-related adverse events remains a significant clinical challenge in pediatric cardiology. Pharmacogenetics provides a framework to individualize drug selection and dosing by incorporating genetic variability alongside established clinical and developmental factors. This review outlines the current clinical utility and emerging role of pharmacogenetics in pediatric cardiology, emphasizing applications most relevant to day-to-day patient care. Established pharmacogenetic associations with direct implications for pediatric cardiac practice include gene-drug pairs involving tacrolimus (CYP3A5), warfarin (CYP2C9, VKORC1, CYP4F2, rs12777823 within the CYP2C), clopidogrel (CYP2C19), flecainide (CYP2D6), metoprolol (CYP2D6), and statins (SLCO1B1, ABCG2, CYP2C9), many of which are supported by guideline-based recommendations from the Clinical Pharmacogenetics Implementation Consortium. This review also highlights pharmacogenetic considerations for commonly prescribed non-cardiac medications that may influence cardiovascular outcomes in children with heart disease, identifies emerging areas for research, and emphasizes that as pharmacogenetic testing becomes increasingly accessible, its thoughtful integration into pediatric cardiology practice may improve therapeutic precision, enhance safety, and reduce preventable adverse drug events.

GIM/FP/GP: [Formula: see text] Nephrology: [Formula: see text].