Jak Inhibitor Induced Anemia in Pediatric Ibd

Abstract INTRODUCTION Hematologic adverse events associated with Janus Kinase inhibitors (JAKi), such as anemia, have not been reported in pediatric populations. Anemia in pediatric IBD is multifactorial, with contributions from inflammation, nutritional deficiencies, and medications. Inhibition of the JAK2 pathway suppresses EPO-driven erythropoiesis, leading to anemia, a phenomenon not well reported in children with IBD and JAKi use. Case Descriptions We report 4 patients (ages 4-15 years) with IBD (2 with UC, 2 with CD) managed at our tertiary care pediatric IBD center who developed anemia following initiation of JAKi therapy (1 patient on tofacitinib and 3 patients on upadacitinib). All patients had failed or were intolerant to anti-TNF and/or other biologic agents. Anemia was detected within 4-8 weeks of JAKi initiation or dose escalation. Hemoglobin declines ranged from ∼4-6 g/dL from prior baselines, with actual hemoglobin levels between 4.1-10.3 g/dL. Three out of the 4 patients required blood transfusions given the significance of their anemia (Hb 7 g/dL). Laboratory evaluation revealed macrocytosis in 2/4 cases but no other causes of macrocytosis was found, such as abnormal B12 or folate levels. No evidence of hemolysis or bleeding was found in all patients. IBD related disease activity and objective markers including CRP and calprotectin were stable despite the anemia, indicating anemia was likely not related to active IBD. While 3 of the patients had concurrent iron deficiency, their anemia did not resolve with iron repletion and recurred while on the same dose of JAKi. All patients’ anemia improved/resolved after discontinuation or dose reduction of JAKi. DISCUSSION While tofacitinib is a Jak1/3 receptor inhibitor and Upadacitinib is a selective JAK1 inhibitor, they both have JAK2 inhibition at higher doses. Disruption of JAK2 mediated EPO activation impairs proliferation and survival of erythroid progenitors, resulting in decreased red cell production and macrocytic anemia. This mechanism is distinct from iron deficiency or anemia of chronic inflammation seen in IBD. Macrocytic anemia in our cases was not attributable to B12 or folate deficiency, therefore, we believe it is due to suppression of erythropoiesis. Further, anemia in our patients could not be attributed to their IBD. Despite correction of iron deficiency in 2/4 patients, their anemia recurred while on the same dose of JAKi and improved with dose reduction. To date, there are no studies looking at optimal dosing of JAKi in pediatric patients. Development of anemia unexplained by other factors while on JAKi might be an important dose related side effect. Recognition of this adverse effect is essential for timely intervention to prevent further complications. Further studies are needed to delineate risk factors, optimal monitoring, and dosing for JAKi for pediatric IBD.