Hemophagocytic lymphohistocytosis in trisomy 21: successful treatment with interferon inhibition

Abstract

Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation primarily driven by the cytokine interferon gamma. It can be either a genetic or acquired disorder associated with infection, malignancy, and rheumatologic disorders. Trisomy 21 can express a wide range of phenotypes which include immune dysregulation and shares inherent pathophysiology with a group of disorders termed interferonopathies. Knowledge of this overlap in seemingly unrelated conditions could provide a basis for future research, and most importantly, alternative therapeutic interventions in acute life threatening clinical scenarios. Herein, we describe two patients with trisomy 21 presenting with HLH that was refractory to conventional treatment. Both patients were successfully managed with novel interventions targeting the interferon pathway. Case presentation We describe a 17-month-old male and 15-month-old female with trisomy 21 presenting with a myriad of signs and symptoms including fever, rash, cytopenias, and hyperferritinemia, both ultimately diagnosed with HLH. Each had relapsing, refractory HLH over time requiring several admissions to the hospital receiving conventional high dose corticosteroids and interleukin-1 inhibition therapy. Successful steroid-free remission was achieved after targeting interferon inhibition with emapalumab induction followed by long-term maintenance on baricitinib. Conclusion To our knowledge, these are the first reported cases of relapsed, refractory HLH in patients with trisomy 21 successfully treated with emapalumab and transitioned to a steroid-sparing regimen with oral baricitinib for maintenance therapy. Trisomy 21 autoimmunity and HLH are both thought to be driven by interferon gamma. Targeting therapy toward interferon signaling in both HLH and autoimmunity in trisomy 21 may have potential therapeutic benefits. Further investigation is needed to determine if trisomy 21 may predispose to the development of HLH given this common pathway.

The Role of Vitamin D On Interferon- Levels in Indonesian Children with Down Syndrome And Its Contributing Factors: A Cross-sectional Study

“…Since autoimmunity and HLH in trisomy 21 are thought to be driven by IFN-γ, targeting interferon signaling may have potential therapeutic bene ts. 34 This study showed a signi cant role of high VD levels in decreasing IFN-γ (p-value 0.039, R 2 5.8%). VD plays an important role in regulating T helper cells as well as in the secretion of IFN-γ.…”

“…11 It is estimated that individuals with DS are four to six times more likely to develop autoimmune diseases such as celiac disease, T1DM, and autoimmune thyroiditis (AITD). 8 as well as susceptibility to leukemia 12 and life-threatening conditions of immune dysregulation primarily driven by the cytokine IFN-γ, such as hemophagocytic lymphohistiocytosis (HLH) 13 . Several studies have found lower VD levels in children with DS than in children without DS [9][10][11] ; this has recently been tied to an increased risk of autoimmunity 14 .…”

JAK inhibition decreases the autoimmune burden in Down syndrome

“…In mouse models of DS, both normalization of IFNR gene copy number and pharmacologic JAK1 inhibition rescue their lethal immune hypersensitivity phenotypes 22,48 . Furthermore, we recently demonstrated that IFN transcriptional scores derived from peripheral immune cells correlate significantly with the degree of immune remodeling and hypercytokinemia in DS 42 , and we and others have reported the safe use of JAK inhibitors for treatment of diverse immune conditions in DS, including alopecia areata 49 , psoriatic arthritis 50 and hemophagocytic lymphohistocytosis 51 through small case series. Encouraged by these results, we launched a clinical trial to assess the safety and efficacy of the JAK inhibitor tofacitinib (Xeljanz, Pfizer) in DS, using moderateto-severe autoimmune/inflammatory skin conditions as a qualifying criterion (NCT04246372).…”

Case report: emapalumab treatment for a pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patient with cytokine storm enabling allogeneic hematopoietic cell transplantation

“…Emapalumab specifically targets and inhibits IFN-γ, reducing the occurrence of cytokine storms. Their combined use can regulate the immune response of patients with HLH at different levels ( 10 , 24 , 25 ). Furthermore, plasma exchange helps in clearing deposits of cytokines including IFN-γ, improving the effectiveness of emapalumab.…”