Autoimmune rheumatologic diseases
Monogenic autoinflammatory syndromes (MAIS) are characterized by primary over-activation of the innate immune system. Induction of the inflammasome complex by innate immune sensors and increased production of IL-1b are implicated in its pathogenesis. Macrophage activation syndrome (MAS) is defined by acute hyper-inflammation and unopposed cytokine release. The early therapeutic use of IL-1b inhibition has profoundly improved the prognosis MAS. Significant overlap in clinical presentation and laboratory markers between patients with MAIS and MAS led us to explore the role of free IL-18 and therapeutic use of IL-1b inhibition in a patient with MAIS due to CDC42 mutation. We report the case of an 20 months-old female who presented with hydrops fetalis in-utero, and later developed failure-to-thrive, splenomegaly, anemia, thrombocytopenia, rashes, frequent febrile episodes along with massive increase in CRP, ESR and ferritin. Whole Exome Sequencing (WES) identified a heterogenous likely pathogenic de novo variant in cell division control protein 42 homolog (CDC42) c.563G>A (p.C188Y).
Because of significant clinical overlap to MAS, we measured IL-6, IL-18, free IL-18 and IL-18 binding protein, all of which were highly increased. Her IL1-b level was normal, but an increase in IL-1b is hardly ever detectable in the serum despite playing a critical role in this type of inflammation. With this rationale we started the IL-1 receptor antagonist anakinra, with immediate, dramatic clinical improvement.
Significant increase in free IL-18 and extremely encouraging clinical response to therapy with anakinra in a patient with novel CDC42 mutation suggests a mechanistic link between MAS and defects in CDC42.