To the Editor, Mendelian type I interferonopathies are an increasingly recognized cause of treatment-refractory multisystem inflammation [1]. Here we report the beneficial effect of the JAK 1/2 inhibitor ruxolitinib in an infant with progressive neurological and lupus-like disease due to MDA5 gain-of-function. This female demonstrated delayed motor development from early infancy with lower limb hypertonia and dysarthria. Cranial MRI at age 29 months revealed a non-specific periventricular high signal T2 signal. Spinal cord imaging was normal. Her father had experienced a slowly progressive spastic paraparesis affecting his lower limbs, so that a diagnosis of hereditary spastic paraparesis was suggested. At 3 years of age, she presented with a 2-week history of retching, reduced appetite, and weight loss. Cognition was age appropriate and vision and hearing were normal. However, regression became evident over the following 6 months, with evolution of her motor disorder, continued retching, irritability, and the onset of oculogyric crises. Repeat imaging demonstrated more diffuse cerebral white matter signal change, with the spinal cord again normal. She continued to deteriorate, and at age 3 years 8 months developed an acute flaccid monoparesis of the right upper limb. As previously described [2], imaging revealed a longitudinally extensive transverse myelitis, significant cerebral atrophy, and increased white matter T2 high signal. Strongly positive serum and cerebrospinal fluid (CSF) aquaporin 4 antibody titers led to a diagnosis of neuromyelitis optica. Antinuclear antibodies (1: 160), anti-neutrophil cytoplasmic antibodies, and antidouble-stranded DNA (82.6 IU/mL) antibodies were also detected. Given a raised CSF neopterin (1035, normal range 7–65 nmol/L) and upregulation of interferon-stimulated genes (ISGs) in peripheral blood, a provisional diagnosis of type I interferonopathy was subsequently confirmed by the finding of a pathogenic IFIH1 mutation (c. 1483G. A; p. Gly495Arg). Rheumatology assessment highlighted alopecia, palmar erythema, livedo, and arthritis. Elevated erythrocyte sedimentation rate, transaminases, urinary protein/creatinine ratio, and lupus anticoagulant indicated a lupus-like illness. A dramatic improvement of her monoparesis and social interaction was observed following steroid treatment, comprising oral prednisolone tapering over 6 weeks supplemented by 4 weekly