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The type I interferonopathies, Mendelian disorders characterised by constitutive upregulation of the type I interferon (IFN) pathway, are associated with a spectrum of phenotypes particularly involving the brain and the skin.1 Mutations in the 3′−5′ DNA exonuclease TREX1 were the first described cause of the severe encephalopathy Aicardi-Goutières syndrome (AGS),2 of which acral vasculitic lesions are a well-recognised feature. Familial chilblain lupus (FCL) is the name given where such lesions occur in the absence of neurological disease.3 TREX1 dysfunction, due to biallelic loss of function or dominant negative heterozygous mutations, is postulated to lead to aberrant immune recognition of self-nucleic acids inducing the production of type I IFNs. These potent cytokines drive the expression of IFN-stimulated genes (ISGs) through the engagement of a common receptor and the subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2. We describe, to our knowledge for the first time, the efficacy of the JAK1/2 inhibitor ruxolitinib in a patient with TREX1-related skin disease. Parental consent was obtained for the use of ruxolitinib on a compassionate basis.
The patient carried a previously recorded dominant negative heterozygous mutation in TREX1 (c.52G>A, p.D18N) identified by Sanger sequencing and inherited from her asymptomatic mother (online supplementary figures S1 and S2). Her disease, starting at age 6 months, was characterised by painful chilblain-like lesions of the fingers, toes and cheeks. She was treated with hydroxychloroquine without obvious effect. From 2 years of age she presented recurrent episodes of polyarthritis, together with fevers, growth failure (weight and height falling from +0.5 SD to – 2 SD) and chronic pain. Development, neurological examination and cerebral imaging were normal. Treatment with methotrexate and steroids was initiated at the age of 3 years, without benefit.
We recorded persistently enhanced expression of ISGs4 in blood over a 3-year period (figure 1C), and raised levels of IFNα protein5 (figure 1D). Based on our experience of JAK1/2 inhibition in the treatment of STING-associated vasculopathy with onset in infancy (SAVI),6 and considering the severity of the phenotype and constitutive activation of the type I IFN pathway in our patient, we trialled the use of a JAK1/2 inhibitor, ruxolitinib, at an initial dose of 5 mg twice a day (0.62 mg/kg/day). Treatment was associated with a rapid clinical improvement within 1 week (online supplementary figure S3). Hydroxychloroquine was discontinued 3 months later. At last follow-up, after 12 months (M12) of ruxolitinib, her general condition had markedly improved, with an almost complete resolution of her skin lesions (figure 1A, B and online supplementary figure S3), resumption of normal activities of daily living and increase in weight (from −2 SD to +0.5 SD) and height (from −2 SD to +0.6 SD), for which reason the dose of ruxolitinib was increased to 7.5 mg twice a day, 0.8 mg/kg/day. Ruxolitinib was well tolerated. Pharmacokinetic analysis was consistent with published data.6 Despite marked clinical efficacy, the IFN score fluctuated, normalising at M3 but rising again at M6 (figure 1C), while IFNα levels fell but remained elevated above normal levels (figure 1D). The explanation for these results, which are consistent with those observed in patients with SAVI treated with JAK1/2 inhibitors,6 7 remains unclear, but indicates either an effect at the level of the tissue that is not captured by blood sampling, or changes in other cytokines, some of which were assessed here (online supplementary figure S4).
Overall, our observations suggest that JAK1/2 inhibition might be a relevant therapeutic option for skin vasculopathy in the phenotypic spectrum of FCL and AGS. Whether such therapy has a role in the treatment of the neurological involvement seen in the type I interferonopathies remains to be determined.
CB and MLF contributed equally.
Handling editor Josef S Smolen
Contributors CB, DB, AC and BN collected clinical data. MLF, GIR, VB, DD and LC performed the experiments and analysed the data. CB and MLF wrote the paper. SB, YJC and BN supervised the study. All authors have read the final approval of the version published.
Funding MLF is supported by the Institut National de la Santé et de la Recherche Médicale (grant number 000427993). YJC acknowledges the European Research Council (GA 309449), and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' programme bearing the reference ANR-10-IAHU-01. YJC and DD acknowledge the ANR (grant CE17001002).
Competing interests None declared.
Patient consent Parental/guardian obtained.
Ethics approval The study was approved by the Comité de Protection des Personnes (ID-RCB/EUDRACT: 2014-A01017-40).
Provenance and peer review Not commissioned; externally peer reviewed.