Assessment of Clinical Response to Janus Kinase Inhibition in Patients With Familial Chilblain Lupus and TREX1 Mutation.

Abstract

Importance:

Familial chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available.

Objectives:

To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial chilblain lupus and assess the effect of cold on patient fibroblasts.

Design, Setting, and Participants:

In this case series, 3 patients with familial chilblain lupus due to TREX1 mutation underwent treatment with baricitinib for 3 months.

Interventions:

Doses of baricitinib, 4 mg, were administered daily for 3 months.

Main Outcomes and Measures:

Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed.

Results:

All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro.

Conclusions and Relevance:

These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold in TREX1-deficient cells. This finding may be relevant to other type I IFN-mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.

• Authors: Nick Zimmermann, Christine Wolf, Reiner Schwenke, Anne Lüth, Franziska Schmidt, Kerstin Engel, Min Ae Lee-Kirsch, Claudia Günther
• Journal: JAMA dermatology (JAMA Dermatol) Vol. 155 Issue 3 Pg. 342-346 (03 01 2019) ISSN: 2168-6084 [Electronic] United States
• PMID: 30673078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Azetidines
• Janus Kinase Inhibitors
• Phosphoproteins
• Purines
• Pyrazoles
• Sulfonamides
• Exodeoxyribonucleases
• three prime repair exonuclease 1
• baricitinib

Topics

• Adult
• Azetidines (therapeutic use)
• Chilblains (diagnosis, drug therapy, genetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Exodeoxyribonucleases (genetics)
• Female
• Humans
• Janus Kinase Inhibitors (therapeutic use)
• Lupus Erythematosus, Cutaneous (diagnosis, drug therapy, genetics)
• Male
• Mutation
• Pedigree
• Phosphoproteins (genetics)
• Prognosis
• Purines
• Pyrazoles
• Risk Assessment
• Sampling Studies
• Sulfonamides (therapeutic use)
• Treatment Outcome