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Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and
Michael J Murphy1, Diana Gruenstein2, Alice Wang1
1Department of Dermatology, Yale School of Medicine, Yale University, New Haven, Connecticut.
Importance:
Persistent erythema multiforme (PEM) is poorly understood and lacks effective therapies other than glucocorticoids.
Objective:
To report outcomes following treatment of PEM with Janus kinase (JAK) inhibition and to elucidate cytokine drivers of erythema multiforme (EM).
Design, Setting, And Participants:
This was a retrospective case series of 4 patients with PEM treated with tofacitinib and/or upadacitinib in 2015 to 2021 at the dermatology clinics of 2 major tertiary referral centers. Four consecutive patients with PEM refractory to multiple treatment approaches were treated. In 1 patient, skin biopsy specimens were obtained for RNA sequencing and proteomic analysis before and during treatment. Molecular findings were validated through RNA in situ hybridization analysis of cytokine expression in biopsy specimens from a total of 12 patients with EM (3 treated with tofacitinib in this study and 9 historic samples).
Interventions:
Treatment with tofacitinib, 5 to 10 mg, twice daily or upadacitinib, 15 mg, once daily.
Main Outcomes And Measures:
Change in PEM activity was assessed in all 4 patients treated with a JAK inhibitor. Median (range) follow-up was 20.5 months (10.0-36.0 mo).
Results:
The study population of 4 female patients had a mean (SD) age of 46.2 (13.7) years and a mean (SD) disease duration of 21.75 (11.30) years. Marked clinical improvement was noted in all 4 patients. In 1 patient with a robust improvement following treatment with tofacitinib, RNA sequencing identified interferon gamma (IFN-γ) and interleukin 15 (IL-15) as cytokines with activity both highly upregulated at baseline in lesional skin and subsequently suppressed following tofacitinib treatment. Measurement of IFNG- and IL15-positive cells in additional EM biopsy specimens of 12 patients showed significant upregulation of IFNG (8.72 cells per mm; 95% CI, 2.60-14.84) and IL15 (14.13 cells per mm; 95% CI, 0.14-28.11) compared with normal skin (P = .008 and P = .045, respectively).
Conclusions And Relevance:
The results of this case series study suggest that JAK inhibition may be effective in treating PEM and that IFN-γ and IL-15 may be important cytokine mediators of the disease.
Insights
Janus kinase (JAK) inhibition shows promise for treating persistent erythema multiforme (PEM), a condition with limited options. This study found that JAK inhibitors like tofacitinib and upadacitinib led to significant clinical improvement in patients with PEM.
Area of Science:
- Dermatology
- Immunology
- Molecular Biology
Background:
- Persistent erythema multiforme (PEM) is a challenging dermatological condition with few effective treatments beyond glucocorticoids.
- The underlying cytokine drivers of PEM remain poorly understood, hindering the development of targeted therapies.
Purpose of the Study:
- To evaluate the efficacy of Janus kinase (JAK) inhibition in treating patients with persistent erythema multiforme (PEM).
- To identify key cytokine mediators involved in the pathogenesis of erythema multiforme (EM) through molecular analysis.
Main Methods:
- A retrospective case series involving 4 patients with refractory PEM treated with tofacitinib and/or upadacitinib.
- Skin biopsy analysis using RNA sequencing and proteomic analysis in one patient to identify cytokine profiles before and during treatment.
- Validation of cytokine expression (IFN-γ and IL-15) in biopsy specimens from 12 EM patients via RNA in situ hybridization.
Main Results:
- All 4 patients treated with JAK inhibitors experienced marked clinical improvement in PEM.
- RNA sequencing revealed upregulation of interferon gamma (IFN-γ) and interleukin 15 (IL-15) in lesional skin, which were suppressed by tofacitinib.
- Significant upregulation of IFNG and IL15 was confirmed in a larger cohort of EM patients compared to normal skin.
Conclusions:
- Janus kinase (JAK) inhibition demonstrates potential as an effective therapeutic strategy for persistent erythema multiforme (PEM).
- Interferon gamma (IFN-γ) and interleukin 15 (IL-15) are implicated as significant cytokine mediators in the pathogenesis of EM.
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