Key Points

Is Janus kinase (JAK) inhibition effective for persistent erythema multiforme (PEM), and what are the important molecular targets?

Four patients with PEM treated with JAK inhibition experienced marked clinical improvement, while RNA sequencing and proteomic evaluation in a single patient before and during treatment revealed that interferon gamma (IFN-γ) and interleukin 15 (IL-15) were both overproduced in erythema multiforme and modulated by tofacitinib. In these and other PEM cases (total, 12 patients), RNA in situ hybridization confirmed significant upregulation of IFN-γ and IL-15.

The findings of this case series study suggest that cytotoxic responses in patients with PEM may be promoted by IFN-γ and IL-15 and may be controlled with JAK inhibition.

Persistent erythema multiforme (PEM) is poorly understood and lacks effective therapies other than glucocorticoids.

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).

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).

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.

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