Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis

Abstract

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 PARTICIPANTSThis 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). RESULTSThe 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 RELEVANCEThe 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.

Erythema multiforme associated with anti‐plakin antibodies: a multicentric retrospective case series

“…Indeed, Murphy et al reported the efficacy of Janus kinase inhibition in four patients and demonstrated high upregulation of both interferon-c and interleukin-15 in EM lesions. 19 The main limitation of this study is the retrospective design and the absence of a control group. In fact, a comparative study between EM-PLK+ and EM without anti-PLK-Abs may determine whether anti-PLK-Abs constitute a prognostic factor for the severity of EM and if there could be a correlation between the EM phenotype and type of anti-PLK-Abs.…”

“…Indeed, Murphy et al . reported the efficacy of Janus kinase inhibition in four patients and demonstrated high upregulation of both interferon‐γ and interleukin‐15 in EM lesions 19 …”

Hyperkeratotic erythema multiforme variant in 17 dogs

“…12 In humans, the oral JAK inhibitors upadacitinib and tofacitinib led to a marked improvement in four patients affected with persistent EM. The effectiveness of JAK inhibitors in EM is likely to be related to their inhibition of interferonγ (JAK1/2), IL-15 (JAK1/3) and type I interferons (JAK1/ TYK2) 20 ; however, the precise mechanism of action of JAK inhibitors in human and canine EM warrants further investigations.…”

“…In human EM skin lesions, T-lymphocyte/natural killer cell cytotoxicity and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signalling were highly upregulated pathways in a recent transcriptome study. 20 In the present report, various immunomodulatory drugs that target innate immune, lymphocyte responses and JAK-STAT pathways, such as glucocorticoids, ciclosporin, oclacitinib, mycophenolate mofetil or azathioprine, were used initially to treat dogs with HKEM.…”

Novel Treatments for Chronic Erythema Multiforme Inform Translational Science and Disease Pathogenesis

“…While TNF has been shown to only be weakly expressed in EM lesions, the successful use of TNF inhibitors, including thalidomide and adalimumab, have suggested this pathway may nevertheless play an important role in CEM pathogenesis, potentially through systemic mechanisms rather than local lesional effects. 1,5,8,9 Alternatively, Murphy and colleagues 7 chose to study the use of Janus kinase (JAK) inhibitors in the treatment of CEM. This work is an extension of prior work by Damsky and King, 10 who described 2 patients with idiopathic EM who were treated successfully with the JAK inhibitor tofacitinib, suggesting that JAK-signal transducer and activator of transcription (STAT) signaling may play a role in CEM disease.…”