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Janus Kinase Inhibitors effective in persistent erythema multiforme: JAMA case series
Janus Kinase Inhibitors effective in persistent erythema multiforme: JAMA case series
Erythema multiforme (EM) is an inflammatory disorder which presents with different morphology of lesions but characteristically have target lesions on the acral skin with mucosal erosions. Typically, EM occurs in the setting of infection, such as herpes simplex virus (HSV), and is self-limited. EM may recur 1 or more times per year and is termed recurrent EM, associated with HSV reactivation. When EM lesions are present nearly continuously or continuously and are not clearly associated with HSV; this is defined as persistent erythema multiforme (PEM). While some cases of recurrent or PEM may improve with antiviral (eg, HSV) therapy, others do not. Recently a case series describing efficacy of JAK inhibitors in 4 patients with PEM was published in the Journal of American Academy of Dermatology.
Four consecutive patients with biopsy-confirmed PEM, refractory to prior treatment approaches were treated with a JAK inhibitor. A patient report and physical examination by a physician were used to assess responses to therapy.
Biopsy specimens were obtained from patient 4 For molecular analysis, before initiating treatment with tofacitinib and again after 28 days of treatment when clinical resolution of lesions was observed. The biopsy tissue was divided and used for: (1) RNA sequencing (RNA-seq) and (2) protein purification from tissue interstitial fluid followed by multiplex cytokine analysis. The RNA-seq data were analyzed using Ingenuity Pathway Analysis (IPA) to identify relevant molecular mediators.
Additionally, the authors evaluated pretreatment biopsy specimens from 3/4 patients with PEM who were treated with tofacitinib, plus an additional 9 EM biopsy specimens from dermatopathology archive (12 total) and 7 healthy control biopsy specimens. Levels of IFNG and IL15 mRNA levels were measured using RNA in situ hybridization. Statistical analyses were done.
Results
Four patients with PEM (mean [SD] age, 46.2 (13.7) years were females. Two of the patients had Fitzpatrick phototype II skin tone, 1 had type III, and 1 had type V. The patients' mean (SD) disease duration was 21.75 (11.3) years. All patients showed marked improvement with tofacitinib and were generally able to achieve clear or nearly clear skin, although titration of the dose was often necessary (doses ranged from 5 mg once daily to 10 mg twice daily). Improvement was typically noted within days to weeks. No adverse events were observed in any of the study patients.
Molecular Analysis
It was found that T/NK cell cytotoxicity and JAK-signal transducer and activator of transcription signalling were highly upregulated before tofacitinib and reduced during treatment. The transcriptional activity of multiple proinflammatory cytokines, including IFN-γ, IL-15, IL-6, and tumour necrosis factor (TNF) among others, were downregulated after treatment. Of these, IFN-γ (JAK1/2), IL-15 (JAK1/3), and IL-6 (JAK1/2) are JAK-signal transducer and activator of transcription (STAT) dependent while TNF signals is NF-κB dependent. The authors also found that tofacitinib downregulated STAT1 (IFN-γ), STAT3 (IL-6 and IL-15), and STAT5 (IL-15) signaling.
We measured protein levels from tissue interstitial fluid that was purified from the biopsy tissue before and after tofacitinib. Although the measured decrease in IFN-γ was small, a marked decrease in its transcriptional target CXCL10 was observed, likely reflecting strong inhibition of IFN-γ activity. IL-6, IL-10, and TNF also decreased during tofacitinib use.
The authors found significantly elevated expression 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) in the EM cases compared with controls (P = .008 and P = .045, respectively.
To conclude the authors hypothesized that IFN-γ and IL-15 could be important mediators of EM and thus JAK inhibitors can play a role in the treatment of persistent EM.
References
- Murphy MJ, Gruenstein D, Wang A, Peterson D, Levitt J, King B, Damsky W. Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis. JAMA Dermatol. 2021 Dec 1;157(12):1477-1482.
MBBS
Dr Manoj Kumar Nayak has completed his M.B.B.S. from the prestigious institute Bangalore medical college and research institute, Bengaluru. He completed his M.D. Dermatology from AIIMS Rishikesh. He is actively involved in the field of dermatology with special interests in vitiligo, immunobullous disorders, psoriasis and procedural dermatology. His continued interest in academics and recent developments serves as an inspiration to work with medical dialogues.He can be contacted at editorial@medicaldialogues.in.
Dr Kamal Kant Kohli-MBBS, DTCD- a chest specialist with more than 30 years of practice and a flair for writing clinical articles, Dr Kamal Kant Kohli joined Medical Dialogues as a Chief Editor of Medical News. Besides writing articles, as an editor, he proofreads and verifies all the medical content published on Medical Dialogues including those coming from journals, studies,medical conferences,guidelines etc. Email: drkohli@medicaldialogues.in. Contact no. 011-43720751