JAK inhibition may prevent drug hypersensitivity reactions

JAK inhibition may prevent drug hypersensitivity reactionsTo the Editor: Drug hypersensitivity reactions (DHRs) are a major clinical problem with potential for significant morbidity and mortality.Presentation ranges from a pruritic rash (maculopapular exanthem [MPE]) to life-threatening reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), characterized by skin and mucosal blistering, and drug reaction with eosinophilia and systemic symptoms (DRESS), notable for potentially severe organ disease.There are several limitations to clinical care.Whether a patient will progress to severe disease is unknown, there is no agreed upon treatment, it is often unclear to what drug a patient reacted, and there is no validated test to identify a culprit drug (1, 2).Consequently, the standard of care is typically to discontinue all possible culprit drugs and never rechallenge, even if a possible culprit drug is potentially life-saving.Recently, this standard has been challenged, either anecdotally in patients with cancer or in patients with HIV and tuberculosis when the culprit drug and/or risk of progression to severe DHR is questionable (3, 4).In the latter, stepwise rechallenge has been tried with some patients tolerating the needed drug.The rechallenged drug is promptly discontinued, and systemic steroids started upon first signs of a reaction (5).Anecdotal cases and case series suggest that systemic steroids can effectively abort a reaction with this approach (5).While a major advancement, patients are at risk for a reaction, and those that do react can no longer receive the potentially life-saving medication.An alternative approach is needed.JAK-STAT activation has been observed in SJS/TEN, DRESS, and MPE (6-8), and JAK inhibitors (JAKi) have been successfully used in DRESS (7, 9, 10) and SJS/TEN (6).The JAKi ruxolitinib is an approved treatment for acute graft-versus-host-disease (GVHD), which can present identically to DHR.Ruxolitinib is now being trialed in GVHD prophylaxis.Furthermore, JAKi prevented SJS/TEN in mouse models, including a humanized mouse rechallenge model ( 6).Herein, we present three clinical cases of DHR where prophylaxis with JAKi allowed successful rechallenge to cancer therapies along with translational data supporting JAKi prophylaxis in DHR.HLA-B*57:01 transgenic (tg) or control mice were prophylaxed with tofacitinib, ruxolitinib, or vehicle before treatment with abacavir (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.200914DS1).Abacavir can induce DHR in humans expressing HLA-B*57:01 (11).Abacavir-treated HLA-B*57:01tg mice develop a drug-specific CD8 + T cell-mediated MPE-like dermatitis (12, 13).Prophylaxis with JAKi prevented development of MPE-like dermatitis, as demonstrated clinically, histologically, and by reduced ear thickness (Figure 1, A-C).Decreased DC skin infiltration and maturation (Figure 1D) and reduced skin infiltration of total immune cells, antigen-presenting cells, and T cells (Supplemental Figure 1B) were observed, including near-complete absence of skin infiltrating effector CD44 hi CD62L lo CD8 + T cells (Figure 1E).In humans, differential gene expression analysis comparing individual forms of DHR to healthy skin supported JAK-STAT activation, with significantly increased transcription of JAK2, JAK3, STAT1, and STAT2 (Supplemental Figure 2A).Tissue staining for activated protein confirmed increased expression of phosphorylated JAK1, JAK2, and JAK3 and STAT1 and STAT2 in all three forms of DHR compared with that of healthy controls (Supplemental Figure 2, B-F).Three patients with varying severity of DHR were prophylaxed with JAKi prior to rechallenge with cancer treatment thought to be causative in their DHR.All patients had aggressive tumors without alternative treatment options.Each would not have been considered for rechallenge in the absence of prophylaxis.A 64-year-old male with lung adenocarcinoma developed a progressive pruritic rash with focal burning pain and peripheral eosinophilia 5 weeks after starting lorlatinib (Figure 1F).He had no other drug exposures or signs or symptoms of infection.Dermatologic examination and histology supported MPE with features concerning for potential progression to severe DHR (Figure 1G).Systemic steroid taper did not resolve the rash.Lorlatinib was discontinued.The patient was treated with highest-potency topical steroids with resolution of rash and eosinophilia.Given the absence of available cancer treatment options, ruxolitinib 5 mg twice daily was initiated.Two weeks later the patient started lorlatinib 25 mg daily (one-quarter dose), which was increased to 50 mg and then 75 mg over 2 months.After 6 weeks without DHR recurrence, ruxolitinib was tapered to once daily.The patient experienced transient eosinophilia.After normalization of eosinophilia, ruxolitinib was tapered to once every other day, then discontinued.The patient remained