INTRODUCTION
The use of Janus kinase inhibitors (JAKi) in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a topic of interest for many clinicians and researchers.1,2 In recent studies, JAKi has been shown to have rates of infectious events that are only mildly increased compared to placebo. Similarly, there is no reported risk of pulmonary toxicity in JAKi-treated patients compared to placebo-treated patients.1 Though data regarding the possible use of JAKi in COVID 19 patients is growing, clarification of the risks associated with JAKi therapy is critical. Baricitinib and upadacitinib have promising preclinical safety data, and may be therapeutically beneficial in COVID-19 patients with underlying skin disease, potentially reducing cytokine storm seen in severe cases.1,2 The safety potential of abrocitinib, an investigational JAKi, however, has not been addressed.
Abrocitinib is an oral small molecule that selectively inhibits JAK1 and several important cytokine signaling pathways— interleukin (IL)-4, IL-13, IL-31, and interferon —that are known to have an important role in the pathophysiology of AD.3 Like other JAK inhibitors, abrocitinib blocks the activity of IL-6, a cytokine thought to play a central role in SARS-CoV-2 associated cytokine release syndrome (CRS), in addition to other pathogenic cytokines.2 Disease severity in patients with symptoms of CRS correlates with serum cytokine levels, as mean IL-6 concentrations are 2.9 times higher in patients with severe disease and predictive of respiratory failure.5 One potentially important characteristic of abrocitinib is its EPO sparing effect, as recent evidence has supported the use of human recombinant EPO for ameliorating the course and outcome of seriously ill COVID-19 patients.5,6
In phase II and phase III trials for patients with atopic dermatitis (AD), abrocitinib has had good safety results. The most frequently reported adverse events in patients were nausea, headache and nasopharyngitis. However, there was no significant difference in the incidence of nasopharyngitis in patients treated with 200 mg abrocitinib verus placebo.3,7 Elevated creatine phosphokinase levels were identified without evidence of clinical disease. No significant clinical changes in hemoglobin level and neutrophil or lymphocyte counts were observed, consistent with selective inhibition of JAK1 vs JAK2.7 Thrombocytopenia, however, was reported in patients treated with 200 mg abrocitinib, but platelet values trended upward toward baseline after maximum treatment and no reports of bleeding disorders were identified.3,7 The incidence of herpes simplex reactivation (herpangina, eczema herpeticum) was slightly increased in patients treated with 100 mg abrocitinib, but the conditions resolved without any complications.3,7
While there is insufficient evidence to recommend that JAK inhibitors be continued in all patients acutely infected with SARS-CoV-2, there is encouraging preclinical data that supports continuing abroctinib treatment in these patients. Nonetheless, as clinicians we must remain informed of the risks of treatments and be prepared to carefully evaluate patients reporting any adverse effects.
Abrocitinib is an oral small molecule that selectively inhibits JAK1 and several important cytokine signaling pathways— interleukin (IL)-4, IL-13, IL-31, and interferon —that are known to have an important role in the pathophysiology of AD.3 Like other JAK inhibitors, abrocitinib blocks the activity of IL-6, a cytokine thought to play a central role in SARS-CoV-2 associated cytokine release syndrome (CRS), in addition to other pathogenic cytokines.2 Disease severity in patients with symptoms of CRS correlates with serum cytokine levels, as mean IL-6 concentrations are 2.9 times higher in patients with severe disease and predictive of respiratory failure.5 One potentially important characteristic of abrocitinib is its EPO sparing effect, as recent evidence has supported the use of human recombinant EPO for ameliorating the course and outcome of seriously ill COVID-19 patients.5,6
In phase II and phase III trials for patients with atopic dermatitis (AD), abrocitinib has had good safety results. The most frequently reported adverse events in patients were nausea, headache and nasopharyngitis. However, there was no significant difference in the incidence of nasopharyngitis in patients treated with 200 mg abrocitinib verus placebo.3,7 Elevated creatine phosphokinase levels were identified without evidence of clinical disease. No significant clinical changes in hemoglobin level and neutrophil or lymphocyte counts were observed, consistent with selective inhibition of JAK1 vs JAK2.7 Thrombocytopenia, however, was reported in patients treated with 200 mg abrocitinib, but platelet values trended upward toward baseline after maximum treatment and no reports of bleeding disorders were identified.3,7 The incidence of herpes simplex reactivation (herpangina, eczema herpeticum) was slightly increased in patients treated with 100 mg abrocitinib, but the conditions resolved without any complications.3,7
While there is insufficient evidence to recommend that JAK inhibitors be continued in all patients acutely infected with SARS-CoV-2, there is encouraging preclinical data that supports continuing abroctinib treatment in these patients. Nonetheless, as clinicians we must remain informed of the risks of treatments and be prepared to carefully evaluate patients reporting any adverse effects.
DISCLOSURES
Dr. Wu is or has been an investigator, consultant, or speaker for
AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers
Squibb, Celgene, Dermavant, Dermira, Dr. Reddy’s Laboratories,
Eli Lilly, Janssen, LEO Pharma, Novartis, Regeneron, Sanofi
Genzyme, Sun Pharmaceutical, UCB, and Valeant Pharmaceuticals
North America LLC. Ms. Uppal, Mr. Kearns, and Ms. Chat have no
conflicts of interest to declare.
REFERENCES
1. Peterson D, Damsky W, King B. The use of Janus kinase inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). J Am Acad Dermatol. 2020;82(6):e223-e226.
2. Napolitano M, Fabbrocini G, Patruno C. Reply: potential role of Janus kinase inhibitors in COVID-19. J Am Acad Dermatol. 2020;83(1):e65.
3. Gooderham MJ, Forman SB, Bissonnette R, et al. Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial. JAMA Dermatology. 2019;155(12):1371-1379.
4. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis [published online ahead of print, 2020 Apr 28]. J Med Virol. 2020;10.1002/jmv.25948. doi:10.1002/jmv.25948
5. Vazquez ML, Kaila N, Strohbach JW, et al. Identification of N-{cis-3-[Methyl(7Hpyrrolo[ 2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A selective JAK1 clinical candidate for the treatment of autoimmune diseases. J Med Chem. 2018;61(3):1130-1152.
6. Ehrenreich H, Weissenborn K, Begemann M, Busch M, Vieta E, Miskowiak KW. Erythropoietin as candidate for supportive treatment of severe COVID-19. Molecular Medicine. 2020;26(1):58.
7. Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatology. 2020:e201406.
2. Napolitano M, Fabbrocini G, Patruno C. Reply: potential role of Janus kinase inhibitors in COVID-19. J Am Acad Dermatol. 2020;83(1):e65.
3. Gooderham MJ, Forman SB, Bissonnette R, et al. Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial. JAMA Dermatology. 2019;155(12):1371-1379.
4. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis [published online ahead of print, 2020 Apr 28]. J Med Virol. 2020;10.1002/jmv.25948. doi:10.1002/jmv.25948
5. Vazquez ML, Kaila N, Strohbach JW, et al. Identification of N-{cis-3-[Methyl(7Hpyrrolo[ 2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A selective JAK1 clinical candidate for the treatment of autoimmune diseases. J Med Chem. 2018;61(3):1130-1152.
6. Ehrenreich H, Weissenborn K, Begemann M, Busch M, Vieta E, Miskowiak KW. Erythropoietin as candidate for supportive treatment of severe COVID-19. Molecular Medicine. 2020;26(1):58.
7. Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatology. 2020:e201406.
AUTHOR CORRESPONDENCE
Jashin J. Wu MD jashinwu@gmail.com
