The use of Janus kinase inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Authors: Danielle Peterson, William Damsky, Brett King
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: During the time of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, questions arise regarding patients being treated with immunomodulatory therapies. In particular, is there an increased risk of acquiring the infection or experiencing a worse outcome from SARS-CoV-2? Although this exact question is presently unanswerable, we can look at safety data from clinical trials to try to understand patient susceptibility to different infections. Others have addressed this in the context of biologic1Lebwohl M. Rivera-Oyola R. Murrell D.F. Should biologics for psoriasis be interrupted in the era of COVID-19?.J Am Acad Dermatol. 2020; 82: 1217-1218Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar or classical small molecule therapy,2Price K.N. Frew J.W. Hsiao J.L. Shi V.Y. COVID-19 and immunomodulator/immunosuppressant use in dermatology.J Am Acad Dermatol. 2020; 82: e173-e175Abstract Full Text Full Text PDF Scopus (88) Google Scholar but the risk of Janus kinase inhibitor (JAKi) treatment has not been addressed. In light of the growing off-label use of JAKis in dermatology in addition to pharmaceutical industry-sponsored clinical trials of JAKis for alopecia areata, atopic dermatitis, vitiligo, and other conditions, dermatologists need data to better understand the risks of JAKi treatment so they can best manage and counsel their patients during this unique time. We analyzed and collated adverse events data from JAKi clinical trials. In particular, we focused on infections and pulmonary toxicities observed across the different United States Food and Drug Administration-approved JAKi for their Food and Drug Administration-approved indications. When available, data from phase II or III clinical trials for dermatologic indications was included. Table I summarizes the rates of various infections, including upper respiratory infections, nasopharyngitis, and influenza, for JAKi-treated groups vs placebo groups. Overall, rates of infectious events are only mildly increased in JAKi-treated patients. We also collated pulmonary toxicities of JAKis to identify potential risks of worsening severe respiratory disease from SARS-CoV-2, and such toxicities are all but absent.Table IRate of infections with Janus kinase inhibitors in randomized, double-blind, placebo-controlled trials over 8 to 24 weeks' durationJAK inhibitor specificityJAK inhibitor nameDXTreatment groups (No. patients)Total infections, No. (%)Serious infections, No. (%)URI, No. (%)UTI, No. (%)NP, No. (%)HSV, No. (%)Zoster, No. (%)Influenza, No. (%)Reported pulmonary toxicity∗www.pneumotox.com.JAK1/3TofacitinibRAPlacebo (n = 122)Tofacitinib 5 mg bid (n = 243)Tofacitinib 10 mg bid (n = 245)Study duration 12 weeks(Fleischmann et al, N Engl J Med, 2012;367(6):495-507.)NR001 (<1)6 (5)11 (5)8 (3)3 (3)4 (2)10 (4)2 (2)4 (2)5 (2)NROne case4 (3)2 (1)4 (2)CR: PAH (Habib et al, J Clin Rheumatol, 2018.)UCOCTAVE 1Placebo (n = 122)Tofacitinib 10 mg bid (n = 476)(∼45%-50% on steroids)Study duration 8 weeksOCTAVE 2Placebo (n = 112)Tofacitinib 10 mg bid (n = 429)(∼45%-50% on steroids)Study duration 8 weeks(Sandborn et al, N Engl J Med, 2017;376(18):1723-1736.)19 (16)111 (23)17 (15)78 (18)06 (1)01 (<1)NRNR00009 (7)34 (7)4 (4)21 (5)NRNR1 (<1)3 (<1)02 (<1)NRNRJAK1/2BaricitinibADBREEZE-AD1Placebo (n = 249)Baricitinib 1 mg qd (n = 127)Baricitinib 2 mg qd (n = 123)Baricitinib 4 mg qd (n = 125)Study duration 16 weeksBREEZE-AD2Placebo (n = 244)Baricitinib 1 mg qd (n = 124)Baricitinib 2 mg qd (n = 123)Baricitinib 4 mg qd (n = 123)Study duration 16 weeks(Simpson et al, Br J Dermatol, March 2020, bjd.18898.)NRNRNRNR6 (2)1 (1)3 (2)4 (3)5 (2)6 (5)5 (4)4 (3)4 (2)1 (1)2 (2)4 (3)3 (1)002 (2)26 (10)22 (17)12 (10)12 (10)30 (12)13 (11)16 (13)10 (8)3 (1)7 (6)4 (3)9 (7)11 (5)6 (5)7 (6)5 (4)1 caseBlinded2 cases blindedNRNRNRRARA-BEAM phase 1Placebo (n = 488)Baricitinib 4 mg qd (n = 487)Adalimumab 40 mg q2wk (n = 330)(100% on MTX)Study duration 24 weeks (Taylor et al, N Engl J Med, 2017;376(7) 652-662.)134 (27)176 (36)110 (36)7(1)5 (1)2 (<1)14 (3)15 (3)13 (4)01 (<1)001 (<1)0NR2 (<1)7 (1)4 (1)4 (<1)12 (2)5 (2)RuxolitinibMFCOMFORT IRuxolitinib 15 or 20 mg bid (n = 155)Placebo (n = 151)Study duration 24 weeks (Verstovsek et al, J Hematol Oncol, 2017;10 (1):55.)NRNR34 (22)15 (10)31 (20)7 (5)14 (9)9 (6)6 (4)2 (1)16 (10)1 (1)8 (5)0CR: ARDS (Kerget et al, Respir Med Case Rep, 2017;22:243-245; †Indicates adverse events as a result of abrupt discontinuation of Janus kinase therapy.Herman et al, Ann Am Thorac Soc, 2014;11(7):1145-1148; †Indicates adverse events as a result of abrupt discontinuation of Janus kinase therapy.Beauverd, Samii, Int J Hematol, 2014;100(5):498-501.)†Indicates adverse events as a result of abrupt discontinuation of Janus kinase therapy.CR: Pleural effusion (Tefferi and Pardanani, Mayo Clin Proc, 2011;86(12):1188-1891.)‡Exacerbation of pre-existing condition.CR: PAH (Low et al, Haematologica, 2015;100(6):e244-245.)JAK1UpadacitinibADPlacebo (n = 40)Upadacitinib 7.5 mg qd (n = 42)Upadacitinib 15 mg qd (n = 42)Upadacitinib 30 mg qd (n = 42)Study duration 16 weeks(Guttman-Yassky et al, J Allergy Clin Immunol, 2020;145(3):877-884.)8 (20)22 (52)18 (43)17 (41)02 (5)1 (2)04 (10)7 (17)5 (12)5 (12)NR1 (3)2 (5)4 (10)3 (7)NR000003 (7)00NRRASELECT-BEYONDPlacebo (n = 169)Upadacitinib 15 mg qd (n = 164)Upadacitinib 30 mg qd (n = 165)(∼70% of all groups on MTX, 50% on steroids)Study duration 12 weeks(Genovese et al, Lancet, 2018;391(10139):2513-2124.)51 (30)54 (33)55 (33)01 (1)4 (2)13 (8)13 (8)10 (6)10 (6)15 (9)9 (5)11 (7)7 (4)9 (5)NR1 (1)1 (1)4 (2)000NRAD, Atopic dermatitis; ARDS, acute respiratory distress syndrome; bid, twice daily; CR, case report; DX, diagnosis; HSV, herpes simplex virus; JAK, Janus kinase; MF, myelofibrosis; MTX, methotrexate; NP, nasopharyngitis; NR, not reported; PAH, pulmonary arterial hypertension; q2wk, every other week; qd, once daily; RA, rheumatoid arthritis; URI, upper respiratory infection; UTI, urinary tract infection; Zoster, varicella-zoster virus.∗ www.pneumotox.com.† Indicates adverse events as a result of abrupt discontinuation of Janus kinase therapy.‡ Exacerbation of pre-existing condition. Open table in a new tab AD, Atopic dermatitis; ARDS, acute respiratory distress syndrome; bid, twice daily; CR, case report; DX, diagnosis; HSV, herpes simplex virus; JAK, Janus kinase; MF, myelofibrosis; MTX, methotrexate; NP, nasopharyngitis; NR, not reported; PAH, pulmonary arterial hypertension; q2wk, every other week; qd, once daily; RA, rheumatoid arthritis; URI, upper respiratory infection; UTI, urinary tract infection; Zoster, varicella-zoster virus. To understand the infection data, an understanding of the mechanism and pharmacokinetics of JAKis is helpful (Fig 1, A). Cytokines can drive autoimmunity when their activity is exaggerated. JAKis, which are taken orally 1 to 2 times per day, largely impact pathogenically elevated cytokine activity, with relative sparing of normal cytokine activity because drug concentrations are subtherapeutic for part of the day (Fig 1, B).3Clark J.D. Flanagan M.E. Telliez J.-B. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.J Med Chem. 2014; 57: 5023-5038Crossref PubMed Scopus (453) Google Scholar Therefore, the immune response to infection is grossly intact. Discontinuation of JAKis in the setting of initial infection, such as with SARS-CoV-2, may be beneficial given the role of JAK-signal transducer and activator of transcription proteins (STAT)-dependent type I (α/β) and type II (γ) interferons in antiviral immunity. The biologic effects of JAKis dissipate rapidly with cessation of the drug, given their short half-lives. The potential role of JAKi treatment for patients with cytokine release syndrome of severe SARS-CoV-2 infection is more complex and an area of active investigation. While anecdotal, we are aware of 3 patients (2 women and 1 man) in their 20s in our care who are taking JAKis for alopecia areata, of whom 2 have tested positive for SARS-CoV-2, and 1 very likely has it (per symptoms). All 3 have had uneventful courses and are recovering after cessation of treatment. In this time of the SARS-CoV-2 pandemic, we must be as informed as possible regarding the risks of the treatments we prescribe our patients. Of course, shared decision making reigns supreme, but without data we, as physicians, will be unable to provide our patients the guidance they rely on us for. Reply: Potential role of Janus kinase inhibitors in COVID-19Journal of the American Academy of DermatologyVol. 83Issue 1PreviewTo the Editor: We read with interest the letter of Peterson et al1 about the use of Janus kinase (JAK) inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The authors reported that discontinuation of JAK inhibitors in the setting of the initial infection, such as with SARS-CoV-2, may be beneficial given the role of JAK-signal transducer and activator of transcription (STAT)–dependent type I (α/β) and type II (γ) interferons in antiviral immunity. However, data in the literature regarding the possible use of JAK inhibitors in COVID 19 patients is growing. Full-Text PDF