JAK-STAT pathway inhibitors in dermatology

Miot, Hélio Amante; Criado, Paulo Ricardo; Castro, Caio César Silva de; Ianhez, Mayra; Talhari, Carolina; Ramos, Paulo Müller

doi:10.1016/j.abd.2023.03.001

Hélio Amante Miot ^** Corresponding author. E-mail:helio.a.miot@unesp.br (H.A. Miot).

Design of the study

drafting and approval of the final version of the manuscript

Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil

https://orcid.org/0000-0002-2596-9294

Paulo Ricardo Criado

Design of the study

drafting and approval of the final version of the manuscript

Centro Universitário Faculdade de Medicina do ABC, Santo André, SP, Brazil

Faculdade de Ciências Médicas de Santos, Santos, SP, Brazil

https://orcid.org/0000-0001-9785-6099

Caio César Silva de Castro

Design of the study

drafting and approval of the final version of the manuscript

Hospital de Dermatologia Sanitária do Paraná, Curitiba, PR, Brazil

Escola de Medicina, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil

https://orcid.org/0000-0001-9767-5765

Mayra Ianhez

Design of the study

drafting and approval of the final version of the manuscript

Department of Tropical Medicine and Dermatology, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil

https://orcid.org/0000-0003-3604-3128

Carolina Talhari

Design of the study

drafting and approval of the final version of the manuscript

Department of Dermatology, Universidade do Estado do Amazonas, Manaus, AM, Brazil

https://orcid.org/0000-0003-2283-069X

Paulo Müller Ramos

Design of the study

drafting and approval of the final version of the manuscript

Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil

https://orcid.org/0000-0002-1561-414X

⋆
Study conducted at the Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil.

* Corresponding author. E-mail:helio.a.miot@unesp.br (H.A. Miot).

Conflicts of interest

Dr. Caio Castro: Advisory Board - Sanofi, Aché, Sun-Pharma, Galderma. Speaker - Abbvie, Jansen, Novartis, Sanofi, Leo-Pharma. Clinical Research - Abbvie, Pfizer, Jansen, Sanofi.

Dr. Paulo Criado: Clinical research for Pfizer, Novartis, Sanofi and Lilly; Advisory board Pfizer, Galderma, Takeda, Hypera, Novartis, Sanofi. Speaker: Pfizer, Abbvie, Sanofi, Hypera, Takeda, Novartis.

Dr. Hélio Miot: Advisory Board - Johnson & Johnson, L’Oréal, Theraskin and Pfizer; clinical research: Abbvie and Merz.

Dr. Mayra Ianhez: Speaker and Advisory Board - Abbvie, Sanofi-Genzyme, Pfizer, Janssen, Galderma, Theraskin.

Dr. Paulo Müller Ramos: Advisory Board - Pfizer;

Dr. Carolina Talhari: None declared.

JAK	Cytokines and growth factors
JAK1	IFNα, IFNβ, IFNγ, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-11, IL-13, IL-15, IL-19, IL-21, IL-22, IL-27, IL-28, IL-29, IL-31, IL-35, Ciliary neurotrophic factor (CNTF), Oncostatin-M (OSM), Cardiotrophin (CT-1)
JAK2	IFNγ, IL-3, IL-5, IL-6, IL-10, IL-11, IL-13, IL-12, IL-19, IL-22, IL-23, IL-27, IL-35, granulocyte-macrophage colony stimulating factor (GM-CSF), erythropoietin (EPO), thyroid peroxidase (TPO), leptin, myeloproliferative leukemia (MPL) viral oncogene, prolactin, growth hormone (GH)
JAK3	IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-21
TYK2	IFNα, IFNβ, IL-10, IL-11, IL-12, IL-19, IL-22, IL-23, IL-27, IL-28, IL-29

Drug	Inhibitory concentration (IC₅₀)	Metabolism	Plasma half-life
Tofacitinib	JAK1: 2.9 nM	Hepatic CYP3A4 > CYP2C19	6 to 8h
	JAK2: 1.2 nM
	JAK3: 1.1 nM
	TYK2: 42 nM
Baricitinib	JAK1: 4.0 nM	Hepatic CYP3A4	10 to 13h
	JAK2: 6.6 nM
	JAK3: 787 nM
	TYK2: 61 nM
Ruxolitinib	JAK1: 6.4 nM	Hepatic CYP3A4	3 to 4h
	JAK2: 8.8 nM
	JAK3: 487.0 nM
	TYK2: 30.0 nM
Ritlecitinib	JAK1: 1.638 nM	Hepatic: CYP450; Serum: glutathione-S-transferase	2 to 3h
	JAK2: 1.507 nM
	JAK3: 0.3 nM
	TYK2: 3.779 nM
Abrocitinib	JAK1: 29 nM	Hepatic CYP2C19 > CYP2C9 > CYP3A4 > CYP2D6	3 to 5h
	JAK2: 803 nM
	JAK3: > 10.000 nM
	TYK2: 1.259 nM
Upadacitinib	JAK1: 14 nM	Hepatic CYP3A4 > CYP2D6	6 to 15h
	JAK2: 593 nM
	JAK3: 1.860 nM
	TYK2: 2.715 nM
Delgocitinib	JAK1: 2.8 nM	NA: topical use	NA: topical use
	JAK2: 2.6 nM
	JAK3: 13.0 nM
	TYK2: 58.0 nM

Increase the levels of JAKi				Reduce the levels of JAKi
Powerful OAT3 inhibitors	Powerful CYP2C19 inhibitors	Powerful CYP3A4 inhibitors	Moderate CYP3A4 inhibitors	Weak CYP3A4 inducers	Powerful CYP3A4 inducers
Colchicine-probenecid Probenecid	Amitriptyline, Chloramphenicol, Clomipramine, Delavirdine, Fluconazole, Fluoxetine, Fluvoxamine, Gemfibrozil, Imipramine, Isoniazid, Lansoprazole, Miconazole, Stiripentol, Ticlopidine, Tioconazole, Zafirlukast	Atazanavir, Boceprevir, Clarithromycin, Cobicistat, Conivaptan, Curcumin, Danoprevir, Darunavir, Delavirdine, Econazole, Efavirenz, Elvitegravir, Ergotamine, Idelalisib, Indinavir, Itraconazole, Ketoconazole, Loperamide, Lopinavir, Mibefradil, Midostaurin, Naloxone, Nefazodone, Nelfinavir, Nilotinib, Posaconazole, Ribociclib, Ritonavir, Saquinavir, Stiripentol, Sulfamethoxazole-Trimethoprim, Telaprevir, Telithromycin, Terfenadine, Tipranavir, Troleandomycin, Voriconazole	Fusidic acid, Amiodarone, Amprenavir, Anastrozole, Aprepitant, Barnidipine, Ciclosporin, Clobazam, Clozapine, Crizotinib, Danazol, Desvenlafaxine, Diltiazem, Dimethyl sulfoxide (DMSO), Dronedarone, Erythromycin, Fluconazole, Fluvoxamine, Fosamprenavir, Fosnetupitant, Haloperidol, Imatinib, Idalpine, Isavuconazole, Isavuconazonium, Isoniazid, Isradipine, Linagliptin, Lovastatin, Luliconazole, Miconazole, Mifepristone, Milnacipran, Netupitant, Nicardapine, Nilvadipine, Paroxetine, Primaquine, Risperidone, Sertraline, Simeprevir, Tioconazole, Venetoclax, Venlafaxine, Verapamil, Zimeldine, Ziprasidone	Clonazepam, Colchicine, Diazepam, Pantoprazole, Prednisone, Ritonavir	Valproic acid, Atorvastatin, Carbamazepine, Dexamethasone, Efavirenz, Phenytoin, Phenobarbital, Rifampicin, Simvastatin

Dermatosis	Drug	Administration route / number of patients	Adverse events
Alopecia areata	Tofacitinib	Orally	No severe adverse events
		Orally	28.9% URTI
		90 patients³⁴34 Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients. J Am Acad Dermatol. 2017;76:22-28. doi: 10.1016/j.jaad.2016.09.007. https://doi.org/10.1016/j.jaad.2016.09.0...	one reversible leukopenia
			one elevation of transaminases that normalized with weight loss
		Orally and topical	56.8% URTI
		Orally and topical	13.2% acne
		252 patients³⁵35 Guo L, Feng S, Sun B, Jiang X, Liu Y. Benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis. J Eur Acad Dermatol Venereol. 2020;34:192-201. doi: 10.1111/jdv.15937. https://doi.org/10.1111/jdv.15937...	29.1% headache
			7.7% transaminase alteration
Vitiligo	Tofacitinib and ruxolitinib	Orally and topical	8.9% acne and transaminase alteration
Vitiligo	Tofacitinib and ruxolitinib	45 patients³⁶36 Phan K, Phan S, Shumack S, Gupta M. Repigmentation in vitiligo using janus kinase (JAK) inhibitors with phototherapy: systematic review and Meta-analysis. J Dermatolog Treat. 2022;33:173-177. doi: 10.1080/09546634.2020.1735615. https://doi.org/10.1080/09546634.2020.17...	4.4% URTI
Atopic dermatitis	Baricitinib (BREEZE AD 1 and 2)	Orally	17.3% nasopharyngitis (1 mg dosage)
		Orally	Oral herpes simplex, headache, diarrhea
		1,239 patients⁴¹41 Reich K, DeLozier AM, Nunes FP, Thyssen JP, Eichenfield LF, Wollenberg A, Ross Terres JA, Watts SD, Chen YF, Simpson EL, et al. Baricitinib improves symptoms in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: patient-reported outcomes from two randomized monotherapy phase III trials. J Dermatolog Treat. 2022;33:1521-1530. doi: 10.1080/09546634.2020.1839008. https://doi.org/10.1080/09546634.2020.18...	One patient had thromboembolism: she was a smoker and used oral contraceptives (4 mg dose)
	Abrocitinib^a a The dosage considered in the JADE MONO-2 study for adverse events was 200 mg/day. (JADE MONO 2)	Orally	14.2% nausea
		Orally	7.7% nasopharyngitis and headache
		1,233 patients⁴²42 Silverberg JI, Thyssen JP, Simpson EL, Yosipovitch G, Stander S, Valdez H, Rojo R, Biswas P, Myers DE, Feeney C, et al. Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes. Am J Clin Dermatol. 2021;22:541-554. doi: 10.1007/s40257-021-00604-9. https://doi.org/10.1007/s40257-021-00604...	5.8% acne
			5.2% vomiting
			3,2% URTI
	Upadacitinib^b b Adverse events expressed according to the dosages used (15 and 30 mg). (Measure Up 1)	Orally	7% to 17% acne
		Orally	9% to 13% URTI
		566 patients⁴³43 Simpson EL, Papp KA, Blauvelt A, Chu CY, Hong HC, Katoh N, Calimlim BM, Thyssen JP, Chiou AS, Bissonnette R, et al. Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials. JAMA Dermatol. 2022;158:404-413. doi: 10.1001/jamadermatol.2022.0029. https://doi.org/10.1001/jamadermatol.202...	8% to 12% nasopharyngitis
			5% to 7% headache
			6% increased CPK

Clinical or laboratory data	Special condition	Comment
Age range	> 65 years of age	High risk of adverse events.
	< 15 years of age	Baricitinib should not be administered.
	< 12 years of age	Do not use JAKi in children under 12 years of age.
Body weight	< 30 kg	Upadacitinib should not be used in children < 30 kg.
Lactating women		JAKi should not be used by lactating women.
Pregnancy	Absolute contraindication	Stop JAKi in individuals at risk of pregnancy.
Pregnancy	Absolute contraindication	In case of pregnancy, discontinue use and request strict follow-up with the gynecologist/obstetrician
Hepatitis B	Positive HBsAg	Viral load ≥ 20 IU/mL (1.3 LogIU/mL): do not use JAKi
	Positive HBsAg	Viral load < 20 IU/mL: monitor every 1‒3 months in addition to transaminases.
	Positive anti-HBcAg or anti-HBsAg	Verify the viral load, as in the previous situation
	Positive anti-HBcAg or anti-HBsAg	If only anti-HBsAg is positive and everything else is negative (HBsAg, HBeAg, anti-HBeAg and anti-HBcAg and negative viral load), JAKi can be used.
Hepatitis C	Positive Anti-HVC	Consult a hepatologist/infectologist.
Hepatitis C	Positive Anti-HVC	Patients with positive anti-HCV were excluded from clinical trials of these medications.
Live virus vaccination		It should be administered 30 days before starting JAKi.
Live virus vaccination		It is contraindicated during treatment.
Active tuberculosis		The use of JAKi must be discontinued/ contraindicated.
Latent tuberculosis/ suspected asymptomatic individual	Positive PPD, IGRA/ Quantiferon gold	Tuberculosis chemoprophylaxis (isoniazid) at least three weeks before starting JAKi.
Latent tuberculosis/ suspected asymptomatic individual	Positive PPD, IGRA/ Quantiferon gold	If using JAKi: chemoprophylaxis for 6 to 9 months.
Previous history of cancer		Monitor the onset of adverse events
Renal dysfunction	Creatinine clearance > 30 mL/min/ 1.73 m²	Do not exceed 2 mg/d of baricitinib.
	Creatinine clearance > 30 mL/min/ 1.73 m²	Do not exceed 50 mg/d of abrocitinib
	Creatinine clearance ≤ 30 mL/min/ 1.73 m²	Upadacitinib 15 mg/d should be preferred
	Creatinine clearance ≤ 30 mL/min/ 1.73 m²	Do not exceed 50 mg/d of abrocitinib
Risk of thromboembolism		Cautious use of JAKi; preference for JAK1 inhibitors.
Potentially severe infections		The use of oral JAKi is contraindicated.
Hematological alterations	Lymphopenia < 500/mm³	The use of oral JAKi is contraindicated.
	Neutropenia < 1.000/mm³	The use of upadacitinib and abrocitinib is contraindicated.
	Neutropenia < 500/mm³	The use of oral JAKi is contraindicated.
	Thrombocytopenia < 50.000/mm³	The use of abrocitinib is contraindicated.
Severe hepatic alteration	Child's Class C	The use of upadacitinib and abrocitinib is contraindicated.
Recurrent herpesvirus infection		Consider the risk of herpes reactivation with JAKi.
HIV infection		The use of oral JAKi is contraindicated.

JAKi	AD	PSO	VITI	AA	LP	LE	DM	LV	PG	GA	LN	SARC	MOR	HS	GVHD	ECZh
Oral
Tofacitinib	X	X	X	X			X	X	X	X	X	X	X
Baricitinib	X	X				X		X	X
Abrocitinib	X
Upadacitinib	X													X
Ruxolitinib				X	X		X					X			X
Delgocitinib		X
Ritlecitinib			X	X
Elsubritinib						X
Itacitinib		X													X
Peficitinib		X
Deucravacitinib		X
Filgotinib		X
Solcitinib		X
Pacritinib															X
Deuruxolitinib				X
Gusacitinib																X
Topical
Tofacitinib	X		X	X	X					X
Ruxolitinib	X	X	X	X							X
Brepocitinib		X
Delgocitinib	X															X
Cerdulatinib			X

ORAL JAKi	Study (duration)	Daily dosage	EASI75	EASI90	IGA 0/1 (or -2 points)
Upadacitinib⁴³43 Simpson EL, Papp KA, Blauvelt A, Chu CY, Hong HC, Katoh N, Calimlim BM, Thyssen JP, Chiou AS, Bissonnette R, et al. Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials. JAMA Dermatol. 2022;158:404-413. doi: 10.1001/jamadermatol.2022.0029. https://doi.org/10.1001/jamadermatol.202... ,⁶⁹69 Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017;77:521-546. doi: 10.1007/s40265-017-0701-9. https://doi.org/10.1007/s40265-017-0701-... (> 12 years of age)	Measure Up 1 (16 weeks)	30 mg	80%	66%	62%
		15 mg	70%	53%	48%
		Placebo	16%	8%	8.4%
	Measure Up 2 (16 weeks)	30 mg	73%	62%	52%
		15 mg	60%	48%	38.8%
		Placebo	13%	8%	4.7%
	AD Up (+ topical corticoid 16 weeks)	30 mg	77%	63%	58.6%
		15 mg	65%	43%	39.6%
		Placebo	26%	13%	10.9%
Abrocitinib⁴²42 Silverberg JI, Thyssen JP, Simpson EL, Yosipovitch G, Stander S, Valdez H, Rojo R, Biswas P, Myers DE, Feeney C, et al. Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes. Am J Clin Dermatol. 2021;22:541-554. doi: 10.1007/s40257-021-00604-9. https://doi.org/10.1007/s40257-021-00604... (> 12 years of age)	JADE MONO-1 (12 weeks)	200 mg	63%	39%	43.8%
		100 mg	40%	19%	23.7%
		Placebo	12%	5%	7.9%
	JADE MONO-2 (12 weeks)	200mg	61%	38%	38.1%
		100mg	45%	24%	28.4%
		Placebo	10%	4%	9.1%
Baricitinib⁴¹41 Reich K, DeLozier AM, Nunes FP, Thyssen JP, Eichenfield LF, Wollenberg A, Ross Terres JA, Watts SD, Chen YF, Simpson EL, et al. Baricitinib improves symptoms in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: patient-reported outcomes from two randomized monotherapy phase III trials. J Dermatolog Treat. 2022;33:1521-1530. doi: 10.1080/09546634.2020.1839008. https://doi.org/10.1080/09546634.2020.18... ,⁷⁰70 Silverberg JI, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, Costanzo A, Rosmarin D, Lynde C, Liu J, Gamelli A, et al. Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results. J Allergy Clin Immunol. 2022;149:977-987 e914. doi: 10.1016/j.jaci.2021.07.036. https://doi.org/10.1016/j.jaci.2021.07.0... (> 18 years of age)	BREEZE AD-1 (16 weeks)	4 mg	25%	16%	17%
		2 mg	19%	11%	11%
		1 mg	17%	9%	12%
		Placebo	9%	5%	5%
	BREEZE AD-2 (16 weeks)	4 mg	21%	21%	14%
		2 mg	18%	18%	11%
		1 mg	13%	13%	9%
		Placebo	3%	6%	5%
	BREEZE AD-7 (+topical corticoid 16 weeks)	4 mg	48%	24%	31%
		2 mg	43%	17%	24%
		Placebo	23%	14%	15%

Topical JAKi	Study (duration)	Concentration 2× day	EASI 75	IGA 0/1 (or -2 points)
Ruxolitinib⁷¹71 Reich K, Kabashima K, Peris K, Silverberg JI, Eichenfield LF, Bieber T, Kaszuba A, Kolodsick J, Yang FE, Gamalo M, et al. Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020;156:1333-1343. doi: 10.1001/jamadermatol.2020.3260. https://doi.org/10.1001/jamadermatol.202...	TRuE - AD 1 (8 weeks)	1.5% cream	62.1%	53.8%
		0.75% cream	56.0%	50.0%
		Vehicle	24.6%	15.1%
	TRuE - AD 2 (8 weeks)	1,5% cream	61.8%	51.3%
		0.75% creme	51.5%	39.0%
		Vehicle	14.4%	7.6%
Tofacitinib⁷²72 Mohney LA, Singh R, Feldman SR. Review of Ruxolitinib in the Treatment of Atopic Dermatitis. Ann Pharmacother. 2023;57:207-216. doi: 10.1177/10600280221103282. https://doi.org/10.1177/1060028022110328...	NCT02001181 (4 weeks)	2% ointment		68.0%
	NCT02001181 (4 weeks)	Vehicle		13.0%
Delgocitinib⁷³73 Bissonnette R, Papp KA, Poulin Y, Gooderham M, Raman M, Mallbris L, Wang C, Purohit V, Mamolo C, Papacharalambous J, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175:902-911. doi: 10.1111/bjd.14871. https://doi.org/10.1111/bjd.14871... ,⁷⁴74 Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kaino H, Nagata T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J Am Acad Dermatol. 2020;82:823-831. doi: 10.1016/j.jaad.2019.12.015. https://doi.org/10.1016/j.jaad.2019.12.0...	OBA 4-1 (4 weeks)	0.5% cream	26.4%	Body - 10.4%
		0.5% cream	26.4%	Face - 22.8%
		Vehicle	5.8%	Body ‒ 3.8%
		Vehicle	5.8%	Face - 4.0%
	JapicCTI-184064 (4 weeks)	0.5% cream	37.7%
	JapicCTI-184064 (4 weeks)	Vehicle	4.4%

[1] ⋆
Study conducted at the Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil.

Brasil

Brasil

JAK-STAT pathway inhibitors in dermatology^☆ ⋆ Study conducted at the Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil.

Abstract

Brasil

Brasil

JAK-STAT pathway inhibitors in dermatology☆ ⋆ Study conducted at the Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil.

Abstract

JAK-STAT pathway inhibitors in dermatology^☆ ⋆ Study conducted at the Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil.