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

Abstract

The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different JAK-STAT signaling patterns have potential indications for various medical conditions. The main dermatological targets of JAK-STAT pathway inhibitors are inflammatory or autoimmune diseases such as psoriasis, vitiligo, atopic dermatitis and alopecia areata; however, several dermatoses are under investigation to expand this list of indications. As JAK-STAT pathway inhibitors should gradually occupy a relevant space in dermatological prescriptions, this review presents the main available drugs, their immunological effects, and their pharmacological characteristics, related to clinical efficacy and safety, aiming to validate the best dermatological practice.

Keywords
Alopecia areata; Atopic dermatitis; Janus Kinase Inhibitors; Psoriasis; Treatment; Vitiligo

Introduction

The Janus kinase (JAK) and signal transducer/activator of transcription (STAT) signaling pathway comprise a family of molecules linked to the intracellular domains of receptors for various cytokines and growth factors, which mediate their signaling to the nucleus.11 Chapman S, Kwa M, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part I. A comprehensive review. J Am Acad Dermatol. 2022;86:406-413. doi: 10.1016/j.jaad.2021.07.002.
https://doi.org/10.1016/j.jaad.2021.07.0...
The naming of one of these kinases as Janus refers to the Roman god who represented the beginning or opening of a process, which had two faces that were associated with the two JAK domains: one catalytic and one similar to the kinase. Historically, the beginning of the day, the month and the year were intended as a sacrament to Janus, thus, according to legend, the month of January originates from his name.

The JAK-STAT pathway belongs to a complex system of protein kinases, evolutionarily conserved, in which extracellular mediators control the expression of specific genes involved in several cell functions such as mitosis, differentiation, apoptosis, hematopoiesis, development of the immune system (innate and adaptive) and exocrine gland activity. Additionally, it participates in cellular responses to insults, such as hypoxia, ultraviolet irradiation, endotoxin stimulation, oxidative and hyperosmolar stress.22 Dudley AC, Thomas D, Best J, Jenkins A. The STATs in cell stress-type responses. Cell Commun Signal. 2004;2:8. doi: 10.1186/1478-811X-2-8.
https://doi.org/10.1186/1478-811X-2-8...

Thus, several inflammatory or autoimmune dermatoses are the subject of study for the indication of drugs that are JAK-STAT pathway inhibitors (JAKi).33 Chapman S, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part II. A comprehensive review. J Am Acad Dermatol. 2022;86:414-422. doi: 10.1016/j.jaad.2021.06.873.
https://doi.org/10.1016/j.jaad.2021.06.8...
Since this therapeutic class has shown to be promising in replacing the chronic use of classic immunosuppressants (e.g., cyclosporine, azathioprine, mycophenolate, methotrexate, corticosteroids) due to its action selectivity, JAKi should gradually appear in the dermatological prescription.

This is a narrative review that included articles published on JAKi, targeting the main dermatological diseases in the MEDLINE, Scielo and Google Scholar databases, which evaluated the period from 1992 (from the first foundations of the intracellular signaling process) to the present day. The authors describe the main available drugs, their immunological effects, and their pharmacological characteristics, related to clinical efficacy and safety, aiming to support the best dermatological practice.

The JAK-STAT pathway

JAK enzymes are tyrosine kinases attached to the intracellular domains of transmembrane receptors for certain cytokines and growth factors. After the coupling of molecules to the extracellular domains of their receptors, a conformational change occurs in their structure that leads to the phosphorylation of specific tyrosine residues in JAK dimers. This phosphorylation allows the recruitment of proteins such as STAT transcription factors, which dimerize and are translocated to the cell nucleus (via nuclear import Ran) to regulate the transcription of specific genes (Fig. 1).44 Li WX. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol. 2008;18:545-551. doi: 10.1016/j.tcb.2008.08.008.
https://doi.org/10.1016/j.tcb.2008.08.00...

Figure 1
Schematic representation of the (canonical) JAK-STAT signaling pathway. (A) Several cytokines and growth factors present in the extracellular environment depend on transmembrane receptors to initiate the process of cell signaling and nuclear transcription of the genes associated with each pathway. (B) Cytokine coupling with the extracellular domain of the transmembrane receptor leads to a change in its conformation and phosphorylation of JAK dimers, located in the intracellular domain of the receptor, that transphosphorylate their terminal tyrosine residues. This process induces the dimerization and phosphorylation of inactive STAT units that migrate to the nucleus and mediate the transcription of genes related to the specific cytokine pathway. (C) Inhibitors of the JAK-STAT (JAKi) signaling pathway prevent JAK phosphorylation by disrupting cytokine or growth factor nuclear signaling. Source: the authors

Each JAK subtype contains a specific tyrosine residue for ATP-dependent phosphorylation, with this specificity differentiating them among themselves, and among over 500 human tyrosine kinases.55 Lin CM, Cooles FA, Isaacs JD. Basic Mechanisms of JAK Inhibition. Mediterr J Rheumatol. 2020;31:100-104. doi: 10.31138/mjr.31.1.100.
https://doi.org/10.31138/mjr.31.1.100...

The main components of the JAK-STAT pathway are four JAK enzymes (JAK1, JAK2, JAK3 and Tyrosine Kinase 2 [Tyk2]), and seven STAT enzymes (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6). They are distributed as dimers, whose composition varies according to the transmembrane receptor and cell types involved.11 Chapman S, Kwa M, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part I. A comprehensive review. J Am Acad Dermatol. 2022;86:406-413. doi: 10.1016/j.jaad.2021.07.002.
https://doi.org/10.1016/j.jaad.2021.07.0...
Therefore, according to the inhibition pattern for different JAK-STAT pathways, different cytokine signaling profiles are affected.

The selective blocking of cytokine groups signaling is a hallmark of the immunomodulatory effect of JAKi in comparison to conventional immunosuppressants (e.g., cyclosporine or corticosteroids), which suppress a wide range of mediators; or to immunobiological drugs, which specifically suppress one cytokine.66 Spinelli FR, Meylan F, O'Shea JJ, Gadina M. JAK inhibitors: Ten years after. Eur J Immunol. 2021;51:1615-1627. doi: 10.1002/eji.202048922.
https://doi.org/10.1002/eji.202048922...
Table 1 depicts the main cytokines and growth factors affected by blocking of JAK subtypes.

Table 1
Main cytokines and growth factors influenced by the signaling of different JAK subtypes in humans

Since JAK units are only coupled to type I and type II cytokine receptors, JAKi do not directly mediate the signaling of TNF (α, β), TGF (α, β), EGF, chemokines (e.g., IL-8, CXC, CX3C), PDGF and IL-1 (α, β), which are pathogenic in a number of dermatoses.77 Foxwell BM, Barrett K, Feldmann M. Cytokine receptors: structure and signal transduction. Clin Exp Immunol. 1992;90:161-169. doi: 10.1111/j.1365-2249.1992.tb07922.x.
https://doi.org/10.1111/j.1365-2249.1992...
,88 Takeuchi T. Cytokines and cytokine receptors as targets of immune-mediated inflammatory diseases-RA as a role model. Inflamm Regen. 2022;42:35. doi: 10.1186/s41232-022-00221-x.
https://doi.org/10.1186/s41232-022-00221...

The JAK-STAT signaling pathway constitutes a fruitful line of research in cell biology, involving aspects related to the behavior of mutant variants of its enzymes, intracellular regulation by inhibitors/activators, effects of non-canonical activation, and interaction with other inflammatory, apoptotic, or cell growth pathways, which are medically relevant subjects but are beyond the scope of this review.99 Deng S, Wang C, Wang Y, Xu Y, Li X, Johnson NA, Mukherji A, Lo UG, Xu L, Gonzalez J, et al. Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance. Nat Cancer. 2022;3:1071-1087. doi: 10.1038/s43018-022-00431-9.
https://doi.org/10.1038/s43018-022-00431...

10 Brooks AJ, Putoczki T. JAK-STAT Signalling Pathway in Cancer. Cancers (Basel). 2020;12. doi: 10.3390/cancers12071971.
https://doi.org/10.3390/cancers12071971...

11 Chen DY, Khan N, Close BJ, Goel RK, Blum B, Tavares AH, Kenney D, Conway HL, Ewoldt JK, Chitalia VC, et al. SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway. J Virol. 2021;95:e0086221. doi: 10.1128/JVI.00862-21.
https://doi.org/10.1128/JVI.00862-21...

12 Clere-Jehl R, Mariotte A, Meziani F, Bahram S, Georgel P, Helms J. JAK-STAT Targeting Offers Novel Therapeutic Opportunities in Sepsis. Trends Mol Med. 2020;26:987-1002. doi: 10.1016/j.molmed.2020.06.007.
https://doi.org/10.1016/j.molmed.2020.06...

13 Dolatabadi S, Jonasson E, Linden M, Fereydouni B, Backsten K, Nilsson M, Martner A, Forootan A, Fagman H, Landberg G, et al. JAK-STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma. Int J Cancer. 2019;145:435-449. doi: 10.1002/ijc.32123.
https://doi.org/10.1002/ijc.32123...

14 Barbosa OA, Andrade TG, de Almeida Sousa MD, Correia JW. Portal venous thrombosis associated with JAK 2 mutation in pregnancy - case report. J Obstet Gynaecol. 2021;41:659-661. doi: 10.1080/01443615.2020.1824215.
https://doi.org/10.1080/01443615.2020.18...

15 Tsilifis C, Freeman AF, Gennery AR. STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions. J Clin Immunol. 2021;41:864-880. doi: 10.1007/s10875-021-01051-1.
https://doi.org/10.1007/s10875-021-01051...
-1616 Majoros A, Platanitis E, Kernbauer-Holzl E, Rosebrock F, Muller M, Decker T. Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses. Front Immunol. 2017;8:29. doi: 10.3389/fimmu.2017.00029.
https://doi.org/10.3389/fimmu.2017.00029...

Main characteristics of JAKi (in dermatology)

JAKi are small molecules (<500 kD), which favors their intestinal absorption and skin permeation, despite being little lipophilic (log p between 1.5 and 2). Because they are final drugs and do not depend on metabolization for the pharmacological effect, their rapid absorption leads to an early clinical effect, since their plasma peaks and elimination half-lives are also brief (<18 h).1717 Nakashima C, Yanagihara S, Otsuka A. Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors. Allergol Int. 2022;71:40-46. doi: 10.1016/j.alit.2021.10.004.
https://doi.org/10.1016/j.alit.2021.10.0...

In topical formulations, JAKi do not result in high serum drug levels, minimizing systemic adverse effects and drug interactions.1717 Nakashima C, Yanagihara S, Otsuka A. Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors. Allergol Int. 2022;71:40-46. doi: 10.1016/j.alit.2021.10.004.
https://doi.org/10.1016/j.alit.2021.10.0...
,1818 Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, Forman SB, Venturanza ME, Sun K, Kuligowski ME, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85:863-872. doi: 10.1016/j.jaad.2021.04.085.
https://doi.org/10.1016/j.jaad.2021.04.0...
Additionally, they reach high concentrations in the epidermis and upper dermis, which justifies their effectiveness in eczema, psoriasis, and vitiligo, as discussed below. However, it is recommended not to exceed 20% of the skin surface, to use a thin layer, and not to prolong its use, to reduce the chance of systemic effects.1717 Nakashima C, Yanagihara S, Otsuka A. Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors. Allergol Int. 2022;71:40-46. doi: 10.1016/j.alit.2021.10.004.
https://doi.org/10.1016/j.alit.2021.10.0...

As for selectivity, JAKi can be classified as first-generation (e.g., tofacitinib, baricitinib) or non-selective; or second-generation (e.g., upadacitinib, abrocitinib, ritlecitinib) which are considered the most selective for one of the JAK subtypes. Moreover, JAKi differ in enzymatic blockade (reversible or covalent), and the binding site (type I, II, and allosteric).1919 Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics. 2022;14. doi: 10.3390/pharmaceutics14051001.
https://doi.org/10.3390/pharmaceutics140...

When considering their molecular structures, JAKi can be grouped as JAKiα (baricitinib, delgocitinib, ruxolitinib, tofacitinib) or JAKiβ (abrocitinib, upadacitinib, filgotinib, deucravacitinib). JAKiα have a structure similar to purine, and the condensed bicyclic system is formed by pyrimidine/pyrrole heterocycles. Moreover, all of these drugs exhibit a nucleophilic cyanide group for the kinase binding site. Given the similarity of the JH1 segments between the JAK isoforms, JAKiα inhibit them all, despite different affinities. JAKiβ were specifically synthesized by chemical modeling to optimize the bonds, in an attempt to combine the structure of the JAKiβ with a respective binding site, generating greater selectivity. However, JAKiβ are less comparable among themselves regarding their chemical structure.2020 Eichner A, Wohlrab J. Pharmacology of inhibitors of Janus kinases - Part 1: Pharmacokinetics. J Dtsch Dermatol Ges. 2022;20:1485-1499. doi: 10.1111/ddg.14921.
https://doi.org/10.1111/ddg.14921...

Due to the structural similarity of the JAK group enzymes, the different JAKi exert some inhibitory effect on all four of their subtypes, depending on the concentration used. Table 2 summarizes the pharmacological characteristics of the main JAKi currently used in dermatology. However, most pharmacological and pharmacodynamic indicators are estimated by assays in which inhibitory concentrations are performed by in vitro tests that employ different methodologies, without considering metabolic variations associated with sex, age group, ethnicity, body composition, comorbidities, and the concomitant use of other medications. These characteristics justify caution in their prescription and long-term follow-up, given that pharmacovigilance results of the main drugs are still in progress due to their recent approval (<5 years) by international regulatory agencies.

Table 2
Pharmacological characteristics of the main JAK-STAT pathway inhibitors available on the market

JAKi safety and tolerability

As with other medications, except in immunologically-mediated reactions, adverse effects (AEs) and risks associated with medications that interfere with cytokine signaling and transcription pathways, cell growth factors, and induction of cell apoptosis, are directly proportional to the following conditions: (i) Occurrence of concomitant diseases (latent tuberculosis, HIV infection, HTLV-1, Chagas disease, autoimmune diseases, inflammatory bowel disease (IBD), thrombophilia, liver, kidney and hematological diseases); (ii) Medication dosage; (iii) Treatment duration, and (iv) Metabolic pathways altered by gene polymorphism (glucose-6-phosphate dehydrogenase deficiency, slow acetylation, HLA predisposition to severe adverse reactions, as in the case of abacavir, HLA-B*5701).2121 Han J, Pan C, Tang X, Li Q, Zhu Y, Zhang Y, Liang A. Hypersensitivity reactions to small molecule drugs. Front Immunol. 2022;13:1016730. doi: 10.3389/fimmu.2022.1016730.
https://doi.org/10.3389/fimmu.2022.10167...

Nonetheless, many AEs may be infrequent, or even not present in phase III studies with a limited number of patients and short exposure to the drug, which will only be identified by pharmacovigilance reports, since most JAKi have been in the market for less than five years.2222 Pitts PJ, Louet HL, Moride Y, Conti RM. 21st century pharmacovigilance: efforts, roles, and responsibilities. Lancet Oncol. 2016;17:e486-e492. doi: 10.1016/S1470-2045(16)30312-6.
https://doi.org/10.1016/S1470-2045(16)30...
The dermatologist must be aware of the possibility of AEs arising from the prolonged use of these drugs, as well as to be able to identify subgroups of susceptible patients and, mainly, the possibility of drug interactions.

Drug interactions

Population aging and the availability of new drugs favor the concomitant use of drugs by the population, which maximizes the possibility of drug interactions, for instance, via cytochrome P450 (CYP).2323 Walton A, Paik J, Quebe A, Kannowski CL, Choong C, Anderson S, Owensby JK. Frequency of Prescription Claims for Drugs that May Interact with Janus Kinase Inhibitors Among Patients with Rheumatoid Arthritis in the US. Rheumatol Ther. 2021;8:599-607. doi: 10.1007/s40744-020-00275-8.
https://doi.org/10.1007/s40744-020-00275...

In patients with rheumatoid arthritis (RA) who received JAKi, it was identified that more than 10% of them were prescribed concomitant drugs with potential drug interaction, such as OAT3 (organic anion transporter 3) pump inhibitors, potent CYP3A4 and CYP2C19 inhibitors.2323 Walton A, Paik J, Quebe A, Kannowski CL, Choong C, Anderson S, Owensby JK. Frequency of Prescription Claims for Drugs that May Interact with Janus Kinase Inhibitors Among Patients with Rheumatoid Arthritis in the US. Rheumatol Ther. 2021;8:599-607. doi: 10.1007/s40744-020-00275-8.
https://doi.org/10.1007/s40744-020-00275...

While JAKi is metabolized in the liver by the CYP system, primarily via CYP3A4-metabolizing enzymes, the extent of the metabolism by these pathways and other enzymes varies according to the JAKi used, as well as its level of renal excretion. Table 3 provides an extensive list of drugs that potentially interfere with CYP3A4, CYP2C19 and the OAT3 pump that should be considered when using JAKi concomitantly.

Table 3
Medications that potentially interfere with the serum levels and safety of JAK-STAT pathway inhibitors

It should be noted that commonly used medications such as anxiolytic, antidepressant, antifungal, antilipidemic, and antihypertensive drugs are part of this list, and dermatologists should consider the risks of these interactions. Even recreational drugs (e.g., Cannabis sp.) and plant extracts (e.g., Echinacea purpurea, Hypericum perforatum), which are often omitted by patients, have an effect on the hepatic drug metabolism.2424 Lippert A, Renner B. Herb-Drug Interaction in Inflammatory Diseases: Review of Phytomedicine and Herbal Supplements. J Clin Med. 2022;11. doi: 10.3390/jcm11061567.
https://doi.org/10.3390/jcm11061567...
,2525 Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther. 2001;70:317-326. However, the brief concomitant use of JAKi with potential drugs that promote interaction, such as fluconazole for vulvovaginal candidiasis, does not imply harm.

Different JAKi for systemic use have pharmacokinetic and metabolic particularities, depending on their binding fraction with plasma proteins, rate of hepatic metabolism, and metabolite activity (Table 2).

Tofacitinib is rapidly absorbed after oral administration with peak plasma concentrations within 1 hour, reaching steady-state within 48 hours. Its oral bioavailability is 74%, regardless of food intake, and 40% of the drug is bound to plasma proteins.2020 Eichner A, Wohlrab J. Pharmacology of inhibitors of Janus kinases - Part 1: Pharmacokinetics. J Dtsch Dermatol Ges. 2022;20:1485-1499. doi: 10.1111/ddg.14921.
https://doi.org/10.1111/ddg.14921...
It is mainly eliminated through the liver (70%) and kidneys (30%), which requires lower doses in the presence of liver and kidney disease. The main route of metabolism uses CYP3A4, with a small contribution from CYP2C19, in addition to being a P-glycoprotein substrate. Interactions with midazolam, oral contraceptives, or metformin have not been demonstrated.2626 Gilardi D, Gabbiadini R, Allocca M, Correale C, Fiorino G, Furfaro F, Zilli A, Peyrin-Biroulet L, Danese S. PK, PD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD. Expert Rev Gastroenterol Hepatol. 2020;14:797-806. doi: 10.1080/17474124.2020.1785868.
https://doi.org/10.1080/17474124.2020.17...

Upadacitinib is absorbed over a wide pH range (between 1‒7.5) without major dietary interference, and only 52% is bound to plasma proteins; therefore, relevant interactions dependent on plasma protein displacement are not expected. No dose adjustment is required when upadacitinib is administered to individuals with renal impairment or those with mild or moderate liver impairment.2727 Mohamed MF, Klunder B, Othman AA. Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication. Clin Pharmacokinet. 2020;59:531-544. doi: 10.1007/s40262-019-00855-0.
https://doi.org/10.1007/s40262-019-00855...
It is metabolized by CYP3A4, with lower participation of CYP2D6. Concomitant use with ketoconazole increases Cmax (maximum drug concentration) and AUC (plasma concentration-time curve) by 70% and 75%. Concomitant use with rifampicin decreases Cmax and AUC by 50% and 60%. There is no drug interaction with warfarin, omeprazole, midazolam, and ethinylestradiol + levonorgestrel.2626 Gilardi D, Gabbiadini R, Allocca M, Correale C, Fiorino G, Furfaro F, Zilli A, Peyrin-Biroulet L, Danese S. PK, PD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD. Expert Rev Gastroenterol Hepatol. 2020;14:797-806. doi: 10.1080/17474124.2020.1785868.
https://doi.org/10.1080/17474124.2020.17...

Abrocitinib, after its absorption, binds to plasma proteins in 37%, 85% is excreted through the kidneys, and 9.5% through the stools. As for the unmetabolized form; 0.6% is excreted through the kidneys and 0.3% through the stools.2020 Eichner A, Wohlrab J. Pharmacology of inhibitors of Janus kinases - Part 1: Pharmacokinetics. J Dtsch Dermatol Ges. 2022;20:1485-1499. doi: 10.1111/ddg.14921.
https://doi.org/10.1111/ddg.14921...
Co-administration should adhere to the following recommendations: (i) Concomitant use with CYP2C19 inhibitors (abrocitinib dose should be reduced by half); (ii) Concomitant use with potent CYP2C9/CYP2C19 inducers (not recommended); (iii) OAT3 inhibitors (no need for adjustment).2828 Wang X, Dowty ME, Wouters A, Tatulych S, Connell CA, Le VH, Tripathy S, O'Gorman MT, Winton JA, Yin N, et al. Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals. Eur J Drug Metab Pharmacokinet. 2022;47:419-429. doi: 10.1007/s13318-021-00745-6.
https://doi.org/10.1007/s13318-021-00745...
For examples, special attention to (i) Fluconazole, fluoxetine, fluvoxamine, and ticlopidine (CYP2C19 inhibitors); (ii) Apalutamide and rifampicin (use is not recommended), and (iii) Probenecid and teriflunomide (no dose adjustment required).2828 Wang X, Dowty ME, Wouters A, Tatulych S, Connell CA, Le VH, Tripathy S, O'Gorman MT, Winton JA, Yin N, et al. Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals. Eur J Drug Metab Pharmacokinet. 2022;47:419-429. doi: 10.1007/s13318-021-00745-6.
https://doi.org/10.1007/s13318-021-00745...
Liver failure has no clinically relevant effect on the pharmacokinetics and safety of abrocitinib, thus permitting its use without dose adjustment in mild or moderate liver failure.2929 Wang EQ, Le V, O'Gorman M, Tripathy S, Dowty ME, Wang L, Malhotra BK. Effects of Hepatic Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites. J Clin Pharmacol. 2021;61:1311-1323. doi: 10.1002/jcph.1858.
https://doi.org/10.1002/jcph.1858...

Baricitinib is rapidly absorbed through oral administration in the fasting state, with a plasma peak within one hour, and bioavailability of 80%. High-fat and high-calorie foods reduce absorption by 29%, delaying the plasma peak to three hours. There is 50% binding to plasma proteins, and steady-state is reached within 48 hours. Less than 10% of ingested baricitinib undergoes metabolism by CYP3A4, with no metabolites being detected in the plasma, requiring dose adjustment in mild or moderate liver failure. It is excreted unchanged in urine (69%) and stools (15%), while 6% of the dosage is excreted as metabolites. Glomerular filtration is the main excretion and active secretion mechanism for OAT3, P-glycoprotein, BCRP and MATE2-K. Thus, baricitinib plasma levels increase in patients with mild (×1.4) and moderate (×2.2) renal dysfunction. In patients with creatinine clearance between 30‒60 mL/min, the dose of baricitinib should be reduced to 2 mg/d and is not recommended when creatinine clearance is <30 mL/min.3030 Richez C, Truchetet ME, Kostine M, Schaeverbeke T, Bannwarth B. Efficacy of baricitinib in the treatment of rheumatoid arthritis. Expert Opin Pharmacother. 2017;18:1399-1407. doi: 10.1080/14656566.2017.1359256.
https://doi.org/10.1080/14656566.2017.13...

Adjustment in tofacitinib or baricitinib, but not in upadacitinib dosage, is required with progression in renal failure severity. Although the dosage of tofacitinib needs to be adjusted for patients with moderate liver failure, this is not the case with baricitinib or upadacitinib.3131 Veeravalli V, Dash RP, Thomas JA, Babu RJ, Madgula LMV, Srinivas NR. Critical Assessment of Pharmacokinetic Drug-Drug Interaction Potential of Tofacitinib, Baricitinib and Upadacitinib, the Three Approved Janus Kinase Inhibitors for Rheumatoid Arthritis Treatment. Drug Saf. 2020;43:711-725. doi: 10.1007/s40264-020-00938-z.
https://doi.org/10.1007/s40264-020-00938...
Both moderate and severe renal failure led to greater exposure to the active portion of abrocitinib, suggesting that the dosage of abrocitinib should be halved in moderate or severe renal failure.3232 Wang EQ, Le V, Winton JA, Tripathy S, Raje S, Wang L, Dowty ME, Malhotra BK. Effects of Renal Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites. J Clin Pharmacol. 2022;62:505-519. doi: 10.1002/jcph.1980.
https://doi.org/10.1002/jcph.1980...

Infections and general adverse events

The pharmacological effects of JAKi are proportional to the dosages used, so their prescription should indicate the lowest clinically effective dosage, aiming to minimize the risks associated with immunosuppression, or JAK2 inhibition, mainly hematological AEs.

The use of topical JAKi has shown few systemic AEs; however, acne, previously reported in patients receiving oral JAKi, has been observed in some reports and case series.33 Chapman S, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part II. A comprehensive review. J Am Acad Dermatol. 2022;86:414-422. doi: 10.1016/j.jaad.2021.06.873.
https://doi.org/10.1016/j.jaad.2021.06.8...

Most infectious events related to JAKi are reported after the use of tofacitinib, since it started being marketed in 2012, reflecting the longer duration of use and the large number of patients exposed to this medication and, consequently, the greater number of publications in the literature.3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...

34 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...

35 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...
-3636 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...

The ORALSURV study involved 4,362 individuals with RA, older than 50 years, and with at least one cardiovascular risk factor. Patients previously receiving methotrexate were allocated to receive: tofacitinib 5 mg twice daily; tofacitinib 10 mg twice daily; or an anti-TNFα (etanercept or adalimumab). With regard to infections, the ORALSURV showed that tofacitinib resulted in a similar risk of infections as anti-TNFα, except for its propensity to reactivate latent viruses (e.g., varicella zoster, herpes simplex, and cytomegalovirus).3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...

Regarding serious infectious events (SIEs), the ORALSURV identified a similar risk for tofacitinib 5 mg and anti-TNFα use, even in patients older than 65 years.3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...
The ORALSURV data on SIEs were consistent with data from the currently approved JAKi and bDMARDs (biological disease-modifying anti-rheumatic drugs) development programs, in which the rates of SIEs were similar (3‒4 SIE/100 patient-years) with higher rates being found in the elderly.3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...
,3737 Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, Checchio T, Tensfeldt TG, Hoffman E, Riese R, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362. doi: 10.1186/s13075-015-0880-2.
https://doi.org/10.1186/s13075-015-0880-...

The most common AEs reported in phase III studies of systemic JAKi were headache, nausea, and nasopharyngitis. Viral infections such as herpes simplex virus (HSV), Kaposi's varicelliform eruption (HE, herpetic eczema), and herpes zoster (HZ) are the most common dermatological AEs in AD patients receiving treatment with JAKi.1313 Dolatabadi S, Jonasson E, Linden M, Fereydouni B, Backsten K, Nilsson M, Martner A, Forootan A, Fagman H, Landberg G, et al. JAK-STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma. Int J Cancer. 2019;145:435-449. doi: 10.1002/ijc.32123.
https://doi.org/10.1002/ijc.32123...
Most of the data on HSV infection come from the use of tofacitinib in RA, psoriatic arthritis, and IBD. However, there is a lower incidence of HSV, HZ and HE infections in JAKi1 (selective) clinical trials in patients with AD.3838 Pathania YS. JAK inhibitors in atopic dermatitis associated with risk of viral infections: a critical appraisal. Actas Dermosifiliogr. 2022. doi: 10.1016/j.ad.2022.03.025.
https://doi.org/10.1016/j.ad.2022.03.025...
,3939 Blauvelt A, Silverberg JI, Lynde CW, Bieber T, Eisman S, Zdybski J, Gubelin W, Simpson EL, Valenzuela F, Criado PR, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. J Am Acad Dermatol. 2022;86:104-112. doi: 10.1016/j.jaad.2021.05.075.
https://doi.org/10.1016/j.jaad.2021.05.0...

The JADE REGIMEN trial enrolled 1,233 patients with moderate to severe AD in an open-label (12 weeks) phase with abrocitinib 200 mg/d as monotherapy.3939 Blauvelt A, Silverberg JI, Lynde CW, Bieber T, Eisman S, Zdybski J, Gubelin W, Simpson EL, Valenzuela F, Criado PR, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. J Am Acad Dermatol. 2022;86:104-112. doi: 10.1016/j.jaad.2021.05.075.
https://doi.org/10.1016/j.jaad.2021.05.0...
At the end of the 12 weeks, 798 patients (64.7%) were considered drug responders and randomly allocated to a blinded study with abrocitinib 200 mg/d, 100 mg/d, or placebo (40 weeks). Considering the open phase (induction) and blinded study, the patients completed 52 weeks of follow-up. In the induction phase (12 weeks), SIEs were observed in six patients (0.5%), with HZ occurring in nine patients (0.7%). In the blinded phase (40 weeks), the rates of SIEs and HZ varied among the patients allocated in the three different groups: (i) Placebo, 267 patients, SIEs were observed in two cases (0.7%) and HZ in two cases (0.7%); (ii) Abrocitinib 100 mg/d, 265 patients, SIEs in two cases (0.8%) and HZ in two cases (0.8%); (iii) Abrocitinib 200 mg/d, 266 patients, SIEs were observed in five patients (1.9%), and HZ in nine patients (3.4%). Adding the three groups in the blinded phase (20 weeks; 798 patients), SIEs were seen in nine cases (1.1%) and HZ in 13 patients (1.6%).3939 Blauvelt A, Silverberg JI, Lynde CW, Bieber T, Eisman S, Zdybski J, Gubelin W, Simpson EL, Valenzuela F, Criado PR, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. J Am Acad Dermatol. 2022;86:104-112. doi: 10.1016/j.jaad.2021.05.075.
https://doi.org/10.1016/j.jaad.2021.05.0...

In a meta-analysis on the efficacy and safety of abrocitinib, baricitinib and upadacitinib in patients with moderate to severe AD, the authors concluded that when the total number of AEs (treatment-emergent adverse events, TEAE) was analyzed, upadacitinib and abrocitinib showed greater incidence than the placebo group, and abrocitinib was associated with an increase in TEAE compared with baricitinib. However, when these JAKi were analyzed in relation to TEAE and the dosage of medication used, only the 30 mg/d dose of upadacitinib increased the incidence of TEAE, with odds ratio (OR) = 13.64. Also in the network meta-analysis, the comparison of adverse events of abrocitinib versus placebo resulted in OR = 5.57; baricitinib versus placebo, OR = 2.92; abrocitinib versus baricitinib, OR = 1.92; abrocitinib versus upadacitinib, OR = 0.41; and baricitinib versus upadacitinib, OR = 0.21. The authors of the meta-analysis point out that most clinical trial studies were conducted with efficacy and safety assessments in a short evaluation period, with no comparison yet in studies between them, and that studies of long-term efficacy and safety must be carried out.4040 Wan H, Jia H, Xia T, Zhang D. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther. 2022;35:e15636. doi: 10.1111/dth.15636.
https://doi.org/10.1111/dth.15636...

As examples of published phase III studies with a considerable sample, randomized and placebo-controlled, Measure Up 1 and Measure Up 2 evaluated 847 and 836 patients with moderate to severe AD allocated in groups receiving 30 mg/d, 15 mg/d of upadacitinib or placebo. The primary efficacy endpoints were assessed at week 16, as well as the recorded AEs (Table 4).

Table 4
Main adverse events, in order of frequency, in the main dermatoses where JAK-STAT pathway inhibitors are used

Regarding infectious-contagious complications, it is important to consider that disease prevalence varies according to the epidemiology of each country. The JAK-STAT pathway transmits the intracellular signaling of more than 50 cytokines and growth factors and is considered the central communication pathway of the immune system, including the defense against pathogens.

The functional alteration of the JAK-STAT system can occur not only by pharmacotherapeutic action, but also by germline loss- or gain-of-function mutations, which determine several immune phenotypes and myeloproliferative diseases. For example: (i) JAK3 loss-of-function mutations are related to severe combined immunodeficiency (SCID); (ii) Loss of function due to STAT1 mutations can generate deficiency of responses linked to interferons (IFNs), INF type 1 (alpha and beta) and INF gamma, resulting in an increase in susceptibility to viral infections; (iii) Loss-of-function mutations in JAK1, TYK2, STAT1 and STAT5B determine intracellular bacterial infections, and STATB5 deficiency can cause recurrent pneumonia; and (iv) Gain-of-function mutation in STAT1 can determine recurrent infections by Candida spp., as STAT1 antagonizes the antifungal effects mediated by IL-17 via STAT3, suppressing this intracellular signaling.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

Patients with chronic inflammatory dermatoses are at greater risk of infection due both to their disease itself (e.g., cutaneous dysbiosis with staphylococcus colonization in AD) and to the treatment they receive, particularly immunosuppressants such as cyclosporine, azathioprine, mycophenolate, and methotrexate.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
As an example, patients with RA have a two-fold risk of having severe infections, particularly bronchopulmonary and genitourinary ones, which contribute to higher mortality.4545 Alves C, Penedones A, Mendes D, Marques FB. The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis. J Clin Rheumatol. 2022;28:e407-e414. doi: 10.1097/RHU.0000000000001749.
https://doi.org/10.1097/RHU.000000000000...
Thus, when prescribing JAKi, one of the factors to be considered is the potential AEs of these drugs, but also the patients age (immunosenescence), associated comorbidities, and aspects of the disease pathogenesis.

Although opportunistic infections were shown to be more frequent across all classes of JAKi, no differences were seen regarding the risk of SIEs in a recent clinical trial network analysis.4545 Alves C, Penedones A, Mendes D, Marques FB. The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis. J Clin Rheumatol. 2022;28:e407-e414. doi: 10.1097/RHU.0000000000001749.
https://doi.org/10.1097/RHU.000000000000...
However, individual clinical trials have not been developed to assess rare outcomes.

An analysis of the long-term extension studies (LTEs) of tofacitinib found an incidence of SIEs of 2.7 cases per 100 patient years.4646 Bertoldi I, Caporali R. Tofacitinib: Real-World Data and Treatment Persistence in Rheumatoid Arthritis. Open Access Rheumatol. 2021;13:221-237. doi: 10.2147/OARRR.S322086.
https://doi.org/10.2147/OARRR.S322086...
When JAKi were combined with disease-modifying antirheumatic drugs (DMARDs), in a US registry of 21,832 RA patients, there was a higher occurrence of SIEs with tofacitinib associated with another DMARD at a rate of 3.67 vs. 2.01 SIEs every 100 patient-years among patients using DMARD alone. The incidence of SIE in the association of tofacitinib + DMARD was even higher than in patients who used tofacitinib + anti-TNFα: 3.67 cases/100 patient-years vs. 2.16 cases/100 patient-years.4747 Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Schoeman C, Thirunavukkarasu K, DeMasi R, et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017;76:1253-1262. doi: 10.1136/annrheumdis-2016-210457.
https://doi.org/10.1136/annrheumdis-2016...
,4848 Machado MAA, Moura CS, Guerra SF, Curtis JR, Abrahamowicz M, Bernatsky S. Effectiveness and safety of tofacitinib in rheumatoid arthritis: a cohort study. Arthritis Res Ther. 2018;20:60. doi: 10.1186/s13075-018-1539-6.
https://doi.org/10.1186/s13075-018-1539-...
However, these data are not yet available on dermatological conditions treated with JAKi.

Real-life data from patients with AD comparing the safety profiles of baricitinib and tofacitinib confirmed HZ as the most frequent adverse event (5.6% tofacitinib × 4.9% baricitinib).4040 Wan H, Jia H, Xia T, Zhang D. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther. 2022;35:e15636. doi: 10.1111/dth.15636.
https://doi.org/10.1111/dth.15636...
The risk is greater in the elderly, and with the co-administration of corticosteroids or methotrexate.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
However, there are few cases of disseminated herpes affecting several dermatomes, without evidence of visceral disease or death from herpetic infection. Clinical trials have shown that upadacitinib has a higher risk of HZ when compared to subjects using immunobiologicals and DMARDS.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
As with first-generation JAKi, upadacitinib in RA patients has been shown to have an increased risk of HZ when prescribed at high doses, where HZ is more likely to occur and be more severe compromising multiple dermatomes.4949 Iwamoto N, Sato S, Kurushima S, Michitsuji T, Nishihata S, Okamoto M, Tsuji Y, Endo Y, Shimizu T, Sumiyoshi R, et al. Real-world comparative effectiveness and safety of tofacitinib and baricitinib in patients with rheumatoid arthritis. Arthritis Res Ther. 2021;23:197. doi: 10.1186/s13075-021-02582-z.
https://doi.org/10.1186/s13075-021-02582...

Thus, HZ virus vaccination is an important, albeit imperfect, means of reducing the burden of HZV infection.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
However, both the varicella vaccine (Varivax®, for non-immune individuals under 50 years of age) and the zoster vaccine (Zostavax® for individuals ≥50 years of age) use live viruses (likewise in yellow fever vaccine) and, as such, it is recommended they are administered at least three to four weeks before starting treatment with JAKi.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

In Brazil, the recombinant vaccine against HZV, Shingrix®, is already available for patients over 50 years old, adults over 18 years old with immunosuppression, or those who are going to receive immunosuppressant drugs, such as JAKi. This vaccine provides protection rates of 91.3% for people aged 70 years and over, and 67.3% for immunocompromised individuals over 50 years of age. The vaccine is constituted of the viral surface glycoprotein E (gE) antigen and should be offered in two doses (0‒2 months). Since it does not use live particles, it can be given concurrently with JAKi treatment.5050 Nakamura Y, Honda D, Takizawa N, Fujita Y. Herpes zoster meningitis in a rheumatoid arthritis patient treated with tofacitinib. BMJ Case Rep. 2022;15. doi: 10.1136/bcr-2021-247276.
https://doi.org/10.1136/bcr-2021-247276....

Efficacy studies on the use of Shingrix® in an immunocompromised population aged ≥65 years and in individuals treated for IBD with immunosuppressants aged ≥50 years, showed good protection against HZ. As both (JAKi and Shingrix®) are newly available, long-term follow-up of this combination should reveal details of the immunization profile in these patients.

JAKi reduce different cytokine and growth factor receptor signaling, depending on the type of JAK inhibition. Tofacitinib, a JAK1/3 inhibitor, has important effects on the development of naïve B lymphocytes. This suggests a loss in the capacity to immunize against new antigens. A decreased immune response to pneumococcal polysaccharide vaccine 23-valent (PPSV-23) was found, especially in patients receiving concomitant methotrexate: tofacitinib, 45.1% vs. healthy controls, 68.4%. Temporary discontinuation of tofacitinib for two weeks (one week before and one week after the vaccination) did not restore the pneumococcal vaccine efficacy. The results for the influenza vaccine were not affected by the use of tofacitinib.5151 Speeckaert R, Lambert J, Puig L, Speeckaert M, Lapeere H, De Schepper S, van Geel N. Vaccinations in Patients Receiving Systemic Drugs for Skin Disorders: What Can We Learn for SARS-Cov-2 Vaccination Strategies? Drugs R D. 2021;21:341-350. doi: 10.1007/s40268-021-00349-0.
https://doi.org/10.1007/s40268-021-00349...

However, most patients with psoriasis treated with tofacitinib develop adequate immunity against pneumococcal infection (pneumococcal conjugate vaccine-13) and tetanus vaccine. Vaccination with the pneumococcal conjugate vaccine-13 (PCV-13) was successful in 68% of RA patients treated with baricitinib, while only 43% achieved a ≥ 4-fold increase in antitetanic IgG concentrations. However, most patients were also taking methotrexate (89%) and/or corticosteroids (30%). Similar results were found for upadacitinib, with a satisfactory humoral response (≥2-fold increase in antibody levels) for the PCV-13 vaccine at 12 weeks in 65% and 55%, in patients using 15 mg/d and 30 mg/d.5151 Speeckaert R, Lambert J, Puig L, Speeckaert M, Lapeere H, De Schepper S, van Geel N. Vaccinations in Patients Receiving Systemic Drugs for Skin Disorders: What Can We Learn for SARS-Cov-2 Vaccination Strategies? Drugs R D. 2021;21:341-350. doi: 10.1007/s40268-021-00349-0.
https://doi.org/10.1007/s40268-021-00349...

Thus, the opinion of the authors of this review is that at least three to four weeks before starting the use of systemic JAKi, the entire vaccination schedule should be updated, in accordance with the guidelines of the local health authority, including those of the Brazilian Ministry of Health. And, during treatment with JAKi, the vaccination schedule should be followed (except for live viruses), without treatment interruption.

As with other immunosuppressants and anti-TNFα immunobiologicals, there is a concern regarding Mycobacterium tuberculosis infection with the use of JAKi,1717 Nakashima C, Yanagihara S, Otsuka A. Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors. Allergol Int. 2022;71:40-46. doi: 10.1016/j.alit.2021.10.004.
https://doi.org/10.1016/j.alit.2021.10.0...
and all patients receiving treatment with JAKi should be screened and investigated for latent or active tuberculosis.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
The risk of tuberculosis infection depends on the epidemiological risk of each region. The incidence of tuberculosis with tofacitinib was higher in endemic regions (0.75/100 patient-years) compared to lower-risk regions (0.02/100 patient-years).4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
,5252 Winthrop KL, Park SH, Gul A, Cardiel MH, Gomez-Reino JJ, Tanaka Y, Kwok K, Lukic T, Mortensen E, Ponce de Leon D, et al. Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75:1133-1138. doi: 10.1136/annrheumdis-2015-207319.
https://doi.org/10.1136/annrheumdis-2015...

As Brazil has endemic rates of tuberculosis, which can remain latent for decades, surveillance must occur before and during the use of immunosuppressants such as JAKi through PPD testing (Tuberculin test/Mantoux test) or interferon-gamma release assays (IGRA: ELISPOT, Quantiferon gold, Quantiferon gold plus), which show a slightly better performance.5353 Barros GM. The rise of tuberculosis: regression in combating advances as a legacy of COVID-19? Einstein (Sao Paulo). 2022;20:eCE0196. doi: 10.31744/einstein_journal/2022CE0196.
https://doi.org/10.31744/einstein_journa...
,5454 Fortun J, Navas E. Latent tuberculosis infection: approach and therapeutic schemes. Rev Esp Quimioter. 2022;35 Suppl 3:94-96. doi: 10.37201/req/s03.20.2022.
https://doi.org/10.37201/req/s03.20.2022...
Positive tuberculosis screening testing should be discussed with the infectologist to consider treatment of latent tuberculosis with isoniazid, for nine months, since 5% to 10% of patients show activation, especially immunosuppressed ones.

Within the scope of JAKi use, these medications bring a greater risk of general infections, risk of opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP), HZ, tuberculosis, cytomegalovirus, and Epstein-Barr virus infections, and thus it is recommended: 1) Screening of hepatitis B virus infection prior to treatment; 2) P. jirovecii prophylaxis in patients with additional risk factors, such as corticosteroid use; 3) Screening for latent tuberculosis; 4) Monitoring of viral load in HBsAg negative but anti-HBcAg positive patients due to the risk of reactivation of occult hepatitis C virus infection; 5) During the chronic use of JAKi, physicians should also be aware of the increase in other opportunistic infections, such as invasive fungal infections, especially in patients who already have an additional risk, due to factors such as previous or concomitant use of corticosteroids, low blood lymphocyte count or high-dose JAKi-dependent therapy.5555 Qian J, Xue X, Shannon J. Characteristics of adverse event reporting of Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to the US Food and Drug Administration. J Manag Care Spec Pharm. 2022;28:1046-1052. doi: 10.18553/jmcp.2022.28.9.1046.
https://doi.org/10.18553/jmcp.2022.28.9....

Invasive fungal infections were detected in LTEs and in tofacitinib trials with 15 cases among 9,291 patients; Candida spp. was the most common, followed by cryptococcosis, histoplasmosis, and Pneumocystis jirovecii.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

Thromboembolic events

Baricitinib, tofacitinib, ruxolitinib, and upadacitinib include warnings for potential deep vein thrombosis, pulmonary embolism, and arterial thrombosis events.5656 Shalabi MMK, Garcia B, Coleman K, Siller A, Jr., Miller AC, Tyring SK. Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology: A Review of Their Utilization, Safety Profile and Future Applications. Skin Therapy Lett. 2022;27:4-9. Although these risks seem to be low and dosage-dependent, further studies are needed to determine the exact mechanism behind their thrombotic effects.

The finding by the ORALSURV study of an increased risk of venous thromboembolism (VTE) with a dosage of 10 mg/d of tofacitinib compared to anti-TNFα supports this fact observed for the first time in clinical trials with patients with RA at a dosage of 4 mg/d of baricitinib, reinforcing the concept that VTE can be a true adverse event related to the use of JAKi in patients with RA.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

Although biological plausibility is still lacking, it is reasonable to speculate that greater modulation of JAK2, observed with higher dosages of tofacitinib and baricitinib, would mediate the thrombotic effects.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
However, reassuringly, JAKi used in the treatment of RA at their currently approved dosages, still do not seem to carry an excessive risk of thromboembolic events.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

The ORALSURV study reported that tofacitinib 5 mg/d and anti-TNFα use are associated with a similar risk of VTE, and this is consistent with real-world data.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
Additionally, VTE incidence rates observed in the pivotal studies of tofacitinib and upadacitinib were similar (and were lower in the filgotinib studies), and the rates in the active comparator groups of these regimens (methotrexate or adalimumab) were not higher. Even for baricitinib, for which the initial imbalance in VTE risk between 2 mg/d and 4 mg/d dosages in the first 12 weeks of phase III trials raised suspicion, similar long-term incidence rates were reported for both dosages, of 0.5/100 patient-years, in line with population-based RA studies.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...
,5757 Taylor PC, Takeuchi T, Burmester GR, Durez P, Smolen JS, Deberdt W, Issa M, Terres JR, Bello N, Winthrop KL. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81:335-343. doi: 10.1136/annrheumdis-2021-221276.
https://doi.org/10.1136/annrheumdis-2021...

Finally, baricitinib 4 mg/d given for two weeks did not increase the risk of VTE in the treatment of COVID-19, a condition that carries itself an increased risk of VTE at baseline.5858 Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, Piruzeli MLB, Goldman JD, Alatorre-Alexander J, de Cassia Pellegrini R, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9:1407-1418. doi: 10.1016/S2213-2600(21)00331-3.
https://doi.org/10.1016/S2213-2600(21)00...
As the ORALSURV findings suggest that there is a dosage-dependent risk with tofacitinib compared to anti-TNFα, until more substantiated research is performed with each of these compounds, it is prudent to avoid JAKi in patients with an elevated risk of VTE, particularly those with a history of VTE who are not currently anticoagulated.4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

In 2021, the FDA issued a safety communication and required revisions of the precautionary packaging for the following JAKi: tofacitinib, baricitinib, and upadacitinib, to include information about the risk of severe cardiac events, cancer, thrombosis, and death.5555 Qian J, Xue X, Shannon J. Characteristics of adverse event reporting of Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to the US Food and Drug Administration. J Manag Care Spec Pharm. 2022;28:1046-1052. doi: 10.18553/jmcp.2022.28.9.1046.
https://doi.org/10.18553/jmcp.2022.28.9....

Malignant neoplasms

The overall rate of occurrence of malignancies with the use of JAKi in randomized clinical trials involving RA patients and long-term extension studies was similar to that observed with bDMARDs.3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...

In the ORALSURV study, the incidence rate of malignancy (per 100 patient-years) was 1.13 for patients treated with tofacitinib at a dosage of 5 mg 2x/day and 1.13 with tofacitinib 10 mg 2x/day, in comparison with 0. 77 for anti-TNFα.3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...
,4444 Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253-261. doi: 10.1080/1744666X.2022.2014323.
https://doi.org/10.1080/1744666X.2022.20...

The increased risk of malignancies was driven by differential rates of several types of cancer (particularly lung cancer and lymphoma), which were seen primarily in the North-American study groups (compared to the rest of the world), among older individuals with a history of smoking.3333 Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18:301-304. doi: 10.1038/s41584-022-00767-7.
https://doi.org/10.1038/s41584-022-00767...
An increased risk of non-melanoma skin cancer was also observed, which was previously seen with a dosage of 10 mg/d of tofacitinib in ulcerative colitis.5959 Sands BE, Long MD, Reinisch W, Panes J, Loftus EV, Nduaka CI, Soonasra A, Mundayat R, Lawendy N, Chan G, et al. Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program. Inflamm Bowel Dis. 2022;28:234-245. doi: 10.1093/ibd/izab056.
https://doi.org/10.1093/ibd/izab056...
However, higher rates of melanoma were observed in patients using anti-TNFα, 0.09 vs. 0.02, for any dosage of tofacitinib.5959 Sands BE, Long MD, Reinisch W, Panes J, Loftus EV, Nduaka CI, Soonasra A, Mundayat R, Lawendy N, Chan G, et al. Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program. Inflamm Bowel Dis. 2022;28:234-245. doi: 10.1093/ibd/izab056.
https://doi.org/10.1093/ibd/izab056...

The mechanism by which JAKi may be associated with some types of cancer is unknown, but it is speculated that some JAKi, depending on their selectivity and effect on natural killer (NK) cells, could lower host immunosurveillance, making existing cancer or “de novo” have a greater possibility of evolution, as with other immunosuppressants.6060 Nocturne G, Pascaud J, Ly B, Tahmasebi F, Mariette X. JAK inhibitors alter NK cell functions and may impair immunosurveillance against lymphomagenesis. Cell Mol Immunol. 2020;17:552-553. doi: 10.1038/s41423-019-0320-3.
https://doi.org/10.1038/s41423-019-0320-...

In summary, when oral JAKi are evaluated in general, reported rates of venous thromboembolism ranged from no events to 0.1%‒0.5% in specific phase 3 dermatology clinical trials, when compared to no events on placebo. Cardiovascular event rates ranged from no events to 0.4%‒1.2% compared to no events to 0.5%‒1.2% on placebo. Rates of severe infections were 0.4%‒4.8% compared with no events to 0.5%‒1.3% on placebo. Non-melanoma skin cancer rates ranged from no events to 0.6%‒0.9% compared with no events on placebo. Non-melanoma skin cancer rates ranged from no events to 0.2%‒0.7% compared to no events to 0.6% on placebo. Most patients who developed these adverse events had risk factors for the specific event. The most common adverse effects were upper airway infections, nausea, headache, acne, and dyslipidemia. 6161 Samuel C, Cornman H, Kambala A, Kwatra SG. A Review on the Safety of Using JAK Inhibitors in Dermatology: Clinical and Laboratory Monitoring. Dermatol Ther (Heidelb). 2023:1-21. doi: 10.1007/s13555-023-00892-5.
https://doi.org/10.1007/s13555-023-00892...

Contraindications for JAKi

The main contraindication for JAKi is the uncertainty in the diagnosis of the inflammatory disease that requires treatment.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...
Several inflammatory dermatoses can mimic cutaneous T-cell lymphoma, such as atopic dermatitis and psoriasis; alopecia can be related to syphilis; hidradenitis suppurativa, to infectious processes such as tuberculosis, actinomycosis, paracoccidioidomycosis, and metastatic Crohn's disease. The inadvertent use of JAKi in these conditions can trigger severe outcomes.

Other contraindications for JAKi include (i) Hypersensitivity to medication components (e.g., Tween 80); (ii) Tuberculosis; (iii) Altered kidney function (baricitinib); (iv) Severe liver function alteration (upadacitinib and abrocitinib); (v) Neutropenia < 500 cells/mm3 (baricitinib) or < 1,000 cells/mm3 (upadacitinib and abrocitinib); (vi) Anemia (hemoglobin ≤ 9 g/dL); (vii) Active infectious processes; (viii) Pregnant women, women wishing to become pregnant or with an active sex life and not using a contraceptive method; (ix) Thrombocytopenia < 50,000 mm3 (abrocitinib).6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...

The prescription should also be reconsidered if the patient shows to be unable to undergo infectious screening testing before starting treatment or regular follow-up during treatment.

Assessment of patients before and during JAKi use

Anamnesis and general clinical examination, in addition to the dermatological examination, must be performed due to potential complications with viral, bacterial and fungal infectious diseases, in addition to neoplasms.

It is necessary to evaluate the patients history of weight loss of unknown cause, professional or family contacts with infectious diseases (tuberculosis, Chagas disease, leprosy), failure to carry out periodic cancer prevention testing indicated for the patients age group, and family history of cancer or inborn errors of immunity (immunodeficiencies).6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...

Palpation of lymph node chains, liver, spleen, pulmonary and cardiac auscultation, Giordano's sign assessment are essential in each consultation. Other data to be verified before treatment are shown in Table 5.

Table 5
Clinical and laboratory considerations on the use of JAK-STAT pathway inhibitors

Patients using systemic JAKi should undergo blood tests (hemogram, lipidogram, liver and kidney function), and chest X-ray, before treatment and periodically during treatment, every two months, repeating them when indicated.

Event management during treatment with JAKi

Treatment with JAKi may promote an increase in serum lipids, with an increase in total cholesterol, LDL, HDL, and triglycerides.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...
Cholesterol and triglyceride levels should be monitored during treatment so that, when necessary, oral antilipidemic drugs should be used according to clinical protocols.6363 Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune AN, Bertolami A, Pereira AC, Lottenberg AM, Sposito AC, et al. Atualização da diretriz brasileira de dislipidemias e prevenção da aterosclerose - 2017. Arq Bras Cardiol. 2017;109:1-76. doi: 10.5935/abc.20170121.
https://doi.org/10.5935/abc.20170121...

CPK elevation during treatment with JAKi is common; however, it is usually unrelated to myopathy, which requires attention to laboratory follow-up results.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...
It is postulated that increase in CPK levels during the use of upadacitinib occurs due to JAKi1 inhibiting the physiological action of Oncostatin M (OSM), which blocks the differentiation of myoblasts into myocytes, where more CPK is produced. Once this inhibitory pathway is lost, more myoblasts differentiate into myocytes and CPK synthesis increases, without rhabdomyolysis, through cell differentiation only. It is even believed that high OSM levels determine sarcopenia in RA patients. Suspicion of rhabdomyolysis due to JAKi should include myalgia, cramps, and darkening of the urine, constituting a clinical urgency.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...

Patients receiving JAKi should be monitored for elevated transaminases and advised to seek medical attention if they experience systemic symptoms: digestive symptoms such nausea/vomiting/anorexia and rash/pruritus/jaundice.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...

The risk of cytopenias is greatest among patients aged > 65 years of age. JAKi should be discontinued in cases of neutropenia (< 1,000 neutrophils/mm3), lymphopenia (< 500 lymphocytes/mm3), anemia (hemoglobin < 8 g/dL), or thrombocytopenia (< 50,000 mm3).6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...
Neutropenia and lymphopenia increase the risk of infection and the patient should be advised to seek medical attention in case of fever, chills, sore throat or cough. If symptoms of fatigue, malaise, palpitations, dizziness or dyspnea, abdominal pain of sudden onset, nausea, vomiting, or anorexia occur, the patient must also seek medical attention due to the risk of intestinal perforation. In patients with diverticular disease of the colon, gastrointestinal perforation may follow diverticulitis; these patients should be instructed and carefully followed.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...

Symptoms such as dry cough, dyspnea on exertion, and fever should alert the patient to seek medical attention, at risk of interstitial lung disease. In this case, blood tests should be ordered: CRP, LDH, KL-6 (Krebs von den Lungen-6), and SP-D (surfactant protein D), with the serum levels of the latter two being very sensitive in the diagnosis of drug-hypersensitivity pneumonitis.6464 Okamoto T, Fujii M, Furusawa H, Tsuchiya K, Miyazaki Y, Inase N. The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respir Med. 2015;109:1576-1581. doi: 10.1016/j.rmed.2015.10.005.
https://doi.org/10.1016/j.rmed.2015.10.0...
Additionally, chest radiography or computed tomography and blood gas analysis should be ordered, and JAKi should be discontinued until the diagnosis is achieved.

Pneumonia due to P. jirovecii can occur and the measurement of β-D glucan levels can help to establish the diagnosis. Moreover, influenza, COVID-19, Mycoplasma, Chlamydia and Legionella infections should be ruled out in patients with radiological images of an interstitial parenchymal pattern, which may constitute atypical non-pneumocystis pneumonia, and when infectious causes have been excluded, pneumonia of drug-induced rheumatic pulmonary disease should be considered. X-rays images showing exudate in the lung may indicate bacterial pneumonia or tuberculosis.6262 Saeki H, Akiyama M, Abe M, Igarashi A, Imafuku S, Ohya Y, Katoh N, Kameda H, Kabashima K, Tsunemi Y, et al. English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis. J Dermatol. 2022. doi: 10.1111/1346-8138.16635.
https://doi.org/10.1111/1346-8138.16635...

JAKi in inflammatory and autoimmune dermatoses

Most inflammatory or autoimmune dermatoses do not result from the effect of only one cytokine; however, they follow inflammatory profiles that can be inhibited by modulating the JAK-STAT pathway. The immunological basis and clinical results of the main JAKi in dermatology are shown below. Table 6 shows JAKi with dermatological indications described in the literature, and Fig. 2 summarizes the main drugs with clinical trials for use in dermatology.

Figure 2
Diagram representing the main JAKi that show favorable results in clinical studies for inflammatory and autoimmune dermatoses. AA, Alopecia areata; AD, Atopic dermatitis; DM, Dermatomyositis; PSO, Psoriasis; VITI, Vitiligo; HS, Hidradenitis suppurativa; GVHD, Graft-versus-host disease; Abro, Abrocitinib; Upa, Upadacitinib; Bari, Baricitinib; TDelgo, Topical Delgocitinib; Tofa, Tofacitinib; TRuxo, Topical Ruxolitinib; Ruxo, Ruxolitinib; Ritle, Ritlecitinib; Deucra, Deucravacitinib; Solci, Solcitinib; Itaci, Itacitinib; Deuruxo, Deuruxolitinib

Table 6
Dermatological indications for JAK-STAT pathway inhibitors as reported in the literature

Atopic dermatitis (AD)

AD has a high prevalence, especially in children and young adults. Its chronic and recurrent course, associated with allergic and psychological comorbidities, has an important impact on quality of life.6565 Weil C, Sugerman PB, Chodick G, Liang H, Wang H, Calimlim BM, Dorfman A, Shalev V, Ben Amitai D, Leshem YA. Epidemiology and Economic Burden of Atopic Dermatitis: Real-World Retrospective Data from a Large Nationwide Israeli Healthcare Provider Database. Adv Ther. 2022;39:2502-2514. doi: 10.1007/s12325-022-02120-6.
https://doi.org/10.1007/s12325-022-02120...
Its pathogenesis is complex and depends on the interaction of several elements. Skin barrier failure occurs in about 80% of the patients, especially due to the filaggrin gene loss-of-function mutations. Transepidermal water loss, changes in the skin microbiome, together with antigen permeability and neural hyperreactivity favor local inflammatory response exacerbation, manifesting mainly as eczema and pruritus.6666 David Boothe W, Tarbox JA, Tarbox MB. Atopic Dermatitis: Pathophysiology. Adv Exp Med Biol. 2017;1027:21-37. doi: 10.1007/978-3-319-64804-0_3.
https://doi.org/10.1007/978-3-319-64804-...
,6767 Huang IH, Chung WH, Wu PC, Chen CB. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front Immunol. 2022;13:1068260. doi: 10.3389/fimmu.2022.1068260.
https://doi.org/10.3389/fimmu.2022.10682...

Despite being considered an inflammatory disease with a predominance of the Th2 pattern, several cytokines act together to create and maintain an environment of cutaneous hyperreactivity, which also changes in different disease stages.33 Chapman S, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part II. A comprehensive review. J Am Acad Dermatol. 2022;86:414-422. doi: 10.1016/j.jaad.2021.06.873.
https://doi.org/10.1016/j.jaad.2021.06.8...
The involvement, especially of IL-4, IL-5, IL-10, IL-13, IL-31, IFNγ, IL-17, IL-22, and IL-33, in the cutaneous microenvironment, are indications of the potential of JAKi, (mainly JAK1) in their treatment.6767 Huang IH, Chung WH, Wu PC, Chen CB. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front Immunol. 2022;13:1068260. doi: 10.3389/fimmu.2022.1068260.
https://doi.org/10.3389/fimmu.2022.10682...
,6868 Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139:S65-S76. doi: 10.1016/j.jaci.2017.01.011.
https://doi.org/10.1016/j.jaci.2017.01.0...

Experimental models have shown that AD treatment with JAKi led to rapid pruritus suppression, skin barrier and cutaneous nerve fiber improvement, and reduction of lymphocytic infiltrate and inflammatory cytokines (e.g., IL-4 and IL-13).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-...

In Brazil, baricitinib, abrocitinib and upadacitinib are approved for oral use in moderate to severe AD; ruxolitinib 1.5% cream is available in the US market, and delgocitinib 0.5% cream should be approved in 2023. Despite being effective in the treatment of AD, no clinical trials have been developed with oral tofacitinib, and most studies are case reports and series.6767 Huang IH, Chung WH, Wu PC, Chen CB. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front Immunol. 2022;13:1068260. doi: 10.3389/fimmu.2022.1068260.
https://doi.org/10.3389/fimmu.2022.10682...
Table 7 summarizes pivotal clinical trial results of the main JAKi in AD.

Table 7
Results of main clinical studies on JAK-STAT pathway inhibitors used in the treatment of atopic dermatitis

In clinical studies, all systemic JAKi outperformed placebos, with rapid control of pruritus, improved quality of life and sleep, and reduced eczematous area. Higher dosages and the association of JAKi with topical corticosteroids promoted better treatment performance, albeit with a higher rate of adverse effects.

When comparing individual studies, oral abrocitinib and upadacitinib showed a greater proportion of clinical score reduction than baricitinib.4040 Wan H, Jia H, Xia T, Zhang D. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther. 2022;35:e15636. doi: 10.1111/dth.15636.
https://doi.org/10.1111/dth.15636...
,7676 ilverberg JI, Thyssen JP, Fahrbach K, Mickle K, Cappelleri JC, Romero W, Cameron MC, Myers DE, Clibborn C, DiBonaventura M. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis. J Eur Acad Dermatol Venereol. 2021;35:1797-1810. doi: 10.1111/jdv.17351.
https://doi.org/10.1111/jdv.17351...
Despite differences between the studies regarding patient age groups and ethnicities, duration, and different rescue strategies, ≥ 60% of those taking upadacitinib at a dosage of 15 mg/d and ≥ 70% at a dosage of 30 mg/d are expected to achieve a ≥ 75% reduction in the Eczema Area Severity Index (EASI75).4040 Wan H, Jia H, Xia T, Zhang D. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther. 2022;35:e15636. doi: 10.1111/dth.15636.
https://doi.org/10.1111/dth.15636...
,4343 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...
As for abrocitinib at doses of 100 mg/d and 200 mg/d, these values are ≥ 40% and ≥ 60%. And, for baricitinib 2 mg/d and 4 mg/d, these are ≥ 18% and ≥ 21%.4040 Wan H, Jia H, Xia T, Zhang D. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther. 2022;35:e15636. doi: 10.1111/dth.15636.
https://doi.org/10.1111/dth.15636...

The 52-week extension of the AD UP study included 901 patients aged 12 to 75 years with moderate or severe AD, randomized into three groups: upadacitinib 15 mg/d, 30 mg/d and placebo (first 16 weeks), all associated with low-potency topical corticosteroid or calcineurin inhibitor 2×/d. At week 52, the proportion of patients achieving EASI75 was 50.8% for the upadacitinib 15 mg/d group and 69.0% for the 30 mg/d group, while7.4% of patients in the upadacitinib 15 mg/d group and 2.5% of the 30 mg/d group abandoned the study due to lack of efficacy.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...

Also, in the BREEZE-AD3 study, which followed for 52 weeks 292 patients from the BREEZE-AD7 study (16 weeks), using baricitinib 2 or 4 mg/d and topical corticosteroids, a slight loss of efficacy was observed: EASI75 from 51% at week 16 to 43% at week 68. Up to 17.8% of patients treated with baricitinib 2 mg/d and 28.4% of those treated with baricitinib 4 mg/d dropped out of the follow-up due to lack of efficacy.7777 Silverberg JI, Simpson EL, Thyssen JP, Werfel T, Cardillo T, Colvin S, Pierce E, Chen Y, Chen S, Eichenfield L. Long-Term Efficacy (up to 68 Weeks) of Baricitinib in Combination with Topical Corticosteroids in Adult Patients with Moderate-to-Severe Atopic Dermatitis: Analysis of Treatment Responders, Partial Responders and Nonresponders Originating from Study BREEZE-AD7. J Eur Acad Dermatol Venereol. 2022:(ahead of print). doi: 10.1111/jdv.18816.
https://doi.org/10.1111/jdv.18816...

In a real-life study that included 44 adult patients with AD treated with baricitinib, the efficacy and safety drug profile was confirmed; however, the longitudinal follow-up revealed that the percentage of patients who reached EASI75 was 53% at week four, and 33% at week 16, while 7% of the patients abandoned treatment due to insufficient efficacy.7878 Vittrup I, Elberling J, Skov L, Ibler KS, Jemec GBE, Mortz CG, Bach RO, Bindslev-Jensen C, Dalager MG, Egeberg A, et al. Short-term real-world experience with baricitinib treatment in Danish adults with moderate-severe atopic dermatitis. J Eur Acad Dermatol Venereol. 2022. doi: 10.1111/jdv.18804.
https://doi.org/10.1111/jdv.18804...
These data indicate the possibility of a slight loss of treatment efficacy from the fourth week onward.

There are still no randomized trials comparing oral JAKi with other immunosuppressants (e.g., cyclosporine, azathioprine, and methotrexate) in AD. There is also no data available regarding the association of topical and systemic JAKi, or variable dosage regimens, such as the use of high dosages in the first weeks, with subsequent dosages reduction or change in strategy to minimize costs and adverse effects.

The Heads Up study compared 692 adults with AD randomized to use oral upadacitinib 30 mg/d vs. Dupilumab 300 mg every 14 days for 24 weeks. At week 16, EASI75 was achieved by 71% of the patients using upadacitinib and 61% of those using dupilumab. The other clinical outcomes followed the superiority of upadacitinib, with emphasis on the greater and earlier reduction in pruritus. At week 24, EASI75 decreased to 64% in the upadacitinib group, while the dupilumab group resulted in 59%. Both groups required rescue treatments before week 16: upadacitinib in 20.3% and dupilumab in 17.5%.7979 Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, De Bruin-Weller M, Barbarot S, Prajapati VH, Lio P, Hu X, Wu T, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2021;157:1047-1055. doi: 10.1001/jamadermatol.2021.3023.
https://doi.org/10.1001/jamadermatol.202...

At these dosages, after 24 weeks, the Heads up study showed, in the upadacitinib group, a higher frequency of acne (18.4% vs. 3.2%), HSV (0.9% vs. 0.0%) and HZ (3.4% vs. 1.2%), whereas conjunctivitis was more frequent in the dupilumab group (10.2% vs. 1.4%). One participant from the upadacitinib group died due to bronchopneumonia associated with influenza virus infection. There was a higher frequency of laboratory alterations in the upadacitinib group. Transaminase elevation occurred in 3.4% vs. 1.1%, and two participants from the upadacitinib group abandoned the study for this reason. Anemia (2.0% vs. 0.3%), neutropenia (1.7% vs. 0.6%), and CPK elevation (7.5% vs. 3.2%) were also prevalent in the upadacitinib group.7979 Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, De Bruin-Weller M, Barbarot S, Prajapati VH, Lio P, Hu X, Wu T, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2021;157:1047-1055. doi: 10.1001/jamadermatol.2021.3023.
https://doi.org/10.1001/jamadermatol.202...
The long-term safety profile of dupilumab allows recommending its administration without the need for laboratory follow-up or risk of drug interactions.6767 Huang IH, Chung WH, Wu PC, Chen CB. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front Immunol. 2022;13:1068260. doi: 10.3389/fimmu.2022.1068260.
https://doi.org/10.3389/fimmu.2022.10682...
,7676 ilverberg JI, Thyssen JP, Fahrbach K, Mickle K, Cappelleri JC, Romero W, Cameron MC, Myers DE, Clibborn C, DiBonaventura M. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis. J Eur Acad Dermatol Venereol. 2021;35:1797-1810. doi: 10.1111/jdv.17351.
https://doi.org/10.1111/jdv.17351...

The JADE DARE study compared abrocitinib 200 mg/d vs. dupilumab 300 mg every 14 days in 726 patients with moderate to severe AD for 26 weeks. At the end of the study, 73% of the patients in the abrocitinib group vs. 72% in the dupilumab group achieved EASI75. Conjunctivitis was more prevalent in the dupilumab group (11% vs. 3%), but the following were more frequent in the abrocitinib group: acne (13% vs. 3%), nausea (19% vs. 2%), HSV (6% vs. .5%), HZ (3% vs. 0%) and headache (13% vs. 7%).8080 Reich K, Thyssen JP, Blauvelt A, Eyerich K, Soong W, Rice ZP, Hong HC, Katoh N, Valenzuela F, DiBonaventura M, et al. Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial. Lancet. 2022;400:273-282. doi: 10.1016/S0140-6736(22)01199-0.
https://doi.org/10.1016/S0140-6736(22)01...

Topical JAKi (ruxolitinib and delgocitinib) confirmed the rapid effect onset (< 24 h for pruritus reduction), with a high rate of efficacy, safety and tolerability. So far, topical JAKi is indicated in cases with less than 20% of the affected body area, and non-prolonged use.1818 Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, Forman SB, Venturanza ME, Sun K, Kuligowski ME, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85:863-872. doi: 10.1016/j.jaad.2021.04.085.
https://doi.org/10.1016/j.jaad.2021.04.0...
,7575 Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kabashima K, Oda M, Nagata T. Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study. J Am Acad Dermatol. 2021;85:854-862. doi: 10.1016/j.jaad.2021.06.014
https://doi.org/10.1016/j.jaad.2021.06.0...
,8181 Nakagawa H, Nemoto O, Igarashi A, Saeki H, Oda M, Kabashima K, Nagata T. Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis. J Allergy Clin Immunol. 2019;144:1575-1583. doi: 10.1016/j.jaci.2019.08.004.
https://doi.org/10.1016/j.jaci.2019.08.0...
The effectiveness of topical JAKi increases with active concentration and the number of daily applications. Moreover, the good tolerability and safety profile may prove to be appropriate in the rescue of young patients with moderate to severe AD, who often depend on topical corticosteroids for this purpose. The extended use of 1.5% ruxolitinib cream for up to 44 weeks, with 1249 adults instructed to use it on lesions if necessary, resulted in a good tolerability and safety profile, with no evidence of systemic effects. Between 74% and 78% of the patients reached the end of the study with IGA 0/1.8282 Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Forman SB, Kuligowski ME, Kallender H, Sun K, Ren H, et al. Long-Term Safety and Disease Control With Ruxolitinib Cream in Atopic Dermatitis: Results From Two Phase 3 Studies. J Am Acad Dermatol. 2022:(ahead to print). doi: 10.1016/j.jaad.2022.09.060.
https://doi.org/10.1016/j.jaad.2022.09.0...

When comparing the performances of topical JAKi in individual clinical studies, tofacitinib 2%, delgocitinib 3%, and ruxolitinib 1.5% showed greater reduction in AD scores than expected for PDE4 inhibitors (e.g., crisaborole).7878 Vittrup I, Elberling J, Skov L, Ibler KS, Jemec GBE, Mortz CG, Bach RO, Bindslev-Jensen C, Dalager MG, Egeberg A, et al. Short-term real-world experience with baricitinib treatment in Danish adults with moderate-severe atopic dermatitis. J Eur Acad Dermatol Venereol. 2022. doi: 10.1111/jdv.18804.
https://doi.org/10.1111/jdv.18804...
,8383 Zhang L, Du D, Wang L, Guo L, Jiang X. Efficacy and safety of topical Janus kinase and phosphodiesterase inhibitor-4 inhibitors for the treatment of atopic dermatitis: A network meta-analysis. J Dermatol. 2021;48:1877-18doi: 10.1111/1346-8138.16126.
https://doi.org/10.1111/1346-8138.16126...

In a double-blind comparison involving 51 AD patients using 0.15% triamcinolone cream 2×/d under different ruxolitinib cream concentrations and regimens for eight weeks, both triamcinolone and different dosages of ruxolitinib showed superiority over the vehicle and increase in the effect as a function of time. EASI75 occurred in 56% of patients in the group using 1.5% ruxolitinib 2×/d vs. 47% of those using triamcinolone.8484 Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME, Investigators IS. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol. 2020;145:572-582. doi: 10.1016/j.jaci.2019.08.042.
https://doi.org/10.1016/j.jaci.2019.08.0...

In general, JAKi has not yet been approved for children under 12 years, exactly the population most often afflicted by AD; however, safety studies have advanced to expand the age range of its use.

Finally, oral or topical JAKi showed to be valuable therapeutic options for AD, with a good safety profile, but their indication in AD needs to be well-defined compared to other immunosuppressants, immunobiological, and phototherapy.

Psoriasis

The pathogenesis of psoriasis involves both the innate and adaptive immune systems, based on a complex interaction between keratinocytes, dendritic cells, T-lymphocytes, cytokines, and other inflammatory mediators. The chronic inflammation characteristic of the disease is mainly promoted by IL-23, which induces the differentiation of naïve T-cells into Th17 lymphocytes and their clonal expansion.8585 Kanda N. Psoriasis: Pathogenesis, Comorbidities, and Therapy Updated. Int J Mol Sci. 2021;22. doi: 10.3390/ijms22062979.
https://doi.org/10.3390/ijms22062979...
,8686 Papadopoullos M, Yesudian PD. Understanding psoriasis: the development of the immune pathogenesis. Clin Exp Dermatol. 2022;47:2072-2073. doi: 10.1111/ced.15360.
https://doi.org/10.1111/ced.15360...

IL-23 signal transduction is mediated by TYK2. Activated Th17 cells release proinflammatory cytokines such as TNFα, IL-22, IL-26, and IL-29, which induce keratinocyte proliferation. In psoriasis, there are also increased serum levels of Th1 cytokines (IFNγ and IL-2), as well as decreased levels of IL-10. IL-22, produced by Th22 cells, is a cytokine-mediated by the JAK-STAT pathway and induces keratinocyte proliferation. The release of IL-22, in association with IL-15, is signaled by JAK1 and JAK3; therefore, JAK/TYK inhibition is a potential target for its treatment. However, given the pathogenesis of the disease, second-generation JAKi, selective for JAK2/TYK2, would potentially be more effective than those blocking multiple JAK/TYK isoforms.11 Chapman S, Kwa M, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part I. A comprehensive review. J Am Acad Dermatol. 2022;86:406-413. doi: 10.1016/j.jaad.2021.07.002.
https://doi.org/10.1016/j.jaad.2021.07.0...
,8787 Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, Langley R, Luger T, Thaci D, Buonanno M, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015;173:949-961. doi: 10.1111/bjd.14018.
https://doi.org/10.1111/bjd.14018...
Incidentally, individuals with genetic polymorphism and consequential loss of TYK2 function are at lower risk of developing psoriasis and other immune-mediated diseases.8888 Sohn SJ, Barrett K, Van Abbema A, Chang C, Kohli PB, Kanda H, Smith J, Lai Y, Zhou A, Zhang B, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol. 2013;191:2205-2216. doi: 10.4049/jimmunol.1202859.
https://doi.org/10.4049/jimmunol.1202859...

In general, tofacitinib (2, 5, 10 and 15 mg, 2×/d), solcitinib (200 and 400 mg, 2×/d), baricitinib (8 and 10 mg, 2×/d), and deucravacitinib (3 mg and 6 mg 2×/d) showed a PASI75 response superior to that of placebo at both week 8 and week 12 in RCTs on moderate to severe plaque psoriasis.8989 Zhang L, Guo L, Wang L, Jiang X. The efficacy and safety of tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib in plaque psoriasis - A network meta-analysis. J Eur Acad Dermatol Venereol. 2022;36:1937-1946. doi: 10.1111/jdv.18263.
https://doi.org/10.1111/jdv.18263...
,9090 Papp KA, Menter A, Strober B, Langley RG, Buonanno M, Wolk R, Gupta P, Krishnaswami S, Tan H, Harness JA. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167:668-677. doi: 10.1111/j.1365-2133.2012.11168.x.
https://doi.org/10.1111/j.1365-2133.2012...

A meta-analysis concluded that tofacitinib (15 and 10 mg, 2×/d) and deucravacitinib (6 mg, 2×/d and 12 mg/d) had the best Physician Global Assessment (PGA) and PASI75 responses (at weeks 8 and 12) among JAKi used in the treatment of plaque psoriasis. Although the same meta-analysis showed a satisfactory safety profile of JAKi in the treatment of plaque psoriasis, tofacitinib was not approved by the FDA due to its side effects; the drug is only approved at a dosage of 5 mg 2×/d, for RA therapy. The JAKi under study for the treatment of plaque psoriasis are deucravacitinib, brepocitinib, and ropsacitinib, all TKY2 inhibitors.8989 Zhang L, Guo L, Wang L, Jiang X. The efficacy and safety of tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib in plaque psoriasis - A network meta-analysis. J Eur Acad Dermatol Venereol. 2022;36:1937-1946. doi: 10.1111/jdv.18263.
https://doi.org/10.1111/jdv.18263...

In Brazil, tofacitinib 5 mg 2x daily is approved for the treatment of psoriatic arthritis in adults. However, it may be effective in treating ungueal psoriasis; 33% of patients achieved NAPSI50 at week 16 on tofacitinib 5 mg 2x/d, 44% on 10 mg 2x/d, and 12% on placebo.9191 Merola JF, Elewski B, Tatulych S, Lan S, Tallman A, Kaur M. Efficacy of tofacitinib for the treatment of nail psoriasis: Two 52-week, randomized, controlled phase 3 studies in patients with moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2017;77:79-87 e71. doi: 10.1016/j.jaad.2017.01.053.
https://doi.org/10.1016/j.jaad.2017.01.0...

Currently, the only topical JAKi under study for the treatment of psoriasis is brepocitinib, an orthosteric JAK1 and JAK2 inhibitor. A phase I trial, involving healthy subjects and patients with moderate to severe plaque psoriasis, confirmed its safety and good tolerability.9292 Banfield C, Scaramozza M, Zhang W, Kieras E, Page KM, Fensome A, Vincent M, Dowty ME, Goteti K, Winkle PJ, et al. The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a TYK2/JAK1 Inhibitor (PF-06700841) in Healthy Subjects and Patients With Plaque Psoriasis. J Clin Pharmacol. 2018;58:434-447. doi: 10.1002/jcph.1046.
https://doi.org/10.1002/jcph.1046...

Compared to apremilast, the only other oral drug approved for psoriasis therapy, JAK2/TYK2 inhibitors are more immunologically selective, restricting the possibility of side effects. Deucravacitinib has been approved by the FDA and by the Japanese agency for the treatment of moderate to severe plaque psoriasis in adults.9393 Martin G. Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors. Dermatol Ther (Heidelb). 2023. doi: 10.1007/s13555-022-00878-9.
https://doi.org/10.1007/s13555-022-00878...
A randomized study of 332 patients using 6 mg/d revealed a PASI75 response at week 16 superior to oral apremilast 30 mg 2x daily and placebo (58%; 35% and 13%). The rate of side effects was similar in the three groups. However, combining deucravacitinib with other immunosuppressants is not recommended.9494 Armstrong AW, Gooderham M, Warren RB, Papp KA, Strober B, Thaci D, Morita A, Szepietowski JC, Imafuku S, Colston E, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J Am Acad Dermatol. 2023;88:29-39. doi: 10.1016/j.jaad.2022.07.002.
https://doi.org/10.1016/j.jaad.2022.07.0...

Alopecia areata (AA)

AA has an autoimmune pathogenesis involving the breakdown of the immune privilege in the hair follicle. In areas of AA, an inflammatory infiltrate consisting of CD4+, CD8+, and NK lymphocytes is observed around the bulb of anagen-phase follicles, leading to disruption of melanogenesis and shaft production,9595 Gilhar A, Etzioni A, Paus R. Alopecia areata. N Engl J Med. 2012;366:1515-1525. doi: 10.1056/NEJMra1103442.
https://doi.org/10.1056/NEJMra1103442...
with the presence of TCD8+NKG2D + lymphocytes being determinant for the development of alopecia lesions.9696 Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20:1043-1049. doi: 10.1038/nm.3645.
https://doi.org/10.1038/nm.3645...

IFNγ and IL-15 mainly induce type I cytotoxic response. CD8 + T-lymphocytes produce IFNγ, contributing to the immune privilege breakdown, inducing the production of IL-15 by epithelial cells, which in turn leads to the activation of CD8+NKGD2+ effector cells with more IFNγ production, closing the cycle that perpetuates the disease. Both the action of IFNγ on the epithelial cell and IL-15 on CD8+NKG2D + cells are mediated by the JAK-STAT pathway.9696 Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20:1043-1049. doi: 10.1038/nm.3645.
https://doi.org/10.1038/nm.3645...

Based on the report of AA regrowth with tofacitinib used in the treatment of psoriasis,9797 Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134:2988-2990. doi: 10.1038/jid.2014.260.
https://doi.org/10.1038/jid.2014.260...
multiple case series and non-comparative open-label studies have been published, showing favorable results with the use of systemic JAKi for the treatment of severe AA. The most commonly used drug was tofacitinib, followed by ruxolitinib and baricitinib.9898 Ismail FF, Sinclair R. JAK inhibition in the treatment of alopecia areata - a promising new dawn? Expert Rev Clin Pharmacol. 2020;13:43-51. doi: 10.1080/17512433.2020.1702878.
https://doi.org/10.1080/17512433.2020.17...
,9999 Gupta AK, Wang T, Polla Ravi S, Bamimore MA, Piguet V, Tosti A. Systematic review of newer agents for the management of alopecia areata in adults: Janus kinase inhibitors, biologics and phosphodiesterase-4 inhibitors. J Eur Acad Dermatol Venereol. 2022:(ahead to print). doi: 10.1111/jdv.18810.
https://doi.org/10.1111/jdv.18810...

In a comparative open study, 75 patients with AA affecting more than 30% of the scalp were randomized into two groups: tofacitinib 10 mg/d and ruxolitinib 40 mg/d. After six months of treatment, both groups showed improvement, with no difference between them. The SALT50 score was achieved by 84% of the patients in the ruxolitinib group and 78% in the tofacitinib group at six months.100100 Almutairi N, Nour TM, Hussain NH. Janus Kinase Inhibitors for the Treatment of Severe Alopecia Areata: An Open-Label Comparative Study. Dermatology. 2019;235:130-136. doi: 10.1159/000494613.
https://doi.org/10.1159/000494613...

In two double-blind trials (BRAVE-AA1, BRAVE-AA2) patients with severe AA were randomized into three groups: baricitinib 2 mg/d, 4 mg/d or placebo. A total of 1,200 patients were enrolled for the phase III analysis of these studies at week 36. The SALT20 score was achieved by 20% and 34% in the baricitinib 2 mg/d and 4 mg/d groups, compared to 4% on placebo.101101 King B, Ohyama M, Kwon O, Zlotogorski A, Ko J, Mesinkovska NA, Hordinsky M, Dutronc Y, Wu WS, McCollam J, et al. Two Phase 3 Trials of Baricitinib for Alopecia Areata. N Engl J Med. 2022;386:1687-1699. doi: 10.1056/NEJMoa2110343.
https://doi.org/10.1056/NEJMoa2110343...
The percentage of patients who discontinued treatment due to adverse effects was similar between the groups. In 2022, baricitinib received FDA approval for the treatment of AA.

In the ALLEGRO study, 718 patients were randomized into six groups: ritlecitinib 200 mg/d for four weeks and then 50 mg/d for 20 weeks; ritlecitinib 200 mg/d for four weeks and then 30 mg/d for 20 weeks; ritlecitinib 50 mg/d for 24 weeks; ritlecitinib 10 mg/d for 24 weeks, or placebo. The response to ritlecitinib was dosage-dependent, and 31% of those using 50 mg/d post-loading dosage achieved SALT20 by week 24.102102 King B, Guttman-Yassky E, Peeva E, Banerjee A, Zhu L, Zhu H, Cox LA, Vincent MS, Sinclair R. Safety and Efficacy of Ritlecitinib and Brepocitinib in Alopecia Areata: Results from the Crossover Open-Label Extension of the ALLEGRO Phase 2a Trial. JID Innov. 2022;2:100156. doi: 10.1016/j.xjidi.2022.100156.
https://doi.org/10.1016/j.xjidi.2022.100...

In a phase II trial, 149 patients were divided into four groups: deuruxolitinib 12, 8, 4 mg/d and placebo. There was a dosage-dependent response: 42%%, 26%, 14%, and 7% (placebo) of patients achieved SALT20 at week 24.103103 King B, Mesinkovska N, Mirmirani P, Bruce S, Kempers S, Guttman-Yassky E, Roberts JL, McMichael A, Colavincenzo M, Hamilton C, et al. Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata. J Am Acad Dermatol. 2022;87:306-313. doi: 10.1016/j.jaad.2022.03.045.
https://doi.org/10.1016/j.jaad.2022.03.0...

A double-blind trial recruited 16 participants with universal AA who were instructed to apply 2% tofacitinib ointment, 1% ruxolitinib ointment, 0.05% clobetasol ointment, and placebo at different sites on the scalp. Six patients (38%) on tofacitinib, five (31%) on ruxolitinib, and ten (63%) on clobetasol had partial regrowth in the treatment areas, whereas none showed regrowth on placebo.104104 Bokhari L, Sinclair R. Treatment of alopecia universalis with topical Janus kinase inhibitors - a double blind, placebo, and active controlled pilot study. Int J Dermatol. 2018;57:1464-1470. doi: 10.1111/ijd.14192.
https://doi.org/10.1111/ijd.14192...

In an open-label study, 1.5% ruxolitinib cream was not shown to be effective when compared to placebo,105105 Olsen EA, Kornacki D, Sun K, Hordinsky MK. Ruxolitinib cream for the treatment of patients with alopecia areata: A 2-part, double-blind, randomized, vehicle-controlled phase 2 study. J Am Acad Dermatol. 2020;82:412-419. doi: 10.1016/j.jaad.2019.10.016.
https://doi.org/10.1016/j.jaad.2019.10.0...
whereas 3% delgocitinib ointment also showed no SALT improvement after 12 weeks of treatment.106106 Mikhaylov D, Glickman JW, Del Duca E, Nia J, Hashim P, Singer GK, Posligua AL, Florek AG, Ibler E, Hagstrom EL, et al. A phase 2a randomized vehicle-controlled multi-center study of the safety and efficacy of delgocitinib in subjects with moderate-to-severe alopecia areata. Arch Dermatol Res. 2022. doi: 10.1007/s00403-022-02336-0.
https://doi.org/10.1007/s00403-022-02336...
The low efficacy of topical JAKi can be explained by the difficulty in penetrating the deep layers of the skin, which does not allow reaching the peribulbar inflammation. Vehicles that facilitate skin penetration can improve the possibilities for JAKi in AA.

Treatment of severe AA is challenging, as many patients do not respond to conventional therapy with systemic immunosuppressants or are limited by adverse effects. Severe cases have high rates of recurrence after treatment discontinuation. In a consensus organized by the Brazilian Society of Dermatology (SBD, Sociedade Brasileira de Dermatologia; 2020), the use of systemic JAKi is recommended as an option for extensive AA in cases that are refractory to conventional therapy.107107 Ramos PM, Anzai A, Duque-Estrada B, Melo DF, Sternberg F, Santos LDN, Alves LD, Mulinari-Brenner F. Consensus on the treatment of alopecia areata - Brazilian Society of Dermatology. An Bras Dermatol. 2020;95 Suppl 1:39-52. doi: 10.1016/j.abd.2020.05.006.
https://doi.org/10.1016/j.abd.2020.05.00...
It is worth mentioning that, in the studies that allowed the approval of baricitinib by the FDA, less than 40% of the patients achieved SALT20. Additionally, patients with more than eight years of disease duration (worse prognosis) were not included. Studies comparing systemic JAKi with other immunosuppressants are essential to establish real benefits when comparing available therapies.

Maintenance of the results achieved in AA depends on treatment continuity in most cases. Longer follow-up studies are required to determine the long-term efficacy and safety of JAKi.

Vitiligo

Vitiligo affects genetically susceptible individuals, and autoimmunity is the main cause of melanocyte aggression. Hypo/achromias, whether localized or generalized, are the manifestations of melanocyte destruction driven by cytotoxic T-lymphocytes.108108 van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, Tigges B, Westerhof W, Das P. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site. Lab Invest. 2000;80:1299-1309. doi: 10.1038/labinvest.3780138.
https://doi.org/10.1038/labinvest.378013...

The two main cytokines involved in the pathogenesis of vitiligo are IFNγ and IL-15.109109 Marchioro HZ, Silva de Castro CC, Fava VM, Sakiyama PH, Dellatorre G, Miot HA. Update on the pathogenesis of vitiligo. An Bras Dermatol. 2022;97:478-490. doi: 10.1016/j.abd.2021.09.008.
https://doi.org/10.1016/j.abd.2021.09.00...
The first is produced by tissue-resident memory T cells (TRMs) present in depigmented skin and binds to the IFNγ receptor to stimulate the expression of chemokines such as CXCL9, CXCL10 and CXCL11, which promote the infiltration of autoreactive T-cells.110110 Tang Q, Sousa J, Echeverria D, Fan X, Hsueh YC, Afshari K, MeHugh N, Cooper DA, Vangjeli L, Monopoli K, et al. RNAi-based modulation of IFN-gamma signaling in skin. Mol Ther. 2022;30:2709-2721. doi: 10.1016/j.ymthe.2022.04.019.
https://doi.org/10.1016/j.ymthe.2022.04....
IL-15 is mainly produced by keratinocytes and is involved in signaling for the generation and maintenance of TRMs in damaged skin.111111 Blauvelt A, Asada H, Klaus-Kovtun V, Altman DJ, Lucey DR, Katz SI. Interleukin-15 mRNA is expressed by human keratinocytes Langerhans cells, and blood-derived dendritic cells and is downregulated by ultraviolet B radiation. J Invest Dermatol. 1996;106:1047-1052. doi: 10.1111/1523-1747.ep12338641.
https://doi.org/10.1111/1523-1747.ep1233...

Two JAKi are investigated for the treatment of vitiligo: 1.5% ruxolitinib cream has been approved for use in the US,112112 Rosmarin D, Passeron T, Pandya AG, Grimes P, Harris JE, Desai SR, Lebwohl M, Ruer-Mulard M, Seneschal J, Wolkerstorfer A, et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med. 2022;387:1445-1455. doi: 10.1056/NEJMoa2118828.
https://doi.org/10.1056/NEJMoa2118828...
and ritlecitinib 10‒50 mg/d orally is currently in a phase IIb trial.113113 Ezzedine K, Peeva E, Yamaguchi Y, Cox LA, Banerjee A, Han G, Hamzavi I, Ganesan AK, Picardo M, Thaci D, et al. Efficacy and Safety of Oral Ritlecitinib for the Treatment of Active Nonsegmental Vitiligo: A Randomized Phase 2b Clinical Trial. J Am Acad Dermatol. 2022. doi: 10.1016/j.jaad.2022.11.005.
https://doi.org/10.1016/j.jaad.2022.11.0...
There are anecdotal reports of the use of tofacitinib 5‒10 mg/d orally and topical 2% cream or ointment in vitiligo;114114 Komnitski M, Komnitski A, Komnitski Junior A, Silva de Castro CC. Partial repigmentation of vitiligo with tofacitinib, without exposure to ultraviolet radiation. An Bras Dermatol. 2020;95:473-476. doi: 10.1016/j.abd.2019.08.032.
https://doi.org/10.1016/j.abd.2019.08.03...
,115115 Berbert Ferreira S, Berbert Ferreira R, Neves Neto AC, Assef SMC, Scheinberg M. Topical Tofacitinib: A Janus Kinase Inhibitor for the Treatment of Vitiligo in an Adolescent Patient. Case Rep Dermatol. 2021;13:190-194. doi: 10.1159/000513938.
https://doi.org/10.1159/000513938...
however, no randomized, controlled clinical trials have been published on this drug.

The rationale for the use of JAKi in vitiligo originates from preclinical pharmacological studies that demonstrated the inhibition of the cytolytic action of CD8 + T lymphocytes and NK cells when enzymes of the kinase family (BTK, BMX, ITK, RLK and TEC) are inhibited by ritlecitinib, mainly ITK, in the case of cytotoxic T lymphocytes, and RLK and TEC in the case of NK cells. Ritlecitinib is highly selective for JAK3 and potentially inhibits IL-2 and IL-15; moreover, based on in vitro studies and cell assays, ritlecitinib may decrease the production of IFNγ released by cytotoxic T and NK cells, related to a probable ITK inhibition.116116 Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016;11:3442-3451. doi: 10.1021/acschembio.6b00677.
https://doi.org/10.1021/acschembio.6b006...
,117117 Xu H, Jesson MI, Seneviratne UI, Lin TH, Sharif MN, Xue L, Nguyen C, Everley RA, Trujillo JI, Johnson DS, et al. PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor. ACS Chem Biol. 2019;14:1235-1242. doi: 10.1021/acschembio.9b00188.
https://doi.org/10.1021/acschembio.9b001...

Ruxolitinib is a JAK1 and JAK2 inhibitor, whose 1.5% cream decreased the serum concentration of CXCL10, in addition to decreasing the pro-inflammatory action of chemokines and IL-15, in cell cultures of keratinocytes and melanocytes.118118 Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, Butler K, Kuo F, Sun K, Ji T, et al. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet. 2020;396:110-120. doi: 10.1016/S0140-6736(20)30609-7.
https://doi.org/10.1016/S0140-6736(20)30...
,119119 Martins C, Migayron L, Drullion C, Jacquemin C, Lucchese F, Rambert J, Merhi R, Michon P, Taieb A, Rezvani HR, et al. Vitiligo Skin T Cells Are Prone to Produce Type 1 and Type 2 Cytokines to Induce Melanocyte Dysfunction and Epidermal Inflammatory Response Through Jak Signaling. J Invest Dermatol. 2022;142:1194-1205 e1197. doi: 10.1016/j.jid.2021.09.015.
https://doi.org/10.1016/j.jid.2021.09.01...

Tofacitinib is a JAK1 and JAK3 inhibitor. In a study with a murine model of induced vitiligo, the serum level of CXCL10 was lower in the oral tofacitinib-treated group compared with the placebo group.120120 Hayashi M, Okamura K, Abe Y, Hozumi Y, Suzuki T. Janus kinase inhibitor tofacitinib does not facilitate the repigmentation in mouse model of rhododendrol-induced vitiligo. J Dermatol. 2019;46:548-550. doi: 10.1111/1346-8138.14879.
https://doi.org/10.1111/1346-8138.14879...
However, ritlecitinib has a greater JAK3 inhibitory effect when compared to tofacitinib.117117 Xu H, Jesson MI, Seneviratne UI, Lin TH, Sharif MN, Xue L, Nguyen C, Everley RA, Trujillo JI, Johnson DS, et al. PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor. ACS Chem Biol. 2019;14:1235-1242. doi: 10.1021/acschembio.9b00188.
https://doi.org/10.1021/acschembio.9b001...

Two randomized, double-blind, placebo-controlled studies with 1.5% ruxolitinib cream involved patients older than 12 years with non-segmental vitiligo and an affected area of up to 10% of the body surface area. The patients were randomized to use the drug or the vehicle (2:1), twice a day, applied on the face or body for 24 weeks, after which all of them used the active substance, totaling 52 weeks. The primary endpoints were an improvement from the baseline of at least 75% of the facial VASI (Vitiligo Area Score Index), or F-VASI75 response, (F-VASI score 0 to 3) at week 24.112112 Rosmarin D, Passeron T, Pandya AG, Grimes P, Harris JE, Desai SR, Lebwohl M, Ruer-Mulard M, Seneschal J, Wolkerstorfer A, et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med. 2022;387:1445-1455. doi: 10.1056/NEJMoa2118828.
https://doi.org/10.1056/NEJMoa2118828...

In total, 674 patients were included, 330 in a study called TRue-V1, and 344 in the one called TRue-V2. In the first study, the percentage of patients achieving F-VASI75 response at week 24 was 29.8% in the ruxolitinib group and 7.4% in the placebo group (relative risk, 4.0; 95% confidence interval [95%CI], 1.9 to 8.4); whereas in the second study, these numbers were 30.9% and 11.4%, respectively (relative risk, 2.7; 95% CI, 1.5 to 4.9). The most common adverse effects in each study were acne (6.3 and 6.6%); nasopharyngitis (5.4 and 6.1%) and pruritus at the application site (5.4 and 5.3%), respectively.

An important secondary outcome was the 50% decrease in T-VASI (total affected area) since the start of treatment (T-VASI50). Approximately 20% of patients achieved a T-VASI50 response and 50% of patients achieved F-VASI50. This disproportion is common in vitiligo tests due to the greater concentration of follicles on the face, from where melanoblasts migrate for repigmentation.121121 Pagnoni A, Kligman AM, el Gammal S, Stoudemayer T. Determination of density of follicles on various regions of the face by cyanoacrylate biopsy: correlation with sebum output. Br J Dermatol. 1994;131:862-865. doi: 10.1111/j.1365-2133.1994.tb08590.x.
https://doi.org/10.1111/j.1365-2133.1994...
,122122 Goldstein NB, Koster MI, Hoaglin LG, Spoelstra NS, Kechris KJ, Robinson SE, Robinson WA, Roop DR, Norris DA, Birlea SA. Narrow Band Ultraviolet B Treatment for Human Vitiligo Is Associated with Proliferation, Migration, and Differentiation of Melanocyte Precursors. J Invest Dermatol. 2015;135:2068-2076. doi: 10.1038/jid.2015.126.
https://doi.org/10.1038/jid.2015.126...

To date, there are no randomized controlled trials with oral ruxolitinib in the treatment of vitiligo, nor topical ruxolitinib compared to or associated with the active treatments of choice: phototherapy, calcineurin inhibitors, or topical corticosteroids.

Another randomized, placebo-controlled study used dosage-escalated, oral ritlecitinib for 24 weeks, with a 24-week extension period and 8 weeks of follow-up, in patients with non-segmental vitiligo between 18 and 65 years, affected body area between 4% and 50%, and more than 25% affected facial area.113113 Ezzedine K, Peeva E, Yamaguchi Y, Cox LA, Banerjee A, Han G, Hamzavi I, Ganesan AK, Picardo M, Thaci D, et al. Efficacy and Safety of Oral Ritlecitinib for the Treatment of Active Nonsegmental Vitiligo: A Randomized Phase 2b Clinical Trial. J Am Acad Dermatol. 2022. doi: 10.1016/j.jaad.2022.11.005.
https://doi.org/10.1016/j.jaad.2022.11.0...
The patients were randomized into five groups with ritlecitinib and one with a placebo. Two groups received a loading dosage of 100 or 200 mg/d for four weeks, followed by 50 mg/d maintenance dosage for 20 weeks. Three groups received 50, 30 or 10 mg/d for 24 weeks and one group received a placebo for 24 weeks. The patients were allocated to the extension period based on the response at week 16; non-responders (< 50% T-VASI), were allocated to an open group with brepocitinib, another open group with ritlecitinib + narrow-band UVB phototherapy (NB-UVB), or ritlecitinib 200 mg loading dosage +50 mg/d. The primary endpoint was the change from baseline in central F-VASI at week 24; the secondary endpoint was the proportion of patients with central F-VASI75 at week 24.

A total of 364 patients received treatment, and for comparison purposes with the topical ruxolitinib study, the secondary endpoint results were used. F-VASI75 at week 24 was achieved in 12.1%, 8.5%, 7.7%, 2.7%, 2.3%, and 0% in the ritlecitinib 200/50 mg, 100/50 mg, 50 mg, 30 mg, 10 mg, and in the placebo group, respectively. As for safety, 77% of the patients had some type of adverse effect, with the three most common being nasopharyngitis (15.9%), upper respiratory tract infections (11.5%), and headache (8.8%).

Despite the modest results at week 24, acceleration of repigmentation was observed after week 28. The delay in the repigmentation process is well-founded, which justifies phototherapy as an adjuvant treatment in accelerating repigmentation, at least with the anti-tyrosine kinase medications presented herein, as in the case of tofacitinib, ruxolitinib and even by the allocation of some of the non-responders with ritlecitinib to a ritlecitinib arm associated with NB-UVB.123123 Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol. 2017;77:675-682 e671. doi: 10.1016/j.jaad.2017.05.043.
https://doi.org/10.1016/j.jaad.2017.05.0...
,124124 Pandya AG, Harris JE, Lebwohl M, Hamzavi IH, Butler K, Kuo FI, Wei S, Rosmarin D. Addition of Narrow-Band UVB Phototherapy to Ruxolitinib Cream in Patients With Vitiligo. J Invest Dermatol. 2022;142:3352-3355 e3354. doi: 10.1016/j.jid.2022.05.1093.
https://doi.org/10.1016/j.jid.2022.05.10...

When comparing the studies with topical ruxolitinib and oral ritlecitinib in relation to F-VASI75 at week 24, the ruxolitinib response was superior (30% vs. 12.1%).125125 Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol. 2001;44:999-1003. doi: 10.1067/mjd.2001.114752.
https://doi.org/10.1067/mjd.2001.114752...
It is also relevant that this outcome was achieved with the highest dosage of ritlecitinib, the F-VASI was calculated only in the central facial area, and the ruxolitinib patients had lower phototypes than those in the ritlecitinib study, and they are more difficult to show repigmentation.113113 Ezzedine K, Peeva E, Yamaguchi Y, Cox LA, Banerjee A, Han G, Hamzavi I, Ganesan AK, Picardo M, Thaci D, et al. Efficacy and Safety of Oral Ritlecitinib for the Treatment of Active Nonsegmental Vitiligo: A Randomized Phase 2b Clinical Trial. J Am Acad Dermatol. 2022. doi: 10.1016/j.jaad.2022.11.005.
https://doi.org/10.1016/j.jaad.2022.11.0...

To date, there are no randomized controlled trials with oral ruxolitinib in the treatment of vitiligo, nor topical ruxolitinib compared to, or associated with the topical treatments of choice: calcineurin inhibitors, or topical corticosteroids. However, in a mouse model study, either tofacitinib or ruxolitinib was administered orally, showing the superiority of tofacitinib over ruxolitinib in decreasing vitiligo scores in the affected patients.116116 Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016;11:3442-3451. doi: 10.1021/acschembio.6b00677.
https://doi.org/10.1021/acschembio.6b006...
,126126 Azzolino V, Zapata L, Jr., Garg M, Gjoni M, Riding RL, Strassner JP, Richmond JM, Harris JE. Jak Inhibitors Reverse Vitiligo in Mice but Do Not Deplete Skin Resident Memory T Cells. J Invest Dermatol. 2021;141:182-184 e181. doi: 10.1016/j.jid.2020.04.027.
https://doi.org/10.1016/j.jid.2020.04.02...

Therefore, JAKi has shown to be potential therapeutic for vitiligo, with a good safety profile; however, this must be explored in association with other treatment measures (e.g., phototherapy) to maximize its effectiveness.

Other dermatoses

Hidradenitis suppurative (HS) results from the dysregulation of the innate and adaptive immune system, involving several cytokines mediated by the JAK-STAT pathway (e.g., IL-17, IL-23, IL-10) and, to a lesser extent, TNFα. Tofacitinib 5 mg 2x/d has been reported in two patients with favorable results.127127 Zouboulis CC, Frew JW, Giamarellos-Bourboulis EJ, Jemec GBE, Del Marmol V, Marzano AV, Nikolakis G, Sayed CJ, Tzellos T, Wolk K, et al. Target molecules for future hidradenitis suppurativa treatment. Exp Dermatol. 2021;30 Suppl 1:8-17. doi: 10.1111/exd.14338.
https://doi.org/10.1111/exd.14338...

A retrospective study with 20 patients using upadacitinib showed that, in four weeks, 75% of the individuals reached HiSCR50 and, in 12 weeks, 100%. All of them received 15 mg/d, and those who did not reach HiSCR50 within four weeks had the dosage increased to 30 mg/d.128128 Kozera E, Flora A, Frew JW. Real-world safety and clinical response of Janus kinase inhibitor upadacitinib in the treatment of hidradenitis suppurativa: A retrospective cohort study. J Am Acad Dermatol. 2022;87:1440-1442. doi: 10.1016/j.jaad.2022.07.047.
https://doi.org/10.1016/j.jaad.2022.07.0...
Phase II studies with INCB054707, 15 mg, 30 mg, 60 mg, and 90 mg/d demonstrated that 43%, 56%, 56%, and 88% of the patients achieved hidradenitis suppurativa clinical response (HiSCR) by week eight.129129 Alavi A, Hamzavi I, Brown K, Santos LL, Zhu Z, Liu H, Howell MD, Kirby JS. Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies. Br J Dermatol. 2022;186:803-813. doi: 10.1111/bjd.20969.
https://doi.org/10.1111/bjd.20969...

Pyoderma gangrenosum (PG) is a neutrophilic inflammatory dermatosis with an estimated incidence of three to ten cases/million person-years. Its pathogenesis is poorly understood but seems to involve dysregulation of both innate and adaptive immunity.130130 Maronese CA, Pimentel MA, Li MM, Genovese G, Ortega-Loayza AG, Marzano AV. Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments. Am J Clin Dermatol. 2022;23:615-634. doi: 10.1007/s40257-022-00699-8.
https://doi.org/10.1007/s40257-022-00699...
The frequency of associated immune-mediated comorbidities, and overexpression of inflammatory cytokines, in addition to the response to immunomodulatory drugs (e.g., corticosteroids, anti-TNFα, calcineurin inhibitors) support an underlying immune-mediated mechanism.131131 Goldust M, Hagstrom EL, Rathod D, Ortega-Loayza AG. Diagnosis and novel clinical treatment strategies for pyoderma gangrenosum. Expert Rev Clin Pharmacol. 2020;13:157-161. doi: 10.1080/17512433.2020.1709825.
https://doi.org/10.1080/17512433.2020.17...

There is no standardized approach to the immunosuppressive therapeutic strategy for PG, and there are resistant cases. 131131 Goldust M, Hagstrom EL, Rathod D, Ortega-Loayza AG. Diagnosis and novel clinical treatment strategies for pyoderma gangrenosum. Expert Rev Clin Pharmacol. 2020;13:157-161. doi: 10.1080/17512433.2020.1709825.
https://doi.org/10.1080/17512433.2020.17...
,132132 Orfaly VE, Kovalenko I, Tolkachjov SN, Ortega-Loayza AG, Nunley JR. Tofacitinib for the treatment of refractory pyoderma gangrenosum. Clin Exp Dermatol. 2021;46:1082-1085. doi: 10.1111/ced.14683.
https://doi.org/10.1111/ced.14683...
Dysregulation of the JAK-STAT pathway in PG has already been demonstrated, with JAK1, JAK2, JAK3, and STAT1 to STAT6 being overexpressed in the lesions. Mutations in the JAK-STAT pathway have also been implicated in PG progression.130130 Maronese CA, Pimentel MA, Li MM, Genovese G, Ortega-Loayza AG, Marzano AV. Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments. Am J Clin Dermatol. 2022;23:615-634. doi: 10.1007/s40257-022-00699-8.
https://doi.org/10.1007/s40257-022-00699...
Although there are no controlled clinical trials, several reports have demonstrated the benefits of tofacitinib, ruxolitinib, and baricitinib in PG.132132 Orfaly VE, Kovalenko I, Tolkachjov SN, Ortega-Loayza AG, Nunley JR. Tofacitinib for the treatment of refractory pyoderma gangrenosum. Clin Exp Dermatol. 2021;46:1082-1085. doi: 10.1111/ced.14683.
https://doi.org/10.1111/ced.14683...

133 Scheinberg M, Machado LA, LG MC, Ferreira SB, Michalany N. Successful treatment of ulcerated pyoderma gangrenosum with baricitinib, a novel JAK inhibitor. J Transl Autoimmun. 2021;4:100099. doi: 10.1016/j.jtauto.2021.100099.
https://doi.org/10.1016/j.jtauto.2021.10...

134 Kochar B, Herfarth N, Mamie C, Navarini AA, Scharl M, Herfarth HH. Tofacitinib for the Treatment of Pyoderma Gangrenosum. Clin Gastroenterol Hepatol. 2019;17:991-993. doi: 10.1016/j.cgh.2018.10.047.
https://doi.org/10.1016/j.cgh.2018.10.04...
-135135 Nasifoglu S, Heinrich B, Welzel J. Successful therapy for pyoderma gangrenosum with a Janus kinase 2 inhibitor. Br J Dermatol. 2018;179:504-505. doi: 10.1111/bjd.16468.
https://doi.org/10.1111/bjd.16468...

Dermatomyositis (DM) is a multisystemic disease in which there is an activation of the innate immune system with the secretion of type I interferons. Current treatment options include a combination of photoprotection, glucocorticoids (GCs), immunosuppressants, and immunomodulators.

Tofacitinib has been successfully reported in refractory DM at doses of 5 mg 2x/d in 34 patients, 11 mg/d (extended-release) in 10 patients, and 10 mg 2x/d in two patients. Ruxolitinib was used in seven patients with a maximum dosage of up to 30 mg/d. After the start of the treatment, no recurrences were observed within three to 15 months, with improvement in skin signs, symptoms, and muscle strength tests.136136 Paudyal A, Zheng M, Lyu L, Thapa C, Gong S, Yang Y, Lyu X. JAK-inhibitors for dermatomyositis: A concise literature review. Dermatol Ther. 2021;34:e14939. doi: 10.1111/dth.14939.
https://doi.org/10.1111/dth.14939...
However, most of the studies included in this review were case series, which are susceptible to observational bias, and there was no direct comparison with another method of treatment.

Graft-versus-host disease (GVHD) develops after an allogeneic hematopoietic stem cell transplantation, when the donor T-cells not only recognize the remaining tumor cells as foreign but also the recipients tissue, leading to a potentially severe condition. Typical target organs include the skin, liver and digestive tract. Currently, all approved strategies for the treatment of GVHD are immunosuppressive therapies, such as corticoid therapy.

As GVHD is mainly characterized by increased pro-inflammatory cytokines, systemic sclerosis and damage to internal organs, inhibition of activated tyrosine kinase signaling has shown to be a promising strategy to reduce disease severity and progression. Several small molecules are being studied (phases I to III), including: ruxolitinib, itacitinib, baricitinib, ibrutinib (Bruton's tyrosine kinase inhibitor), and pacritinib.

Treatment with ruxolitinib for patients with acute GVHD refractory to corticosteroid therapy decreases patients serum levels of pro-inflammatory cytokines and the number of activated T-cells, with an overall response rate of 82%. Similar effects were observed in patients treated with itacitinib. In chronic refractory GVHD, a phase III study with ruxolitinib has shown nearly twice the achievement of primary treatment endpoints when compared to the control group.137137 Braun LM, Zeiser R. Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease. Front Immunol. 2021;12:760199. doi: 10.3389/fimmu.2021.760199.
https://doi.org/10.3389/fimmu.2021.76019...

The recognition of JAKi as a therapeutic option for the treatment of chronic pruritic dermatoses started with AD. However, oral gusacitinib was recently given the “fast track” designation by the FDA for the treatment of chronic hand eczema. Moreover, clinical trials with topical delgocitinib have been initiated for chronic hand eczema in pediatric and adult patients; Moreover, as the pathogenesis of prurigo nodularis (PN) involves inflammation mediated by Th2 and Th17/Th22, which can be attenuated through JAKi, phase 2 studies are assessing the role of abrocitinib in the treatment of PN and chronic pruritus of unknown origin.6161 Samuel C, Cornman H, Kambala A, Kwatra SG. A Review on the Safety of Using JAK Inhibitors in Dermatology: Clinical and Laboratory Monitoring. Dermatol Ther (Heidelb). 2023:1-21. doi: 10.1007/s13555-023-00892-5.
https://doi.org/10.1007/s13555-023-00892...

Conclusion and future research

There is an intense scientific activity linked to the development of drugs that interfere at different levels of the JAK-STAT pathway, as well as the investigation of new indications and dosage regimens.

The safety profile of JAK inhibition, especially JAK1 or JAK3, associated with the modulation of the immune response should lead to a progressive increase in the use of JAKi in comparison to immunosuppressive drugs, such as oral corticosteroids, azathioprine, mycophenolate, methotrexate, and cyclosporine, for the treatment of inflammatory and autoimmune dermatoses. However, only clinical trials with active comparators can establish JAKi regarding the best indications, dosage regimens, and pharmacoeconomic aspects.

Finally, the greater availability of molecules should lead to reduced costs for the health system and increased access to patients. On the other hand, its long-term use should clarify aspects related to the maintenance of therapeutic efficacy, the impact of the immunological blocking of selective cytokine pathways, in addition to safety regarding the emergence of infections and malignant neoplasms.

  • Financial support
    None declared.

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Publication Dates

  • Publication in this collection
    28 Aug 2023
  • Date of issue
    Sep-Oct 2023

History

  • Received
    14 Jan 2023
  • Accepted
    2 Mar 2023
  • Published
    23 May 2023
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