Emerging Role of Baricitinib in Dermatology Practice: All We Need to Know!

Abstract

Baricitinib is a competitive inhibitor of the Janus Kinase family of non-receptor protein kinases, predominantly acting against JAK-1 and JAK-2 subtypes. By downregulating transcription of various pro-inflammatory cytokines, this drug has shown efficacy across various dermatoses. Approved for severe cases of alopecia areata and moderate-severe atopic dermatitis in adults, baricitinib is being increasingly tried across many other indications with promising results. It is prudent that dermatologists remain aware of boxed warnings and precautions with the use of this much-discussed molecule, including its infectious, thrombotic, cardiovascular, and malignant ramifications. Long-term data on the use of baricitinib in dermatological conditions are lacking and further research is warranted since most data on safety profile is extrapolated from its use in rheumatology. The present review aims to highlight the immunopathogenic mechanisms of JAK-1/2 blockade, approved and off-label uses in dermatology, along with a concise review of laboratory monitoring and the side-effect profile of baricitinib.

Introduction

Baricitinib is a reversible, competitive inhibitor of the JAK (Janus Kinase) family, acting predominantly on the JAK1 and JAK2 subtypes with a weak potency against other subtypes.^[1,2] Baricitinib received its first FDA approval (2018) for rheumatoid arthritis (RA). This targeted molecular therapy is being widely used in dermatology for diseases such as alopecia areata (AA) and atopic dermatitis (AD).^[3] On June 12, 2022, baricitinib became the first FDA-approved systemic drug for the treatment of severe AA.^[4] Dermatologists should have an in-depth knowledge about this upcoming molecule to optimize its use in various inflammatory dermatoses while maintaining a vigilant eye over its possible adverse events.

Search strategy

The PubMed database was searched using “Baricitinib” as the keyword in the title. Abstracts were screened to include studies in the English language and those pertaining to the use of Baricitinib in dermatological as well as non-dermatological indications, with a focus on dermatology-related articles. From a total of 1008 search results, pertinent 79 articles, along with FDA label data of baricitinib, were included in the review.

Pharmacology

Baricitinib is one of the oral small molecule (OSM) therapies, which by principle can penetrate inside the target cell membrane by virtue of its small molecular size and interaction with intracellular protein moieties.^[5] Baricitinib belongs to the first generation of JAK1/2 inhibitors.

Pharmacokinetics

Baricitinib has a chemical structure of C₁₆H₁₇N₇O₂S with 371.4 Da molecular weight.^[6] It is available as 1, 2, and 4 mg film-coated, immediate-release tablets. The oral bioavailability of baricitinib is about 80% with 50% plasma protein binding and 76 L volume of distribution, suggesting uptake inside tissues.^[6] The peak concentration of the drug is achieved within about 1 h of drug ingestion. The drug is metabolized by CYP3A4 with 75% and 20% of renal and hepatic clearance, respectively, and an elimination half-life of 8 to 12 h.^[7]

Pharmacodynamics

Basics of JAK-STAT pathway

Janus Kinase (JAK) family belongs to a subgroup of non-receptor protein tyrosine kinases which are linked to the intracellular domains of many cytokine receptors. They are characterized by two adjacent domains resembling the face of the Roman God Janus.^[8] In response to certain cytokines binding their receptors, JAKs will initiate downstream signaling pathways. There are four families of JAK: JAK1, JAK2, JAK3, and TYK2.^[9] Based on cytokines, these may homo- or hetero-dimerize and result in autophosphorylation. This in turn will phosphorylate and recruit STAT proteins (Signal Transducer and Activator of Transcription, 7 types: 1, 2, 3, 4, 5a, 5b, and 6), which will eventually result in the transcription of inflammatory mediators.^[10,11]

Mechanism of Baricitinib

Baricitinib inhibits the autophosphorylation of JAK (preferentially JAK1/2). In turn, JAKs will not be able to phosphorylate the receptors to dock STAT proteins. Unphosphorylated STATs lack properties to propagate downstream transcription of pro-inflammatory mediators.^[12] By selectively binding JAK1/2, baricitinib has an antiviral and anti-inflammatory effect from the IFN-α, β, and γ signaling.^[13,14] Detailed mechanism has been explained in [Figure 1].

Figure 1: (a) JAK-STAT signaling pathway: Cytokine binding to its receptor induces dimerization of cytokine receptors resulting in phosphorylation of kinase domains of associated JAKs triggering their enzymatic activity. These activated JAKs cause phosphorylation of tyrosine residues of receptors which further creates a docking site for STATs. STATs undergo JAK-mediated phosphorylation of tyrosine residues resulting in their dimerization and nuclear translocation where they bind to promoter regions of target genes inducing gene transcription. “Created with BioRender.com” (b) Baricitinib binds to the kinase domain of JAKs (JAK1/JAK2) inhibiting their activity thereby preventing JAKs from phosphorylating STATs and leading to the blockade of cytokine signaling. Baricitinib blocks the action of a range of cytokines. “Created with BioRender.com”

Approved indications

Baricitinib has been US-FDA approved for:

• Rheumatoid arthritis^[15] (June 2018): Adult patients, moderate to severe disease having inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies, It is not recommended for use in combination with other JAK inhibitors, biological disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine; dose: 2 mg once daily orally. It may be used as monotherapy or in combination with methotrexate.
• COVID-19 infection^[16] (November 2020: Emergency use approval; FDA approval later in May 2022): Emergency use authorization (EUA) in combination with remdesivir, for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. The recommended dose is 4 mg once daily up to 14 days or until hospital discharge, whichever comes first.
• Alopecia areata^[17] (June 2022): For adult patients with severe AA, a dose of 2 mg once daily can be increased to 4 mg once daily in case of inadequate treatment response. For patients with “nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss”, starting a dose of 4 mg once daily can also be considered. Once there is an adequate response to therapy, the dose can be reduced to 2 mg once daily. Similar to its use in RA, baricitinib is not recommended in AA patients in combination with other JAK inhibitors, DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

In India, the Central Drugs Standard Control Organisation granted EUA for the use of baricitinib in COVID-19 cases (12.10.2021), which was soon withdrawn by the Indian Council of Medical Research in view of inconclusive evidence of its efficacy. The Indian market has launched a generic version of baricitinib without patent waivers. As far as approval is concerned, permission for its use in RA has been filed with regulatory authorities and trials are ongoing for its use in dermatological indications, robust Indian data awaits for the latter.

Indications in dermatology [Table 1] [Figure 2]

Table 1: Indications of baricitinib in dermatology

Figure 2: Type 1 and Type II cytokine receptors and associated signaling JAKs and STATs: Explaining the rationale for using baricitinib in various dermatological disorders. “Created with BioRender.com”

Alopecia areata

Baricitinib has been approved for the treatment of adults with severe AA (vide supra in “approved indications”).

Rationale of use: In the pathogenesis of AA, there is a collapse of immune privilege, and the cytotoxic T cells produce IFN-γ.^[40] This IFN-γ promotes IL-15 production by JAK1/2 signaling, which in turn binds to IL-15 receptor-α. This complex results in the production of more IFN-γ via JAK1/3 signaling. By blocking the key signaling mediated by IFN-γ, baricitinib exerts its therapeutic efficacy in AA.^[3,41]

Clinical evidence: Most robust evidence that led to the approval of baricitinib in AA came from two phase-III double-blind, parallel-group, randomized, placebo-controlled trials: BRAVE-AA1 and BRAVE-AA2.^[42,43] It was concluded that baricitinib is superior to the placebo for regrowth of hair at 36 weeks, compared with the placebo with reported adverse events such as acne, hyperlipidemia, and raised creatine kinase levels.^[43] There have been isolated case reports documenting complete regrowth in about 8 to 9 months of treatment with baricitinib without side effects.^[44] Jabbari et al.^[45] and Uchida et al.^[46] also reported concurrent remission of the chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome symptoms and AD, respectively, while on baricitinib: reiterating the wide scope of JAK inhibitors in inflammatory dermatoses.

Long-term data on baricitinib are lacking, but evidence on tofacitinib suggests that recurrence rates are almost 100% in most studies in an average of 2.7 months after drug discontinuation.^[44,47] Should there be an upper limit to the duration of using JAK inhibitors is yet to be determined warranting longer cohorts and a plan to maintain the patient in remission while balancing the risk/benefit ratio.

Perspective in practice: Baricitinib has been reported to be highly efficacious in AA. Since management of severe cases of AA is fraught with many therapeutic challenges and poses significant psychological distress, baricitinib may be considered in adult patients with a refractory and severe disease with a “Severity of Alopecia Tool” (SALT) score of 50 or higher.^[43,48]

Atopic dermatitis

Baricitinib has been approved for the treatment of “moderate to severe AD in adults who are candidates for systemic therapy” by the European Medicines Agency (EMA) since september 2020.^[49] NICE guidelines (National Institute for Health and Care Excellence) recommend the use of baricitinib as an option for adults with moderate to severe AD who have not responded to treatment with ≥1 systemic therapy with a recommended dose of 4 mg once a day.^[50]

Rationale of use: Th2 cytokines function via JAK1/3 and STAT6, JAK1/2 and STAT1, STAT2, and STAT5 signaling, and thus use of baricitinib is found to decrease the levels of Th2 cytokines such as IL-4, IL-5, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin, as well as cause upregulation of filaggrin.^[51]

Clinical evidence: In the BREEZE-AD trials, baricitinib has shown evidence of efficacy in both physician and patient-reported outcome measures alone or in combination with topical corticosteroids.^[51] Patients achieved rapid and significant improvement across multiple measures: “disease severity, pruritus, skin pain, sleep disturbance and health-related quality of life (HR-QOL)” over 16 weeks. Efficacy was also sustained in longer-term studies up to 68 weeks.^[52]

Perspective in practice: Targeting the inflammatory milieu in atopic skin, baricitinib is reported to give rapid and sustained results in patients with AD. Real-world data along with head-on comparison trials between baricitinib and conventional agents may define the exact role of this molecule in the therapeutic armamentarium of AD.

Psoriasis

Rationale of use: IL-17/23 signaling has a pivotal role to play in the pathogenesis of psoriasis. The IL-23 receptor utilizes JAK2/TYK2 heterodimer for signal transduction, hitherto explaining the potential use of this molecule in psoriasis.^[53]

Clinical evidence: A randomized phase 2 trial of baricitinib in moderate to severe plaque psoriasis demonstrated significant improvement in PASI75 after 12 weeks of treatment.^[18] More studies have been carried out on tofacitinib, whose efficacy is equivalent to or slightly superior to baricitinib in studies. In theory, TYK2 inhibitors would be more selective than these first-generation JAK inhibitors in psoriasis.^[53]

Akin to TNF-alpha inhibitor-induced paradoxical psoriasis, baricitinib has also been reported to trigger new-onset psoriasis when used for a patient with RA. The postulated mechanism includes disruption of cytokine balance tipping toward the increase in IL-6, IL-8, and IL-36 gamma gene expression.^[54]

Perspective in practice: Baricitinib is an emerging treatment option for psoriasis. However, the potential of additive hyperlipidemia and cardiovascular risk due to the drug and psoriasis per se must be borne in mind with appropriate clinical and laboratory monitoring.

Treatment guidelines and monitoring

Pre-treatment evaluation

Thorough clinical history and examination are required at baseline and every visit with emphasis on past infections, organ dysfunction, lymphoproliferative conditions, or malignancies. Baricitinib is contraindicated in chronic kidney disease patients with a GFR(Glomerular Filtration Rate) of less than 30 mL/min/1.73 m².^[55] It is also prudent to avoid this drug in the following clinical scenarios:

• Severe active local or systemic infections such as HIV, hepatitis, active TB, or fungal infections
• Severe hepatic impairment
• Hemoglobin <8 mg/dL, lymphopenia with absolute lymphocyte count <500 cells/mm³, or neutropenia with absolute neutrophil count <1,000 cells/mm³
• Pregnancy and lactation
• In combination with biologic DMARDs

Before initiation of baricitinib, the following baseline investigations are recommended, along with up-to-date immunization as per age. It is recommended to update immunizations in agreement with current immunization guidelines before initiating baricitinib therapy. The interval between live vaccinations and initiation of baricitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

After initiation, laboratory parameters and their frequency of monitoring have been summarized in [Table 2].

Table 2: Laboratory parameters monitoring while using baricitinib

Use in special populations

• Pregnancy:
• There is no data regarding the safety of baricitinib in humans during pregnancy. Studies in animals suggest some embryotoxic effects and thus should be avoided in pregnancy.^[57,58] The drug must be stopped at least 1 month before conception.^[58]
• Lactation:
• There is evidence of the excretion of the drug in breast milk; however, its effect on the infant has not yet been completely elucidated and the risk-benefit ratio needs to be considered. Till then, breastfeeding may be avoided during and after 4 days of the last dose (approximately 5 to 6 elimination half-lives).^[58]
• Renal impairment:
• Baricitinib is not recommended in severe renal impairment (estimated GFR <30 mL/min/1.73 m²). For eGFR of 30-<60 mL/min/1.73 m², the dosage should be halved.^[55]
• Hepatic impairment:
• Baricitinib is not recommended in severe hepatic impairment or when drug-induced liver injury is strongly suspected. No dose adjustment is necessary for patients with mild or moderate hepatic impairment.^[56]
• Pediatric population:
• Emergency use authorization in COVID-19 had been given to baricitinib by the US FDA for the age group of 2 to <18 years needing respiratory assistance.
• Baricitinib has not yet been approved for use in dermatological indications in the pediatric age group. In a recent systematic review of treatment options for pediatric AA by Barton et al.,^[59] only one case regarding the use of baricitinib was found in a 17-year-old male with recalcitrant disease responding to 11 mg dosing of baricitinib.^[45]
• BREEZE-AD-PEDS trial is in phase III to study the safety and efficacy of baricitinib in children and adolescents with AD aged 2 to 17 years.^[60]
• Geriatric population:
• Baricitinib has been used in patients aged >65 years with safety. However, potential drug interactions and renal dysfunction should be borne in mind.

Adverse events

Theoretically, JAK inhibitors as a group carry the propensity to cause many mucocutaneous, laboratory, infective, thrombotic and plausible risk to cause malignancies. The reported possible adverse events with baricitinib mainly with AA^[61] have been depicted in Figure 3. Boxed warnings and precautions regarding the use of baricitinib have been summarized in [Figure 4].

Figure 3: Adverse effects of baricitinib

Figure 4: Boxed warnings and precautions with JAK inhibitors (including baricitinib)*. *In the event of serious infection, Baricitinib should be withheld till the infection is controlled. The risk/benefit ratio is to be considered for use of Baricitinib in cases of chronic or recurrent infections, with a vigil eye on tuberculosis reactivation. Mortality and major adverse cardiovascular events (MACE) have often been associated with having at least one underlying cardiovascular risk factor. In view of lymphomas and other malignancies, caution should be exercised, especially in current or past smokers. Patients with symptoms of thrombosis should discontinue the drug. It should be avoided in patients at risk of thrombosis

Overall, the frequency estimate of adverse events reported are:

• Very common (≥1/10): Upper respiratory tract infections and hypercholesterolemia
• Common (≥1/100 to <1/10): Herpes zoster, herpes simplex, gastroenteritis, urinary tract infections, thrombocytosis, nausea, and ALT ≥3× ULN (Upper limit of normal)
• Uncommon (≥1/1000 to <1/100): Neutropenia, hypertriglyceridemia, AST ≥3× ULN, acne, weight gain, and creatine phosphokinase ≥5× ULN
• Potential incidence of malignancy, cardiovascular events, and thrombosis have not been conclusively reported.

Infections

JAK inhibitors carry the risk of causing infections because of the role of the JAK/STAT pathway in modulating immune responses to microbes.^[62] These can be due to various bacterial, mycobacterial, viral, fungal, and opportunistic pathogens and may lead to serious infections. The most common opportunistic infection associated with JAK inhibitors is herpes zoster, due to interference with functions of IFN-γ and IL-15.^[63] Other infections seen with baricitinib include respiratory and urinary tract infections. In patients with severe AD, Staphylococcus aureus and herpes simplex infections, and eczema herpeticum/Kaposi varicelliform eruption have also been reported with the use of this molecule.^[64] For patients with systemic lupus erythematosus, there is a risk of serious infections on baricitinib, compounded by their background susceptibility to immune dysfunction and concurrent immunosuppression.^[65] There is a risk of hepatitis reactivation but data remain limited.

On comparing adverse events across various indications, rheumatological diseases carry a higher risk of serious infections and herpes zoster than dermatological diseases with the use of baricitinib, with an exception of herpetic infections seen more in AD patients.^[65] WHO pharmacovigilance database on JAK inhibitors reported the highest rates of herpes viral infections with baricitinib compared with tofacitinib or ruxolitinib, along with over-reporting of Pneumocystis infection.^[66]

For patients of hepatitis B/C enrolled with antibody positivity (anti-HBc or anti-HCV) without positivity for HBsAg or viral RNA, viral load, a liaison with a hepatologist is recommended. Tuberculosis reactivation has been reported with baricitinib, but most data are available regarding its use in rheumatology rather than dermatology, warranting a prudent eye and reporting of data.^[67]

Malignancy

Baricitinib use has been associated with higher rates of lymphomas and non-melanoma skin cancers. These rates are higher in patients of RA or systemic lupus erythematosus treated with baricitinib, while evidence is inconclusive for its use in atopic dermatosis or AA.^[65] In a recent long-term study of JAK inhibitors in RA, standardized incidence ratios for malignancies (excluding non-melanoma skin cancers) were found to be 1.07, and the standardized mortality ratio of 0.74, but the exact risk remains unclear with no evidence to suggest an increased risk of malignancy, lung cancer, or lymphomas compared with the population, on long-term use of Baricitinib in RA.^[68] In principle, JAK inhibitors interfere with the functioning of IFN-γ and NK cells, which are crucial for mounting a “cancer immune-editing” response that enables the host to generate an anti-tumor response.^[69] Longer studies and a larger cohort are required to conclude the risk of malignancy in dermatological indications. Till then, baseline clinical evaluation and annual assessments are prudent.

Major adverse cardiovascular events (MACE)

Studies in RA suggest higher rates of MACE defined as “cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke,” with JAK inhibitors compared with TNF blockers, especially in smokers. Theoretically, interference with JAK/STAT signaling will affect various pathways such as IL-15, gp130-mediated IL-6, IL-12, and IFN-γ affecting myocardial health and endothelial function.^[70] WHO pharmacovigilance data on the other hand did not find a higher incidence of MACE with JAK inhibitors.^[70] The risk of MACE is actually compounded and confounded by the presence of underlying risk factors and disease entities.^[68] This risk of MACE persists during and till 1 month of drug discontinuation.^[71] Caution should be warranted in patients having underlying risk factors for cardiovascular disease such as smokers, hypertension, or old age.

Thrombosis

There have been reports of venous thromboembolism with the use of baricitinib in COVID-19 and systemic lupus erythematosus.^[72] This risk, similar to the risk in MACE, is confounded by the inherent susceptibility to thrombosis to the underlying disease in question. A recent systematic review and meta-analysis revealed no increased risk of venous thromboembolism with the use of baricitinib in patients with AD.^[73] The absolute risk may be low, but caution is warranted along with careful follow-through in post-marketing surveillance.^[74]

Gastrointestinal perforations

It was presumed that IL-6 blockade by baricitinib and other JAK inhibitors could lead to gastrointestinal perforations akin to tocilizumab.^[75] However, such an event has not been reported with the use of baricitinib across various indications.^[64,76–78]

On comparison of data regarding the safety profile of baricitinib use in dermatology, rheumatology, and COVID-19 infections, it was found that the rate of infections, malignancies, thrombotic events, and MACE were higher in rheumatology indications, possibly reflecting their underlying risk due to disease per se.^[64]

Problem statements

• JAK inhibitors have been under the constant scrutiny of adverse events and bearing the scourge of being labeled “JAK in the (black) box!”^[74] with four black box warnings on the FDA label.
• Medicolegal repercussions of untoward adverse events must be borne in mind while prescribing the drug with disclosure of possible adverse events in today’s times, where searching for side effects on the internet is not uncommon.
• Studies have documented differential adverse event reporting across various JAK inhibitors, among which baricitinib-related serious adverse events such as mortality and malignancies are over-reported in many studies.^[66,79]
• Most of the warnings were introduced on the label around September 2021. Not many studies had been carried out at that time, focussing on the use of baricitinib for dermatological indications. Data on RA cannot be simply extrapolated; hence, the available literature should be imbibed with critical appraisal and forthcoming real-world data.
• While the labeled warnings are here to stay as of now, it is important to stay cautious in the following subsets: Age >50 years or <18 years (risk of age-related events and absence of long-term safety data, respectively); increase in the baseline risk of malignancy (e.g. smoking or history of malignancy-personal/family) and in the concurrent presence of one or more cardiovascular risk factor (e.g. diabetes, hypertension, and hyperlipidemia).^[80]
• There is a paucity of studies that compare the profile of different JAK inhibitors. Baricitinib showed similar efficacy as other JAK inhibitors in AA in a recent meta-analysis.^[81] In AD, abrocitinib, baricitinib, and upadacitinib were found to be consistent effective therapies with slightly better outcomes of upadacitinib in short-term studies.^[82] Baricitinib and tofacitinib are available in India; however, there is a lack of published studies comparing the two across various dermatological indications; further emphasizing the need for more data on baricitinib in a practical scenario.

Conclusion

Baricitinib is an upcoming oral small molecule with evidence of efficacy and reasonable safety across emerging dermatological indications. This is a new valuable addition to the therapeutic armamentarium for dermatologists for various inflammatory dermatoses. However, larger cohorts with long-term follow-up are required to establish the efficacy and safety of baricitinib in real-world settings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.