Dermatologic Applications and Safety Considerations of Janus Kinase Inhibitors

Steven A. Svoboda, BS¹; Nathan Johnson, MD²; Mariana Phillips, MD²

¹Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
²Section of Dermatology, Department of Internal Medicine, Carilion Clinic, Roanoke, VA, USA

Conflict of interest:
Mr. Svoboda, Dr. Johnson, and Dr. Phillips have no conflicts of interest to disclose

Abstract:
Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, represent a new class of medication that have broad potential to treat dermatologic disease. Currently, the only FDA-approved dermatologic indication for this class of medications is psoriatic arthritis; however, their utility in treating other immune-mediated skin conditions including atopic dermatitis, vitiligo, alopecia areata, and systemic and cutaneous lupus is actively being investigated. Overall, these drugs appear to be well-tolerated and have a safety profile similar to that of other biologics commonly used in dermatologic practice, although an increased risk of thromboembolism has been associated. While risk of mild infection and herpes zoster appears to be increased regardless of JAK selectivity, risk of thrombosis and malignancy based on the subtype of JAK inhibition remains to be seen. Certainly, safety concerns warrant further investigation; however, early data from ongoing clinical trials offer promise for the broad utility of these medications within future dermatologic practice.

Key Words:
Janus kinase inhibitors, JAK inhibitors, jakinibs, baricitinib, ruxolitinib, tofacitinib, dermatologic applications, adverse effects

Background

Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, are a class of medication that offers promise for a number of immunologically driven conditions. Originally developed for the treatment of hematologic diseases, jakinibs have demonstrated efficacy in various autoimmune and autoinflammatory disorders.^1-3 Currently FDA-approved jakinibs include tofacitinib (Xeljanz^®) for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, baricitinib (Olumiant^®) for rheumatoid arthritis, and ruxolitinib (Jakafi^®) for myelofibrosis and polycythemia vera.²

As their name implies, JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes, of which there are four presently identified – JAK1, JAK2, JAK3, and TYK2. These JAK enzymes are tyrosine kinases that play a critical role in mediating the signal transduction of cytokines, particularly those that bind to and activate the type 1 and type 2 cytokine receptors on the surface of cells. More specifically, the phosphorylation of these cytokine receptors by Janus kinases leads to recruitment of Signal Transducer and Activation of Transcription (STAT) proteins which modulate gene expression. It is the immunoregulatory role of cytokines and the aberrant production of cytokines observed in many autoimmune disorders that makes interruption of the JAK-STAT signaling pathway an attractive therapeutic strategy.^1-3

The first JAK inhibitor to reach clinical trials was tofacitinib, an antagonist of JAK1 and JAK3 primarily.¹ It was granted initial approval in 2012 for the treatment of rheumatoid arthritis in patients who had an inadequate response to methotrexate, and since entering into commercial use, its approval has been extended to treatment-resistant psoriatic arthritis and moderate-to-severe active ulcerative colitis as well.^1,2 Other first generation jakinibs that have demonstrated clinical efficacy for these conditions among others include ruxolitinib and baricitinib; however, these agents differ in that their selectivity is for both JAK1 and JAK2.^2,4-7

Due to the variable activity and, in some cases, limited efficacy of the commercially available JAK inhibitors, 2nd generation agents with novel selectivity for Janus kinases are being developed and investigated.^1-3 Unfortunately, the exact relationship between inhibition of specific Janus kinase enzymes and therapeutic effect on target diseases is currently unknown.^1-3,6,8 However, as our understanding of the specific JAK/STAT pathways involved in the pathogenesis of dermatologic disease evolves, selective targeting of Janus kinases may allow for improved treatment precision and avoidance of adverse off-target effects.

Clinical Applications in Dermatology

Within dermatology, JAK inhibitors have been most extensively studied in psoriasis and psoriatic arthritis and have demonstrated clinical efficacy for these patients.⁶ However, their utility in treating other autoimmune/autoinflammatory skin conditions including atopic dermatitis, alopecia areata, vitiligo, and systemic lupus erythematosus is actively being investigated in clinical trials with various 1st and 2nd generation jakinibs (Table 1).

Psoriasis and Psoriatic Arthritis

Excessive activation of the JAK1/JAK2/STAT1 and JAK1/ TYK2/STAT3 pathways – and resultant amplification of proinflammatory genes – triggered by interferon (IFN)-gamma and interleukin (IL)-22, respectively, has been implicated in the pathogenesis of psoriasis.⁹ Therefore, inhibition and subsequent blockade of these overactive signaling pathways represents an attractive therapeutic target. Out of all the jakinibs, tofacitinib has been most widely studied in psoriasis and is currently the only jakinib with FDA-approval for the treatment of psoriatic arthritis.^6,10 This regulatory approval for this indication was granted in 2017 after statistically significant improvements in the American College of Rheumatology 20 (ACR20) assessment were observed in two phase III trials.^11,12 Subsequently, phase III trials demonstrated both 5 mg and 10 mg twice daily tofacitinib to be more effective than placebo in achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI 75), with improvement seen in a dose-dependent manner (46.0, 59.6, and 11.4%, respectively for OPT Pivotal 2).^12,13 These doses also provided significant improvements in nail psoriasis and were sustained for up to 52 weeks.^11-13 Moreover, a phase III noninferiority trial found the 10 mg twice daily dose of tofacitinib to be noninferior to etanercept, 50 mg subcutaneously twice per week, with a similar side effect profile.¹⁴ Unfortunately, a topical tofacitinib 2% ointment did not demonstrate improvement over placebo after a 12 week phase II trial in patients with mild-to-moderate psoriasis.¹⁵

Several other jakinibs have also shown promising early results. Phase II trials of baricitinib, filgotinib, itacitinib, and BMS- 986165 have all have yielded improved outcomes in the PASI 75 and Physician’s Global Assessment when compared to placebo.^16-18 Also, a phase II trial of topical ruxolitinib 1.5% cream was found to be efficacious in reducing the area of psoriatic plaques. However, it was only as effective as standard of care topical calcipotriene and betamethasone dipropionate.¹⁹ Results from ongoing clinical trials of upadacitinib and brepocitinib (PF-06700841) are eagerly awaited. Head-to-head randomized controlled trials comparing the efficacy between jakinibs and existing treatments for psoriasis or psoriatic arthritis have not been conducted.

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions and is driven by barrier dysfunction and abnormal immune activation predominantly of T helper (Th) 2 and Th22 cells, but to a lesser degree Th1 and Th17 subtypes as well.²⁰ JAK inhibition may, therefore, be a viable therapeutic approach as the JAK-STAT pathway underlies the activation of these T helper subsets.²⁰ Both oral and topical formulations of JAK inhibitors have been shown to decrease AD severity and symptoms.²⁰ In 2015, Levy et al. demonstrated efficacy of oral tofacitinib in six patients with moderate-to-severe, recalcitrant AD, noting that overall disease severity decreased by approximately 55% as judged by the SCORing Atopic Dermatitis (SCORAD) index. Additionally, patients had even greater average reductions in sleep loss and pruritus scores.²¹ Though encouraging, this study was inadequately powered to allow for major conclusions about the efficacy of oral JAK inhibitors in treating AD. In 2016, a phase II placebo-controlled trial showed significant improvement in the Eczema Area and Severity Index (EASI) score after 4 weeks of topical tofacitinib in 69 patients.¹⁶ While evidence for the clinical efficacy of JAK inhibitors for A still remains limited at this time, the literature is anticipated to rapidly expand as several phase II and III trials with oral and topical JAK inhibitors are ongoing and near completion. Current agents under investigation include baricitinib, upadacitinib, ruxolitinib (topical), brepocitinib (topical), and abrocitinib (PF-04965842).²⁰

Alopecia Areata

Alopecia areata (AA) is an autoimmune disease of the hair follicle characterized by patchy hair loss of the scalp, and, in some patients, has potential to progress to total scalp hair loss (alopecia totalis) and total body hair loss (alopecia universalis). Numerous case reports have documented the efficacy of oral and topical jakinibs for AA; however, clinical trials thus far have been limited.^6,22-26 A phase I, placebo-controlled, double-blind study in patients with alopecia universalis found significant hair regrowth with two topical JAK inhibitors, 2% tofacitinib and 1% ruxolitinib after 28 weeks. However, only about half of patients responded to the medication, and the response rate was inferior to topical clobetasol.²⁷ In contrast to the topical formulations, an open-label clinical trial comparing the efficacy of oral tofacitinib and ruxolitinib in 75 patients with severe AA found that both medications induced remarkable hair regrowth at the end of 6 months, with a mean change in the Severity of the Alopecia Tool (SALT) score of 93.8 ± 3.25 in the ruxolitinib group and 95.2 ± 2.69 in the tofacitinib group.²⁶ There was no statistically significant difference between the groups regarding hair regrowth at the end of the 6-month treatment, and relapse rate at the end of the 3-month follow-up was the same for both medications. While both drugs were well tolerated with no serious adverse effects reported, approximately two-thirds of cases experienced relapse after drug discontinuation.²⁶

Vitiligo

Numerous case reports, case series, and open-label studies have documented the efficacy of both oral and topical JAK inhibitors for vitiligo, an acquired depigmenting disorder caused by autoimmune destruction of melanocytes.^28-31 In a phase II open-label study of 11 patients, application of ruxolitinib 1.5% cream for 20 weeks resulted in significant improvement in the overall Vitiligo Area Scoring Index (VASI) with facial vitiligo demonstrating the best response.³⁰ Follow-up of five patients at 6 months after treatment cessation revealed that all had maintained their response. While reports of cases employing oral tofacitinib and ruxolitinib documented significant repigmentation during medication administration, both also noted regression within weeks after treatment discontinuation.^28,31 Clinical trials of topical ruxolitinib and two 2nd generation oral jakinibs, brepocitinib and PF-06651600, are currently underway.

Systemic Lupus Erythematosus

Inhibition of JAK2/3 has shown promise in animal models of lupus dermatitis and nephritis.³² While clinical studies are limited, one randomized phase II trial of oral baricitinib 4 mg reported modest efficacy for arthritis and rash severity after 24 weeks in patients with active systemic lupus erythematosus (SLE) who were not adequately controlled despite standard of care therapy.³³ Unfortunately, these improvements were only observed with the 4 mg and not the 2 mg dose. While these preliminary results are promising, data from ongoing trials of 2nd generation jakinibs will help ascertain effectiveness of this drug class for cutaneous lupus.³² To date, there have been no published reports assessing the efficacy of JAK inhibitors in specifically treating subacute and chronic forms of cutaneous lupus erythematosus.

Lichen Planopilaris

As is the case for AA, upregulation of interferons and JAK signaling play an etiologic role in lichen planopilaris (LPP), an inflammatory cicatricial alopecia. A retrospective study found that eight out of ten patients with recalcitrant LPP had clinically measurable improvement after treatment with oral tofacitinib 5 mg twice or three times daily for 2 to 19 months.³⁴ There was a greater than 50% mean reduction of LPP activity index in the eight patients that did observe a benefit. The only adverse effect reported was a 10-pound weight gain in one patient after treatment for 12 months.³⁴

Other Dermatologic Diseases

Evidence from case reports suggests that JAK inhibitors may provide benefit for patients with treatment-refractory or rare diseases without effective therapies such as cutaneous sarcoidosis, dermatomyositis, pemphigus, hidradenitis suppurativa, chronic mucocutaneous candidiasis, hypereosinophilic syndrome, polyarteritis nodosa, mastocytosis, and severe chronic actinic dermatitis.^35-40

Adverse Effects and Safety Considerations

The relatively broad and nonspecific anti-inflammatory and immunosuppressive properties of jakinibs, which allow for their potential efficacy across many indications, are mirrored in the wide array of potential adverse effects seen across this drug class. The primary safety concerns surrounding their use include the risk of infection, malignancy, and thromboembolic events. Nevertheless, jakinibs currently appear to have an acceptable safety profile comparable to that of the biologics already being used to treat many of the same conditions.^10,41 The majority of this safety data originates from clinical trials of tofacitinib and baricitinib in patients with rheumatoid arthritis.

Infection

The most commonly reported adverse events for those taking JAK inhibitors are mild upper respiratory infections and nasopharyngitis. For patients on tofacitinib, these mild infections occur at rates of approximately 10% or less.^6,20,42,43 There is also an increased risk of serious bacterial, fungal, mycobacterial, and viral infections, occurring at rates of 2.6 to 3.6 events per 100 patient-years for those on tofacitinib.²⁹ More specifically, the rates of tuberculosis and non-disseminated herpes zoster is 0.2 and 3.8 to 5.2 events per 100 patient-years, respectively.^43-45 Fortunately, the risk of tuberculosis is extremely low, especially for individuals residing in nonendemic areas. One study found that 21 out of 26 new tuberculosis cases in 5671 patients taking tofacitinib, occurred in countries with a high prevalence of tuberculosis.⁴⁵ Additionally, of 263 patients with latent tuberculosis, none developed active tuberculosis when they took tofacitinib and isoniazid concurrently.⁴⁵

The safety profile of baricitinib appears similar to that of tofacitinib with mild infection, namely nasopharyngitis, being the most common adverse event. In a 24-week, phase II study of 301 patients, only 1% developed a serious infection, but all recovered and continued with the study.⁴⁶ In a 52-week, phase II study of 142 patients, herpes zoster occurred in 11 patients and tuberculosis occurred in none.^46,47 Clinical trials of the 2nd generation jakinibs are reporting similar, if not improved, rates of infection to the 1st generation drugs.⁴⁸ However, phase IV studies and head-to-head trials between jakinibs will be required to establish any differences in risk.

Although the rates of herpes zoster in those taking jakinibs are similar to those of other biologic disease-modifying antirheumatic drugs, immunization with the recombinant zoster vaccine prior to initiating treatment may reduce the risk of this infection. While it is not specifically approved for patients using JAK inhibitors, it has been studied in individuals who are immunocompromised and found to be both safe and efficacious.¹⁰

Malignancy

There is concern about the theoretical increased risk for developing cancer with the use of jakinibs as a result of blocking the action of interferons and natural killer cells, which play an important role in tumor surveillance. While there have been reports of lymphoma and other malignancies associated with tofacitinib and baricitinib, multiple large studies have failed to demonstrate an increased risk of malignancy, with a mean follow-up of 3.5 years.^6,42,44,49 Moreover, a 128-week open-label extension study of tofacitinib did not show any cases of malignancy with prolonged treatment.⁵⁰ Yet, one study of myelofibrosis patients did find a slightly higher rate of aggressive B cell lymphoma in those treated with ruxolitinib. In response to this association, a bioinformatics study evaluating gene expression data from numerous lymphoma cell lines discovered that ruxolitinib can increase the pathological expression of transcription factors important in lymphoma genesis.⁵¹ Consequently, longer-term studies are necessary to further assess the correlation between jakinib therapy and cancer risk. Quantification of these risks based on dosage, duration of treatment, subtype of JAK inhibition, and disease type should be explored.

Thromboembolism

While the potential risks for infection and malignancy have been the primary safety considerations surrounding the use of jakinibs, more recently, concern for increased risk for thromboembolic events has arisen. In July 2019, the FDA issued a black box warning for the 10 mg, twice-daily dose of tofacitinib after a post-market safety review of the FDA’s Adverse Event Reporting System (FAERS) noted an increased rate of pulmonary thrombosis (OR = 2.46, [95% CI = 1.55-3.91]), though not pulmonary embolism (PE) or deep venous thrombosis (DVT), in patients with rheumatoid arthritis.⁵² However, a 2019 systematic review comparing complications associated with 5 mg versus 10 mg tofacitinib twice daily for the treatment of various autoimmune diseases found no difference in the rate of any serious adverse events at the end of the 3- and 6-month follow-up periods.⁵³ To date, approval of the 10 mg dose of tofacitinib is limited to those with treatment-refractory ulcerative colitis.

Baricitinib also has a black box warning denoting the risk for thromboembolic events, as clinical studies have observed an increased incidence of DVT and PE compared to placebo.⁵⁴ However, this risk of thromboembolic events appears to be quite low as it is estimated to be approximately five events per 1000 patient-years for the 4 mg daily dose in patients with RA. For non-RA patients, this risk is estimated to be even less, with one to four events per 1000 patient-years.⁵⁴ It should be noted that patients with RA also carry increased risk for thromboembolic events independent of JAK inhibitor therapy, although marginally increased risk has also been observed in patients with psoriatic arthritis and ulcerative colitis taking tofacitinib.^55,56

Nevertheless, this entire class of medication has come under closer scrutiny in light of these findings. Therefore, future trials of JAK inhibitors should ensure accurate and detailed documentation of any thromboembolic events that occur. Additionally, given the low incidence of thromboembolic events, large observational studies will likely be required to arrive at more definitive conclusions. Furthermore, it is crucial to differentiate whether these thromboembolic risks are attributable to JAK inhibitors or to the disease process itself and its comorbidities.

Lab Abnormalities

JAK inhibitors have also been associated with various laboratory abnormalities including anemia, neutropenia, and thrombocytopenia.^{8,43,44,47,57} These effects may be a consequence of JAK2 inhibition as erythropoietin and colony stimulating factor act through this pathway. Elevations in liver transaminases, high- and low-density lipoproteins, creatinine, and creatine phosphokinase may also be observed.^47,50,58 Importantly, many of these effects have been found to be dose-dependent, and all were reversible upon treatment discontinuation.^53,57,58 Also, long-term use does not appear to progressively worsen these abnormalities, and few patients discontinue treatment as a result of them.^47,50,53 Furthermore, a meta-analysis assessing the cardiovascular risks associated with the hyperlipidemia seen in psoriasis patients treated with baricitinib, found that there was no increased risk of major adverse cardiovascular events for these patients.⁵⁸

Discussion

JAK inhibitors appear to be a viable treatment option for a number of dermatologic conditions. With good oral bioavailability and lack of immunogenicity, they address some of the limitations of biologics. For most patients, jakinibs seem to be well-tolerated as discontinuation rates for safety issues are less than 10%.⁵⁹ The vast majority of adverse events are related to infection, but ensuring that patients are up to date on their immunizations can mitigate this risk to some degree. In particular, live-attenuated vaccines should be administered prior to initiation of therapy, as these should generally be avoided while taking JAK inhibitors. Historically, the live-attenuated zoster immunization was particularly important to administer prior to starting JAK inhibitor therapy; however, with the advent of the killed zoster vaccine (Shingrix), this is less of a concern. Moreover, closely monitoring patients for signs of infection and checking their complete blood count, liver transaminases, creatinine, and creatine phosphokinase may help prevent associated complications.⁶⁰

Nevertheless, additional research is needed to assess long-term efficacy and safety. While the increased risk of malignancy and thromboembolism attributable to JAK inhibitors appears to be quite low, large observational studies will likely be required to obtain a more accurate risk assessment.⁵⁴ Although it is not yet fully understood how selective inhibition of the JAK subtypes may affect the safety profile of these medications, it seems plausible that adverse effects may be influenced by the level and type of JAK inhibition. Head-to-head trials of these various 1st and 2nd generation jakinibs at varying dosages and durations of treatment are necessary to elucidate these risk differences, if any. Given the number of jakinibs in development and currently being tested in randomized trials for both dermatologic and non-dermatologic diseases, we remain optimistic regarding the benefit-risk profile of this class of medication.

Conclusion

Although the only dermatologic condition that is currently approved for treatment with a JAK inhibitor is psoriatic arthritis, their potential applications within dermatology are numerous. These drugs appear to be well-tolerated and have a safety profile relatively similar to that of biologics, excepting the increased risk of thromboembolism, and superior to many disease-modifying anti-rheumatic drugs. Moreover, these drugs seem to have a large overlap in their safety profiles despite differences in JAK selectivity. While risk of mild infection and herpes zoster appears to be increased regardless of JAK selectivity, risk of thrombosis and malignancy based on the subtype of JAK inhibition remains to be seen. Furthermore, thromboembolic and oncologic risk may also be dependent on a number of others factors including dosage, duration of treatment, concurrent treatments, disease type and severity, and comorbidities. While these significant safety concerns certainly warrant further investigation, ongoing clinical trials offer promise for the widespread application of these medications within future dermatologic practice.

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