Mechanism of action of the JAK-STAT pathway

The Janus Kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is a ubiquitous intracellular signaling network that is involved in the signal transduction of numerous dermatologically relevant cytokines¹,². JAK family is composed of four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). The function of JAK proteins is associated with the type of cytokine that binds the receptors and they play a key role in cell growth, development and differentiation. They are especially found in immune and hematopoietic cells, such as lymphocytes, natural killer cells, and mast cells, but cytokine signaling is also important for the biology of nonimmune cells such as keratinocytes, fibroblasts, osteoblasts, synoviocytes, or endothelial cells. JAK1, JAK2, and TYK2 are involved in cell growth processes in different cell types, while JAK3 is critical to hematopoiesis³. Different JAKs are associated with specific cytokine receptors and influence different aspects of immune cell development and function. These proteins modulate the inflammatory process by activating intracytoplasmic transcription factors called STAT. STAT family influences DNA transcription and plays an important role in regulating gene expression, cell differentiation, proliferation, survival and apoptosis. This family is composed of seven proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6); phosphorylated STATs dissociate from the receptor, translocate to the cell nucleus and regulate transcription either positively or negatively of thousands of different genes (Figure 1).

Figure 1 Schematic presentation of the JAK/STAT pathway and the role of JAK inhibition drugs. The primary function of the protein kinases is to transfer phosphate groups from adenosine triphosphate or guanosine triphosphate to the hydroxyl groups of amino acids of the protein targets. Numerous group of cytokines, such as IL-2, IL-6, IL-12, IL-21, IL-22, IL-23, and INF-Υ interacts with type I and II cytokine receptors. Both of these receptor types lack intrinsic enzyme activity and rely on JAKs for signal transduction. After binding, recruited JAKs to initiate a signaling pathway: cytokine receptors of type I and II undergo oligomerization leading to the recruitment of JAKs, which autophosphorylate tyrosine residues. Then, STAT proteins are recruited and bind to the phosphorylated residues leading to activation mediated by phosphorylation by JAKs. Successively, the activated STAT proteins undergo dimerization enabling their translocation to the nucleus and, consequently the modulation of gene expression (adapted from Solimani et al.)². 

Thus, selective JAK inhibitors can simultaneously block the function of multiple cytokines and, consequently, the transcription of genes responsible for inflammation and the control of innate and adaptative immunity. Most cytokine receptors use a combination of JAKs for their activity, enabling the idea of targeting single JAKs. JAK inhibitors are divided into two generations, the first generation blocks more than one type of JAK, while the second generation is more specific and blocks only one type of JAK and consequently has fewer side effects³. The first-generation JAK inhibitors include tofacitinib, ruxolitinib (RUX), baricitinib, and oclacitinib, all of which are approved for use in humans, except oclacitinib⁴. Abrocitinib and upadacitinib are commonly referred to as selective JAK1 inhibitors²,⁴.

Rational for the use of JAK-inhibitors in dermatology

The perpetuation of inflammation in diseased skin strongly relies on the interaction between cytokines, immune, and tissue cells propagating distinct inflammatory cascades. Differently from biologics that target cytokines by intravenous or subcutaneous injection, JAK inhibitors target cytokine signaling by either oral or topical administration. The latter way of application may minimize the risk of side effects. Topical JAK inhibitors do not bear the risk of skin atrophy or telangiectasia, as observed with long courses of topical corticosteroids². There is growing interest in the potential use of these drugs in many dermatological diseases, such as alopecia areata (AA), vitiligo, and atopic dermatitis (AD). The cytokines involved in each of these diseases differ; however, in all three, the effects of cytokine binding are mediated through the JAK pathway, providing a rationale for JAK inhibition. Although there are many JAK inhibition under study, only some are approved for the treatment of dermatological diseases (Table 1).

Atopic dermatitis

Atopic dermatitis (AD) is a common chronic disease of the skin that has a great impact on a patient’s quality of life. The disease can manifest at any age, but its prevalence is higher in children and adolescents. Clinically AD is characterized by the presence of pruriginous eczematous lesions, typically on flexural sites. This heterogeneous condition has a complex pathophysiology; historically AD is thought to be T helper 2 (Th2) dominated disease, but there is growing evidence that the immunological environment of AD is not solely defined by Th2 cells and related cytokines but also by cytokines linked to other Th cells responses such as INF-Υ [(interferon-gamma) Th1], interleukin (IL)—17, IL-22 (Th17) and IL-33². Given the diversity of cytokines implicated in the inflammatory process of AD, there is growing interest in JAK inhibition, which could interfere with multiple cytokines simultaneously.

Various cytokines relevant to the pathophysiology of AD, including IL-4, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin, activate JAK1 containing heterodimeric receptors, thereby mediating Th2 cell differentiation⁵. Additionally, chronic itch is also directly mediated by neuronal JAK1 signaling, and IL-22 drives epidermal hyperplasia via JAK1. Together these findings suggest the importance of JAK1 signaling in the pathogenesis of AD⁶. JAK2 forms homodimeric receptor complexes involved in hematopoiesis. Therefore, selective inhibition of JAK1 is a desirable target to modulate a broad range of cytokines involved in the pathophysiology of AD while avoiding the effects of JAK2 inhibition, such as neutropenia and anemia⁵. A growing body of literature has demonstrated that JAK inhibitors are safe and efficacious in multiple inflammatory skin conditions, including AD²,⁴.

Systemic JAK inhibitors

The first-generation inhibitor of JAK1/2, baricitinib, and JAK1 selective inhibitors, such as abrocitinib and upadacitinib were approved recently by the European Medical Agency (EMA) for the treatment of adult patients with moderate to severe AD. Upadacitinib has extended approval for children 12 years of age and older⁷-⁹. The approval of these systemic JAK inhibitors was a major milestone in the treatment of AD (table 1 and table 2). The safety, and efficacy with rapid relief of pruritus and clinical signs of AD explored by clinical trials (table 3) make these agents a welcome addition to the box of therapeutic options for managing AD. Currently, the monoclonal antibody dupilumab will be the main competitor. Each has its advantages, as some patients prefer a subcutaneous injection with no laboratory monitoring, whereas others may prefer the convenience of oral therapy⁴. There are no reported studies that directly compare JAK inhibitors with each other; however, a recently published network meta-analysis aimed to determine the comparative efficacy and safety of three common oral JAK inhibitors, including abrocitinib, baricitinib, and upadacitinib for moderate-to-severe AD. This network meta-analysis revealed that upadacitinib 30 mg was superior to all regimens and upadacitinib 15 mg was better than remaining regimens except for abrocitinib 200 mg in terms of Investigator’s Global Assessment scale (IGA) and Eczema Area and Severity Index (EASI) response. Moreover, abrocitinib 200 mg was superior to abrocitinib 100 mg, and baricitinib 1, 2, and 4 mg for clinical efficacy. However, upadacitinib 30 mg caused more treatment-emergent adverse effects (AE)¹⁰.

Topical JAK inhibitors

Topical treatments, including corticosteroids and calcineurin inhibitors, are considered standard-of-care therapy for most patients with AD; however, their clinical benefit is often limited by their anatomic use restrictions and local AEs, including skin atrophy, striae, and/or application site reactions. Long-term application of these drugs, particularly in sensitive areas, is not recommended owing to safety/tolerability. Thus, the need remains for a nonsteroidal topical therapy that is highly effective, well tolerated, and provides rapid and durable resolution of inflammatory lesions and pruritus¹¹.

JAK inhibitors have also been developed as a topical treatment option and are gaining attention as a treatment option for various skin diseases. Mean plasma concentrations below those achieved with the oral formulation, low incidence of AEs, and stable hematologic markers support a lack of systemic toxicity with topical JAK inhibition¹².

Delgocitinib, a first-generation pan-JAK inhibitory profile that inhibits all the JAK activities in enzyme assays, inhibits the activation of inflammatory cells, such as T cells, B cells, monocytes, and mast cells, and improves skin barrier dysfunction¹³. In a 52-week, long-term, open-label study for patients aged 16 years with mild-to-severe AD, treated with delgocitinib 0.5% ointment, the proportion of patients with mEASI-50 at week 4, 24, and 52 were 31.5, 42.3, and 51.9%, respectively. While those with mEASI-75 at weeks 4, 24, and 52 were 10.9, 22.7, and 27.5%, respectively. AEs and treatment-related AEs were reported in 69.0% of the patients. The most common AE was nasopharyngitis, followed by contact dermatitis, acne, and application site folliculitis. Study discontinuations due to AEs occurred in 17 patients (3.4%), and the most common AEs leading to study discontinuation were contact dermatitis in five patients (1.0%) and application site irritation in three (0.6%)¹⁴.

In a phase 2a study on adult patients with mild-to-moderate AD using 2% tofacitinib ointment, the mean percentage change in EASI scores from the baseline was significantly greater (p < 0.001) for tofacitinib (81.7%) compared to the vehicle group (29.9%) at week 4. Meanwhile, patients treated with tofacitinib ointment showed significant improvements in pruritus by day 2. Safety/local tolerability was generally similar for both treatments, although more adverse events were observed for a vehicle compared to tofacitinib¹⁵.

Ruxolitinib (RUX) cream, a selective inhibitor of JAK1/2, demonstrated potent anti-inflammatory effects versus vehicle with rapid and sustained itch control in these phase three studies in patients with AD. Two double-blind, randomized, vehicle-controlled trials of identical design (TRuE-AD1 and TRuE-AD2) enrolled a total of 1,249 adult and pediatric subjects aged 12 and older. Patients were randomized 2:2:1 to twice-daily RUX 0.75% cream, 1.5% RUX cream, or vehicle cream for 8 continuous weeks. The primary efficacy endpoint was the proportion of subjects at week 8 achieving IGA treatment success (IGA-TS), defined as a score of 0 (clear) or 1 (almost clear) with ≥ 2-grade improvement from baseline. Efficacy was also assessed using a ≥ 4-point improvement in Itch NRS. In TRuE-AD1/ TRuE-AD2 significantly more patients achieved IGA-TS with 0.75% RUX cream (50.0/39.0%) and 1.5% RUX cream (53.8/51.3%) vs vehicle (15.1/7.6%; p < 0.0001) at week 8. Significantly more patients in TRuE-AD1 and TRuE-AD2 achieved EASI-75 at week 8 with 0.75% RUX (56.0 and 51.5%, respectively) and 1.5% RUX (62.1 and 61.8%) vs vehicle (24.6 and 14.4%). Application site reactions were infrequent (< 1%) and lower with RUX versus vehicle. The most common treatment-related AE was application site burning sensation, which was observed primarily with vehicles (4.4%; 0.75% RUX-0.6%; 1.5% RUX-0.8%). Additionally, significant itch reductions vs vehicle were reported within 12 h of the first application of 1.5% RUX, and further reductions were observed over 8 weeks¹¹. Therefore, it is thought that topical JAK inhibitors rapidly improve AD rash and symptoms relatively safely.

Currently, OPZELURA^® (1.5% RUX cream) is approved in the United States (US) but not in Europe for the treatment of AD, which configurated a major milestone for the treatment of these patients. Table 1.

Alopecia areata

Alopecia areata (AA) is a chronic immune-mediated disease characterized by nonscaring hair loss with clinical heterogeneity¹⁶. The exact etiology of this disease is not yet elucidated, and it is thought that the hair follicle bulb immune privilege collapse is critical in the pathophysiology of the disease. Although it is not yet fully understood what causes immune privilege to collapse, triggering factors suppress immune privilege guardian expression and locally activate the innate immune system mostly via CD8 + NKG2D T cells, leading to subsequent interferon-γ (IFN-γ) production and major histocompatibility complex class I upregulation that further contribute to immune privilege breakdown¹⁶.

Current treatment options for AA, including topical, systemic, and injectable interventions, aim to immunosuppress or immunomodulate the activity of the disease, with a generally unsatisfying response and high relapse rate. Additionally, the available therapeutic options do not seem to influence the long-term course of the disease and thus, an urgent need remains for novel, more effective therapies¹⁶. The nonspecific nature of these treatment modalities, along with their variable efficacy demands effort to achieve more targeted therapies that can better target the pathways involved in the disease process¹⁷.

Local inflammation in AA is largely mediated by the JAK-STAT pathway; in this disease, there is an overexpression of proinflammatory cytokines that signal through their receptors via JAK-STAT. Additionally, this intracellular signaling network has an important role in mediating and maintaining the cytotoxic CD8 + NKG2D + T-cell reaction, which represents a driving component for AA pathogenesis. In alopecia areata, JAK1/2 and JAK1/3 lead to T-cell mediated inflammatory responses, which promote IFN-γ and IL-15 production in hair follicles and further amplify the inflammatory feedback loop¹⁶,¹⁷. Thus, it is not surprising that JAK inhibitors represent an emerging treatment option for AA¹⁶,¹⁷.

There have been a number of case reports and small clinical trials reporting promising outcomes of JAK inhibitors tofacitinib, RUX, and baracitinib for alopecia areata¹⁸. The efficacy and safety of baricitinib were assessed in two randomized, double-blind, placebo- controlled trials (BRAVE-AA1 and BRAVE-AA2) that enrolled a total of 1200 patients with AA and led to its recent approval (2022) by the EMA and the Food and Drug Administration (FDA) (Table 1), which constituted a major milestone for the treatment of AA (Table 1)⁹,¹⁹,²⁰.

Systemic Janus Kinase inhibitors

There have been several publications of clinical research studies on the efficacy of tofacitinib (oral or topical preparation) in the treatment of AA and its variants. Liu et al. 2017, conducted a retrospective study consisting of 90 patients (aged 18-70 years) diagnosed with AA, alopecia universalis, or alopecia totalis. Patients were administered oral tofacitinib 5 or 10 mg twice daily (bid) with or without prednisolone and were evaluated using the severity of alopecia tool (SALT) scoring system at baseline and then at various treatment intervals for 4-8 months. As such, 58% of patients achieved greater than 50% change in SALT score over 4-18 months of treatment, 20% of patients were complete responders and had full regrowth with > 90% reduction in SALT, whereas 56.9% were intermediate to moderate responders (25 patients intermediate and 12 patients moderate) with 51-90% reduction in SALT for intermediate responders and 6-50% reduction in SALT for moderate responders. Additionally, 23.2% of patients were identified as nonresponders with ≤ 5% reduction in SALT²¹.

Multiple case reports have examined the use of RUX in the treatment of AA. In an open-label clinical trial, Mackay-Wiggan et al. aimed to investigate RUX 20 mg orally bid in the treatment of moderate-to-severe AA. All patients received RUX for 3-6 months, followed by a 3-month observational phase to assess treatment response durability. About 9 out of 12 (75%) had significant hair regrowth and achieved the primary outcome of at least 50% regrowth, with seven of the nine responders achieving over 95% regrowth by the end of treatment²². The durability of responses was assessed in the 3-month follow-up period of treatment. Around three out of nine responders noted shedding beginning at week 3 following RUX discontinuation and had marked hair loss at week 12 off the drug; however, hair loss did not reach baseline levels. Around six out of nine responders reported increased shedding without major hair loss²².

Baricitinib is now approved for the treatment of AA (Table 1)⁹. The efficacy and safety of baricitinib once daily were assessed in two randomized, double-blind, placebo-controlled trials (BRAVE-AA1 and BRAVE-AA2) that enrolled a total of 1,200 patients with AA who had at least 50% scalp hair loss as measured by the SALT for > 6 months. In both phase III 36-week studies with extension phases up to 200 weeks, patients were randomized to placebo, 2 or 4 mg baricitinib in a 2:2:3 ratio. Both trials assessed the proportion of patients who achieved at least 80% scalp hair coverage (SALT score of ≤ 20) at week 36 as the primary endpoint. Other outcomes at week 36 included the proportion of patients who achieved at least 90% scalp hair coverage (SALT score of ≤ 10), patients with Scalp Hair Assessment PRO™ score of 0 or 1 with at least a 2-point reduction on the 5-point scale, and assessments of eyebrow and eyelash hair loss. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4 mg baricitinib, 22.8% with 2 mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9, 19.4, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4 mg baricitinib and placebo was 32.6% points, and the difference between 2 mg baricitinib and placebo was 16.6% points (p < 0.001 for each dose vs placebo). In BRAVE-AA2, the corresponding values were 32.6% and 16.1% points (p < 0.001 for each dose vs placebo). Most patients in whom the primary outcome was met had SALT scores of 10 or less at week 36. Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo²⁰. In the study BRAVE-AA2, patients who had received baricitinib 4 mg once daily since the initial randomization and achieved a SALT of ≤ 20 at week 52 were rerandomized in a double-blind manner to continue 4 mg once daily or reduced dose to 2 mg once daily. The results show that 96% of the patients who remained on baricitinib 4 mg and 74% of the patients who were rerandomized to baricitinib 2 mg maintained their response at week 76⁹.

Topical JAK inhibitors

Very limited studies have addressed the efficacy of topical JAK inhibitors in the treatment of AA¹⁷. Liu et al. in 2018 conducted an open-label, single-centre pilot study of 10 patients with AA to assess the efficacy and safety of topical tofacitinib. Patients were treated with tofacitinib 2% ointment applied bid for 6 months and were evaluated periodically for regrowth using SALT. Regrowth occurred in three patients at week 24, one patient had a SALT score percent change of 61%, while the other two patients had 18% and 25% change and seven patients had no regrowth²³. The topical efficacy of RUX has not been well studied; there are only a few data available and the results shown are still not very encouraging²⁴-²⁶.

Treatment results by route of administration and sustainability of response with JAK inhibitors

Phan et al. conducted a meta-analysis that sought to determine the expected response of AA to JAK inhibitor therapy and factors that influence response and recurrence rates. From 30 studies and 289 cases, there were 72.4% responders, 45.7% good responders, and 21.4% partial responders. The mean time to initial hair growth was 2.2 ± 6.7 months. The oral route, regardless of the specific agent of oral JAK inhibitor used in treatment, was significantly associated with four times higher odds of achieving a response when compared to topical therapy¹⁸. Oral JAK inhibitor treatment was also associated with seven times higher odds of achieving a good response (50-100% regrowth) than a partial response (5-50% regrowth) compared to topical treatment, with no difference between tofacitinib, RUX, or baracitinib¹⁸. Thus, so far, oral JAK inhibitors have demonstrated a higher efficacy in the treatment of AA than topical JAK inhibition¹⁸.

The sustainability of treatment results with JAK inhibitors used for AA management has been a topic of concern for many researchers and clinicians¹⁷. In clinical practice, it has been observed that AA frequently recurs after cessation of JAK inhibitors therapy¹⁷,¹⁸,²⁷. In a systemic review and meta-analysis, it has been observed that all cases of relapse were associated with cessation of therapy, on average, after 2.7 months. These results suggest that the therapeutic response may only be maintained whilst the patient is on JAK inhibitor treatment and that once ceased, relapse of AA may be expected within 3 months¹⁸.

Vitiligo

Vitiligo is an acquired, idiopathic, and multifactorial autoimmune disorder characterized by patchy depigmentation in the skin, hair or both²⁸. Depigmentation that characterizes vitiligo is caused by progressive melanocyte destruction. Activated CXCR3⁺ CD8⁺ T cells promote melanocyte detachment and apoptosis through INF-γ (interferon-gamma), which stimulates the JAK/STAT-1 pathway leading to the expression of INF-stimulated genes with further recruitment of CXCR3⁺ CD8⁺ T cells and the formation of a positive-feedback loop. The IFN-γ-chemokine axis has been identified as a potential pathway in the initiation and progression of vitiligo²⁸-³⁰. JAK inhibitors are a promising targeted treatment for vitiligo.

Systemic and topical JAK inhibitors

In vitiligo mouse models, neutralization of IFN-γ with antibody prevents CD8⁺ T-cell accumulation and depigmentation, suggesting a therapeutic potential for this approach²⁹. The JAK/STAT pathway plays a central role in vitiligo and inhibition of this intracellular signaling network has been shown to block IFN-γ signaling and contribute to repigmentation in individuals with vitiligo³¹.

Tofacitinib can induce significant repigmentation in patients with vitiligo; however, concomitant stimulation of melanocytes via skin exposure to ultraviolet light appears to be required to achieve repigmentation³². Baricitinib differs from tofacitinib in that it preferentially inhibits JAK1/2 rather than JAK 3. Given IFN-γ is mediated via JAK1/2, it has been suggested that JAK inhibitors, which predominantly inhibit these JAKs may be more effective than others³². A small number of studies have addressed the efficacy of tofacitinib and baricitinib in the treatment of vitiligo (Table 4) and further research is necessary to determine their safety and efficacy.

Oral RUX interferes with IFN-γ signaling by preferential inhibition of JAK 1 and JAK 2 and has been shown to improve skin conditions in some studies²⁸,³¹. Rapid skin repigmentation on oral RUX was observed in a patient with coexistent vitiligo and AA, with marked declines in serum CXCL10 levels (chemokine ligand 10) after administration³¹. Chemokine ligand 10 (CXCL10), an IFN-γ-induced chemokine, was shown to be critical for autoreactive T-cell recruitment to the skin during the progression and maintenance of vitiligo³³,³⁴. However, topical administration resulted in a higher concentration in the epidermis and dermis, resulting in near-complete inhibition JAK/STAT signaling in this tissue³⁵. In contrast, only partial inhibition of downstream signaling was predicted to occur after oral dosing. Therefore, dermis concentrations of RUX cream are fully effective, whereas corresponding plasma concentrations are negligible. Consequently, this distribution profile should maximize the efficacy of RUX cream in the skin while minimizing the potential for deleterious systemic effects³⁵. Interestingly, according to meta-analyses, it also seems that topical JAK inhibitor formulations perform comparably to oral counterparts³⁶. Two double-blind, randomized, vehicle-controlled trials (TRuE-V1 and TRuE-V2) aimed to evaluate the efficacy and safety of RUX cream for the treatment of vitiligo (Table 4). In both trials, subjects were randomized 2:1 to treatment with 1.5% RUX cream bid or vehicle cream bid for 24 weeks, followed by an additional 28 weeks of treatment with 1.5% RUX cream bid for all subjects³⁷,³⁸. Lesions on the face were assessed with the facial vitiligo area scoring index (F-VASI) and lesions on the total body (including the face) were assessed with the total body vitiligo area scoring index (T-VASI). At week 52, approximately 50% of patients achieved ≥ 75% improvement in the F-VASI75 compared to the F-VASI75 improvement from baseline reported for these patients at week 24 (the primary endpoint of the study), which was approximately 30%. Additionally, a greater proportion of patients at week 52 achieved ≥ 50% improvement in T-VASI50, and over one-third of patients achieved a vitiligo noticeability scale response. Further improvement in percentage change from baseline in facial body surface area with the application of RUX cream was also observed. RUX cream was well tolerated, the most common treatment-related TEAEs were application site acne and pruritus, no serious TEAEs were considered related to treatment and there were no significant changes in hemoglobin or platelet levels³⁷,³⁸. Based on the exciting results of TRuE-V1 and TRuE-V2, RUX was recently approved by the FDA for the topical treatment of ≥ 12 years of patients with nonsegmental vitiligo (Table 1)³⁹.

It appears that vitiligo located on the face responds more robustly to therapy than nonfacial lesions³⁶,⁴⁰,⁴¹. Rothstein et al. conducted an open-label trial of bid RUX 1.5% cream in 12 patients and showed a 23% improvement in VASI scores at week 20. Four patients had significant facial involvement at baseline and had a 76% improvement in facial VASI scores⁴¹.

Several studies have shown superior repigmentation rates in patients with JAK inhibitors and concomitant UV exposure. Joshipura et al. reported significant repigmentation in sun-exposed areas in two patients treated with either topical RUX 1.5% bid or oral tofacitinib 5 mg bid⁴². Another retrospective case series of 10 patients treated with oral tofacitinib showed that five patients achieved some repigmentation at sites of sun exposure or UVB phototherapy³². Phan et al. found that a good response rate or repigmentation rate > 50% was found in 57.8% of patients treated with JAK inhibitors, but when used concurrently with phototherapy, the good response rate improved to 88.9%³⁶. These data suggest that substantial repigmentation in vitiligo using JAK inhibitor may require photoactivation to stimulate melanocytes, which supports a multimodal therapeutic approach.

A few registered ongoing trials are focusing on the use of second-generation JAK inhibitors in the treatment of patients with vitiligo (https://clinicaltrials.gov/).

JAK inhibitors appear to be a promising treatment for vitiligo and the recent approval of RUX in the US was an exciting milestone for the treatment of these patients; however, further studies are required to confirm efficacy, establish safety, and investigate the durability of repigmentation.

Psoriasis vulgaris

Psoriasis (PSO) is a common chronic inflammatory skin disease with well-defined pathogenesis in which IL-23/Th17 signaling axis plays a central role. In the last years, numerous targeted treatments have been developed for PSO². The majority of those affected with PSO have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease⁴³. The implication of multiple cytokines like IL-6, IL-22, IL-23, or INF-γ in PSO pathogenesis that signal through the JAK/STAT pathway suggests that the inhibition of JAKs could be a viable therapeutic option for this disease²,⁴³. Additionally, recent studies have shown that PSO is mainly a JAK3 and JAK1-driven disease with a predominance of STAT3 signaling⁴⁴. STAT3 mediates the signal of most cytokines that are involved in disease pathogenesis, including the central IL-23/IL-17/IL-22 axis, and active STAT3 is found in psoriatic skin⁴⁵,⁴⁶. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or the family of upstream activators JAKs offers additional therapeutic options⁴⁶. Additionally, JAK inhibitors are less expensive when compared to biologics³.

Systemic JAK inhibitors

Tofacitinib, a pan-JAK inhibitor with a predominant anti-JAK3 effect, is the most studied oral JAK inhibitor for the treatment of chronic plaque PSO³. Two-phase three randomized place-controlled trials (OPT Pivotal 1 and OPT Pivotal 2) demonstrated the efficacy of tofacitinib 5 or 10 mg bid over placebo in patients with moderate to severe PSO, improvement in nail PSO was also observed⁴⁷. Nevertheless, tofacitinib 10 mg bid was more effective compared to 5 mg bid dosage⁴⁸. Bissonnette et al. showed that continued tofacitinib worked best in PSO and that treatment discontinuation was associated with a risk of relapse; however, among relapsers, up to 60% recaptured response with tofacitinib⁴⁹. Tofacitinib is approved by the FDA and EMA for the treatment of psoriatic arthritis, but the approval was not extended for PSO (Table 1). It is difficult to see tofacitinib achieving approval for treating PSO at the 5 mg bid dose, and there are safety concerns, as noted by the FDA, of the more effective 10 mg bid dose⁴⁸. Numerous oral JAK inhibitors, such as abrocitinib, solcitinib, itacitinib, peficitinib, were tested for the treatment of PSO⁵⁰-⁵³.

Tyrosine kinase (TYK2) inhibitors, such as deucravacitinib, are promising therapeutic options for the treatment of PSO, given that TYK2 is responsible for mediating immune signaling of IL-12, IL-23, and type I interferons without interfering with other critical systemic functions as other JAK proteins do⁵⁴-⁵⁷. Unlike TYK2, JAK1, 2, and 3 are responsible for mediating a series of signals that support broader systemic responses, such as hematopoiesis, myelopoiesis, lipid metabolism, and bone regulation. Consequently, JAK1, 2, and 3 inhibitors, such as tofacitinib, baricitinib, and ruxolitinib, a raised safety concerns and their clinical research in PSO have been mostly abandoned due to their unfavorable efficacy/safety ratio⁵⁸.

POETYK PSO-1 and 2 enrolled 1686 patients with moderate-to-severe PSO. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. These results were maintained through week 52, with over 65% of patients achieving PASI75 at this point in POETYK PSO-1⁵⁷,⁵⁹. A reduction in signs and symptoms was also reported by patients, with a greater impact on itch. It was well tolerated and safe⁵⁷,⁵⁹.

Deucravacitinib was recently approved by the US for the treatment of patients with moderate to severe plaque PSO and had the potential to become an efficacious, safe, and well-tolerated treatment (Table 1)⁶⁰. Being an oral drug and an IL-23 inhibitor, its approval may have a great impact on clinical practice. Nevertheless, further studies are needed to evaluate long-term treatment effects.

Topical JAK inhibitors

In the past decades, the major advances in PSO therapy have been in systemic agents, such as immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged⁴³. It has been recently reported that psoriatic keratinocytes overexpress JAK1 and 3, making them ideal targets for topical treatment with specific JAK inhibitors⁴⁴. However, so far, the efficacy of topical JAK inhibitors for PSO is not robust²,³.

Tofacitinib showed interesting results as an oral agent for the treatment of PSO and topical therapy is being studied as well (Table 5). Although systemic concentrations of tofacitinib were found in patients treated with topical formulations, serologic levels were 40-fold lower than exposures from the lowest dose tested (2 mg bid) in a previous study of oral tofacitinib in patients with moderate-to-severe PSO⁶¹.

Ruxolitinib (RUX) has been tested in topical formulations to treat mild to moderate PSO with favorable results Table 5 ²,³. Punwani et al. showed that transcriptional markers of immune cell lineage/activation in lesional skin were reduced by topical RUX, with correlations observed between clinical improvement and decreases in markers of T helper 17 lymphocyte activation, dendritic-cell activation and epidermal hyperplasia. Additionally, there was no significant inhibition of STAT3 in peripheral blood cells, suggesting limited systemic exposure⁶². In conclusion of this study, topical RUX in patients with active psoriatic lesions modulates proinflammatory cytokines⁶². Larger studies are needed to clearly establish the efficacy and safety profiles of topical RUX for the treatment of PSO, however, the data available suggest that it may be a promising agent.

Adverse effects and safety profile

JAK inhibitors that are currently approved for the autoimmune disease have an associated black warning box for the potential increased incidence of serious infections, mortality, malignancy, major adverse cardiovascular events (MACE), and thrombosis. This warning was added recently based on results from the ORAL Surveillance study of tofacitinib vs tumor necrosis factor α inhibitors (TNF inhibitors) in rheumatoid arthritis⁶³. In this randomized, open-label, noninferiority, safety endpoint trial involving patients with active rheumatoid arthritis who were 50 years of age or older and had at least one additional cardiovascular risk factor, patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 or 10 mg bid or a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer, excluding nonmelanoma skin cancer, were higher with the combined tofacitinib doses (3.4 and 4.2%, respectively) than with a TNF inhibitor (2.5 and 2.9%), the noninferiority of tofacitinib was not shown.

Safety data for tofacitinib is largely derived from clinical trials in rheumatoid arthritis and PSO, and data form RUX is from clinical trials in myelofibrosis and polycythemia vera⁶⁴.

Cohen et al., showed that the risk of infection and overall mortality in patients treated with tofacitinib is not significantly different from that observed with other biologic agents⁶⁵. On the contrary, the ORAL Surveillance studies showed the incidence of adjudicated opportunistic infections was higher with tofacitinib than with a TNF inhibitor, however, primarily owing to the incidence of herpes zoster and all herpes zoster (nonserious and serious)⁶³. JAK inhibitors are associated with an increased risk of varicella-zoster virus reactivation⁶³,⁶⁶. The higher rates of herpes zoster infection among patients treated with tofacitinib may be related to its mechanism of action of tofacitinib, which involves a decrease in lymphocyte activation and proliferation. Additionally, the human antiviral defense is also associated with intact responses to type I IFN and type II IFN, which receptors signal via JAK-1. Because tofacitinib inhibits signaling through JAK-1, it is possible that such a mechanism is related to an increased risk of herpes zoster infection⁶⁵. Dose-related increases in lipid levels, such as total cholesterol, LDL cholesterol, triglycerides and HDL cholesterol, were observed in clinical trials; elevations were observed at 12 weeks and are generally mild⁶⁷,⁶⁸.

Thrombosis, including deep vein thrombosis (DVT), pulmonary embolism (PE) and arterial thrombosis, has been reported in patients receiving JAK inhibitors used to treat inflammatory conditions. In the ORAL Surveillance study, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers⁶³.

Cytopenia is another potential adverse effect of JAK inhibitors, primarily JAK2 inhibition because signaling via JAK2 is utilized by erythropoietin, thrombopoietin, and G-CSF⁶⁴. In the treatment of bone marrow disorders with RUX, such as myelofibrosis and thrombocytopenia can be limiting⁶⁹; however in a study of 12 patients with AA treated with RUX for up to 6 months, neither this nor other cytopenia was observed²². It may be theorized that patients with healthy bone marrows are less vulnerable to cytopenia observed with JAK2 inhibition⁶⁴.

In addition, respiratory infections and gastrointestinal side effects, such as nausea and diarrhea were observed⁷⁰,⁷¹. Increased levels of transaminases, creatinine phosphokinase, and serum creatinine have also been observed; these changes have generally been graded as mild⁷¹. For topical applications, acne, and pruritus are often described⁷².

However, the long-term safety of JAK inhibitors is still not completely understood, and as investigations of this promising drug class continue, the safety profile should become clearer. In recent years, efforts have been made to develop selective JAK inhibitors with directed targets and, consequently fewer side effects.

Possible future applications

Since the JAK/STAT signaling pathway plays a crucial role in many cytokines, a variety of inflammatory dermatological disorders may benefit from this class of immunomodulators. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for the treatment of other treatment-refractory dermatologic conditions in which activation of the JAK/STAT pathway plays a role, such as dermatomyositis, graft vs host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, pyoderma gangrenosum, cutaneous sarcoidosis, granuloma annulare, blistering skin diseases, etc.²,⁶⁴. The management of chronic hand eczema (CHE) remains a challenge; in a recent phase 2a trial, topical use of delgocitinib ointment resulted in clearance of CHE after 8 weeks of treatment in a significantly greater number of patients than vehicle and was well tolerated⁷³. The results from this study suggest that topical delgocitinib may provide therapeutic benefits to patients with CHE with inadequate responses to topical corticosteroids⁷³.

Conclusion

The well-established efficacy of JAK inhibitors in inflammatory disorders, particularly rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, suggests the potential of their positive effects in a myriad of dermatological dermatoses as well. Dysregulation of the JAK/STAT pathway plays a role in the pathogenesis of many dermatologic diseases, including vitiligo, alopecia areata, PSO, and AD. JAK inhibitors can either be taken orally or have also been developed as a topical treatment option which constitutes a great advantage of this drug class. In the future, JAK inhibitors could prove to be a real alternative therapy for some inflammatory skin diseases. More studies are necessary to determine the doses that will optimize the efficacy, cost-effectiveness, and safety of this drug family for potential use in skin conditions in the long-term Table 6.