¹Texas A&M College of Medicine, Dallas, TX, USA
²University of Texas Medical Branch, Galveston, TX, USA
³University of Texas Health Science Center McGovern Medical School, Houston, TX, USA
⁴Center for Clinical Studies, Webster, TX, USA
⁵Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
None.

Funding resource:
None.

*Co-first authors

Abstract:
Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-in-class, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.

Key Words:
Janus kinase inhibitors, JAK inhibitors, JAK-STAT, tyrosine kinase inhibitors, TYK2 inhibitors, dermatology, ruxolitinib, abrocitinib, upadacitinib, tofacitinib, baricitinib

Introduction

Autoimmune and inflammatory diseases are common and on the rise, affecting 3% to 5% of the Western population.^1-4 These disorders are thought to evolve from a complex, incompletely understood interplay of host genetics, microbiota, and environmental factors that contribute to dysregulated T-cell and B-cell activity against the host, leading to tissue damage.¹ In the realm of dermatology, there have been considerable advances enabling examination of deep molecular processes and immunological pattern analyses that allow us to better understand the pathophysiological mechanisms of autoimmune and inflammatory skin diseases.^5-8 Furthermore, skin biopsy analysis has facilitated our ability to characterize the influencing factors such as cytokines, receptors, and signaling molecules in order to develop targeted therapeutic agents.⁵

Various therapeutics can be used to attenuate the immune response either through direct suppression of T-cell activity or by directly or indirectly blocking cytokines. Glucocorticoids have long been used to suppress an aberrant immune response; however, they have the drawback of eliciting nonspecific immunosuppressive effects. Many cells express steroid receptors and adverse effects of glucocorticoids are common, thus their use in the management of chronic autoimmune or inflammatory diseases should be cautioned given their side effect profile.¹ Cytokine activity can likewise be inhibited by biologic therapy. Most recently, inhibitors of signaling proteins have been introduced for the treatment of psoriatic arthritis and rheumatoid arthritis.¹ These inhibitors target the Janus kinases (JAKs) family of proteins by modulating the inflammatory process through activation of intracytoplasmic transcription factors called signal transducer and activator of transcription (STAT).⁵ STATs get activated, dimerize, and translocate into the nucleus where they modulate the expression of various genes.

Inflammation of the skin relies on this interaction between cytokines, as well as immune and tissue cells, to propagate the different distinct inflammatory cascades. Because of these unique mechanisms, JAK-STAT inhibitors are gaining traction in clinical development as new potential therapeutics for various inflammatory dermatological conditions.

Aims and Objectives

The aim of this literature review is to provide updates on the mechanism of JAK inhibitors and assess their efficacy in the treatment of alopecia areata, psoriasis, psoriatic arthritis, atopic dermatitis, dermatomyositis, and vitiligo. A class-wide safety review and future considerations will also be discussed.

Methods

A review of the literature regarding the mechanism of action and efficacy of JAK inhibitors in skin diseases was done by searching the PubMed, Scopus, and EBSCO databases. The following keywords were used to find articles: ‘Janus kinase-inhibitors’, ‘JAK-inhibitors’, ‘JAK-inhibitors pathway’ combined with ‘dermatology’, ‘atopic dermatitis’, ‘alopecia areata’, ‘psoriasis’, ‘dermatomyositis’, ‘vitiligo’, ‘side effects’, and ‘safety’.

JAK-STAT Signaling Pathway

The JAK-STAT pathway is activated by numerous different cytokines, which bind directly to the Janus kinase receptor and initiate transphosphorylation. This ligand-mediated receptor binding brings two JAKs in close proximity, allowing for its autophosphorylation and activation. The activated JAKs subsequently lead to the phosphorylation of the tyrosine residues on the receptor. The phosphorylation of the tyrosine residues on the receptor recruits STATs, inactive latent transcription factors in the cytoplasm. Using their SH2 domain, the STATs bind to the phosphorylated tyrosine residue on the receptor and are phosphorylated by JAKs. This causes the STATs to dissociate from the receptor, dimerize, and travel from the cytosol into the nucleus where they are able to modify gene transcription.⁹ There are four members within the JAK family of kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), and the STAT family has six proteins (STAT1, STAT2, STAT3, STAT5A/B and STAT6).¹⁰

One or more members of the JAK and STAT families may be recruited by any specific receptor influencing different aspects of immune cell development and function.¹¹ Various combinations of different types of JAK proteins can be associated with several receptors that have variable effects on specific signaling pathways of the immune system, such as the combination of JAK1 and JAK3 related to cytokine receptors fundamental for the function of lymphocytes or the TYK2/JAK2 combination that is essential for the signaling of interferon (IFN)-a, interleukin (IL)-12, and IL-23 receptors.¹¹ The varied distribution amongst different JAK/STAT proteins across distinct cell types shows how a genetic defect of JAKs or STATs might determine various clinical conditions, such as JAK3 deficiency in severe combined immunodeficiency syndrome.¹¹ Additionally, the modulation or inhibition of the activity of these intracellular pathways represents a potential target in immune mediated diseases such as psoriasis and atopic dermatitis.^11,12

The mechanism of action of JAK inhibitors targets the kinase component of JAKs. This prevents the JAK protein from phosphorylating, thus halting the intracellular signaling transduction.¹ First generation JAK inhibitors, such as baricitinib, ruxolitinib, and tofacitinib, inhibit many JAKs. For example, tofacitinib, which is FDA-approved for psoriatic arthritis, inhibits JAK1 and JAK3 mainly, with some selectivity towards the JAK2 isoform.¹³ The rationale behind the nonselective, multi-JAK inhibition is the notion that blocking multiple JAKs may enhance therapeutic efficacy.¹⁴ On the other hand, the second generation JAK inhibitors are more selective to particular JAK isoforms to limit adverse effects and possibly maintain treatment efficacy. Deucravacitinib is a second generation JAK inhibitor that specifically targets TYK2.^13-15 This drug has shown efficacy in the treatment of systemic lupus erythematosus and is currently in a phase III trial for psoriasis.¹ Research into the efficacy of JAK inhibitors continues at a rapid pace as a host of new drug candidates are under development, thus shedding light on their mechanisms in treating rheumatological and dermatological diseases.

Applications in Dermatology

JAK inhibitors have shown significant clinical efficacy in patients with psoriasis and psoriatic arthritis.¹ Currently, the FDA-approved JAK inhibitors in dermatology are oral tofacitinib and upadacitinib for the treatment of psoriatic arthritis^1,2 and topical ruxolitinib for mild to moderate atopic dermatitis. However, the use of first and second generation JAK inhibitors in other dermatological diseases such as alopecia areata, atopic dermatitis, dermatomyositis, vitiligo, and systemic lupus erythematosus is being heavily investigated in numerous clinical trials (Table 1).¹³

Alopecia Areata (AA)

AA is a chronic, autoimmune non-scarring hair loss disorder that involves the destruction of hair follicles by autoreactive CD8 T cells.³ It classically presents as smooth, circular hair loss patches with no erythema, pain, pruritus, or inflammation. JAK-STAT dependent cytokines IFN-γ and IL-15 contribute to signaling cascades through JAK1 and JAK3.³ They lead to the proliferation of autoreactive T cells that are active in AA.

Systemic and topical administration of JAK inhibitors have shown to be beneficial in patients with AA. In 2014, a case report was published featuring a patient with diagnosed alopecia universalis and psoriasis. While using tofacitinib to treat psoriasis, the patient experienced complete regrowth of body and scalp hair, as well as eyelashes and eyebrows.⁴ Since then, several other case reports and studies have been published illustrating the successful treatment of AA using JAK inhibitors (primarily tofacitinib, ruxolitinib, and baricitinib).^5-8,10 However, relapse of hair loss has been reported in the literature after drug discontinuation.⁹ In a recent phase II trial, ritlecitinib and brepocitinib were found to be well tolerated and led to clinically meaningful improvements in hair growth. Approximately 25% and 34% of patients treated with ritlecitinib and brepocitinib, respectively, saw near-complete regrowth.¹⁶ Topical JAK inhibitors for the treatment of localized AA could be proven useful, but more studies are needed for validation. In the case of topical tofacitinib, one pilot study of patients treated with 2% tofacitinib twice daily revealed a poor response with only 3 responders.17Another study describes almost complete regrowth of hair with topical 2% tofacitinib every 12 hours for 7 months.¹⁷ Topical ruxolitinib has also shown various responses in AA, with one study showcasing regrowth at 28 weeks in 5 patients in the area treated. In adolescent patients, topical ruxolitinib 0.6% applied twice daily showed complete growth of the eyebrows observed at 3 months, while there was only 10% regrowth of the scalp.¹⁷ Currently, positive results from numerous early phase clinical trials have increased interest in this area. Further investigation is needed to determine optimal dosing of JAK inhibitors in AA and whether maintenance therapy is required.

Psoriasis and Psoriatic Arthritis

Psoriasis has been the most studied dermatological disease in relation to JAK inhibitors. JAK-STAT dependent cytokines are implicated in the pathogenesis of psoriasis, with IL-12 and IL-23 being fundamental mediators.¹¹ Several phase III randomized controlled clinical trials have shown significant reduction, up to 75%, in the Psoriasis Area and Severity Index (PASI 75) when patients were treated with tofacitinib at both 5 mg and 10 mg twice daily doses, with improvement seen in a dose dependent manner.¹² Improvements from the treatment were sustained up to 52 weeks and side effects appeared to be similar in both dosing regimens. Furthermore, a phase III non-inferiority trial determined that tofacitinib at 10 mg twice daily was non-inferior to etanercept 50 mg twice weekly.¹⁴ Nevertheless, the FDA did not approve tofacitinib for psoriasis, likely attributable to the need for more safety data on the 10 mg dose.

Several other JAK inhibitors have demonstrated promising results. A phase IIb clinical trial of baricitinib showed more patients achieved PASI 75 when compared to placebo in the treatment of moderate-to-severe plaque psoriasis.18 Deucravacitinib, a novel, selective TYK2 inhibitor has demonstrated to be more advantageous in the treatment of moderate-to-severe plaque psoriasis when compared to placebo and apremilast in a phase III clinical trial.¹⁹ Patients achieved PASI 75 after 16 weeks of treatment, with the overall safety of the drug being consistent with previous results.¹⁹

As opposed to systemic therapy, medications administered topically generally have more favorable safety profiles given less systemic absorption. Topical formulations of ruxolitinib and tofacitinib have been tested in phase II clinical trials for psoriasis.²⁰ Side effects in both these trials were mild and there were no signs of systemic symptoms in any of the patients. Treatment with topical ruxolitinib twice daily showed improvement in psoriasis lesion size compared with placebo.²¹ Improvement in psoriasis was also noted in patients treated with topical tofacitinib. Discontinuation of the topical drugs led to worsening of psoriasis.²⁰

Tofacitinib was FDA-approved in December 2017 for the treatment of patients with psoriatic arthritis who have had little to no improvement in their symptoms using methotrexate or other disease-modifying antirheumatic drugs.¹³ The decision was based on the results of two phase III clinical trials that showed statistically significant improvements in American College of Rheumatology 20 (ACR 20) response at 3 months when patients were treated with tofacitinib 5 mg and 10 mg twice daily.¹³ In a recent 24-week, phase III trial, oral upadacitinib was assigned to patients with psoriatic arthritis at a dose of 30 mg or 15 mg once daily, while other patients received either placebo or subcutaneous adalimumab 40 mg every other week. Results showed that the ACR 20 response rate was significantly higher for patients receiving the two doses of upadacitinib versus placebo. Furthermore, only the 30 mg dose of upadacitinib was shown to be superior to adalimumab.²²

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common, chronic and pruritic inflammatory skin diseases. The pathogenesis of this disease is fueled by functional impairment of the epidermal barrier and abnormal immune activation. IL-4 is one of the main culprits in AD known to play a pivotal role in signaling through the JAK-STAT pathway.^1,14

Oral tofacitinib was reported to be efficacious in 6 patients with moderate-to-severe refractory AD. Tofacitinib 5 mg twice daily or daily for 14 weeks led to a decrease in the average Severity Scoring of Atopic Dermatitis (SCORAD) index by approximately 55%.²³ Moreover, the study reported significant reduction in pruritus scores as well. A recently published, randomized, double-blinded, placebo-controlled phase III clinical trial showed that the treatment of moderate-to-severe AD with oral abrocitinib resulted in greater reductions in signs and symptoms of the disease, as well as greater itch response when compared to dupilumab and placebo.²⁴ Abrocitinib’s pending FDA approval has been delayed for an unspecified amount of time as data analysis continues.²⁵ In multiple phase III clinical trials, upadacitinib has been shown to improve skin and itch symptoms in adolescent and adult patients with moderate-tosevere AD.^26,27

Topical JAK-STAT treatments such as tofacitinib, ruxolitinib and delgocitinib have also shown promise in the treatment of AD, with topical delgocitinib being approved in Japan under the trade name Corectim^® and topical ruxolitinib (Opzelura™) receiving FDA approval for mild to moderate AD.²⁸ Topical tofacitinib 2% every 12 hours in 69 patients with mild to moderate AD for 4 weeks led to an 81.7% reduction in Eczema Area and Severity Index score after 4 weeks.²⁸ Topical ruxolitinib was also found to have a therapeutic benefit for patients by week 4 with each variant of ruxolitinib regimen; the drug rapidly improved pruritus and was well tolerated.²⁸ Phase I and phase II studies of delgocitinib proved the therapeutic efficiency of the medication with respect to severity and pruritus, with pruritus improving 1 day after initiating treatment.²⁸

Evidence for clinical efficacy of JAK inhibitors in the treatment of AD has been shown in several other phase II and III clinical trials, forging a possible future when these drugs may become mainstay therapy for the disease.^29-32

Dermatomyositis

Dermatomyositis is an autoimmune myopathy that is characterized by symmetric proximal muscle weakness and rash. Pathogenesis of the disease is mediated by CD4 lymphocytes and complement activation. There have been several reported cases demonstrating the efficacy of JAK inhibitors in treatmentrefractory dermatomyositis.^33-36 A case series of three patients treated with tofacitinib reported that they had improved significantly in their Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.³⁵

Additionally, one case reported a patient with myelofibrosis and concomitant refractory dermatomyositis who improved significantly while on ruxolitinib.³³ Nonetheless, it is unknown whether the improvement of the patient’s dermatomyositis was an indirect effect of treating myelofibrosis or a direct effect of ruxolitinib-mediated JAK inhibition. Furthermore, another case report of a patient with dermatomyositis experienced significant improvement in her cutaneous disease, arthritis, and muscle strength while being treated with tofacitinib.³⁶

Vitiligo

Vitiligo is an autoimmune condition characterized by absence of pigmentation due to loss of melanocytes. While the exact etiology of the disease is unknown, evidence from literature has shown that the destruction of melanocytes is mediated by CD8 T cells.^1,37 As with AA, IFN-γ plays a vital role in the pathogenesis of vitiligo, thus making this disease susceptible to treatment with JAK inhibitors.¹ For example, a patient with generalized vitiligo showed near complete repigmentation of areas in the hands, forearms, and face over 5 months while on tofacitinib.³⁸ However, discontinuation of the drug led to depigmentation in affected areas.³⁸

An additional case report of a patient with both AA and vitiligo experienced hair regrowth and repigmentation while being treated with ruxolitinib.³⁹ As is the case with the previous patient mentioned, depigmentation occurred with discontinuation of the drug. Currently, topical ruxolitinib is in a phase 3 clinical trial to evaluate its efficacy and safety in treatment of vitiligo.⁴⁰ Clinical trials are vital for clarifying the role of JAK inhibitors in
the treatment of vitiligo.

Other Dermatologic Conditions

There is evidence from the literature suggesting that JAK inhibitors are efficacious in the treatment of refractory dermatologic cases or rare diseases with no effective therapies – chronic mucocutaneous candidiasis, cutaneous sarcoidosis, mastocytosis, polyarteritis nodosa, hypereosinophilic syndrome, and chronic actinic dermatitis. Data from case reports and case series hints at potential broader use for JAK inhibitors in the field of dermatology.^1-2,41

Adverse Effects and Safety Profile

The JAK inhibitors that are approved for autoimmune disease have an associated black box warning for the potential increased incidence of malignancy, serious infections, and thrombosis based on data from oral use in rheumatoid arthritis.¹ Tofacitinib and baricitinib have the most data on their safety and side effect profiles. However, the long-term safety of JAK inhibitors is still not completely understood. Current data suggests the safety of JAK inhibitors may be comparable to other biologics, and as investigations of this promising drug class continue, the safety profile should become more clear.¹ According to the literature, JAK inhibitors may potentially increase the risk of malignancies, as they could impair the immune system’s surveillance mechanism to vet inconspicuous cells that could eventually become cancers.¹ The rate of serious infections in patients treated with JAK inhibitors is comparable to that of other biologic agents such as TNF-a,^1,20 though there is an increased risk of herpes zoster with JAK inhibitor usage.^1,21 Baricitinib, tofacitinib, ruxolitinib and upadacitinib all include warnings for potential deep vein thrombosis, pulmonary embolism, and arterial thrombosis.^1,18 Though these risks appear to be low and dose dependent, additional studies are needed to determine the exact mechanism behind it’s pro-thrombotic effects.^1,37 Additional adverse effects include gastrointestinal perforations, hyperlipidemia, as well as impaired drug metabolism due to interaction with the CYP3A4 system.^1,42

Discussion

There is an increasing body of evidence that suggests JAK inhibitors may be an effective treatment for various inflammatory skin conditions. However, numerous cytokines and immunomodulating molecules act via the JAK-STAT pathway and blunting its activity may have unintended consequences. Long-term follow up studies are needed to establish treatment guidelines and evaluate the risk-benefit profile of JAK inhibitors. As mentioned before, tofacitinib was found to be non-inferior to etanercept for plaque psoriasis, but more studies are needed to compare the efficacy of JAK inhibitors to biologics currently approved for dermatologic use.⁴³ Lastly, future studies should assess the utility and safety of JAK inhibitors in pregnancy and for the pediatric population.

Conclusion

Many inflammatory cytokines involved in the pathogenesis of skin disorders signal via the JAK-STAT pathway. Thus, this drug class has the potential for broad therapeutic utility within dermatology. Currently, JAK inhibitors are only FDA approved for dermatologic, rheumatologic, and hematologic conditions. Recent studies show the utility of JAK inhibitors in treating atopic dermatitis, psoriasis, psoriatic arthritis, vitiligo, and alopecia areata. However, more robust studies are needed to assess long-term safety and establish treatment guidelines. JAK inhibitors are poised to become important additions to the therapeutic arsenal for a wide range of inflammatory skin conditions.

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¹Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
²Texas A&M University College of Medicine, Dallas, TX, USA
³Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract
Epidermolysis bullosa (EB) is a group of rare mucocutaneous fragility disorders often presenting in infancy and early childhood with painful blistering of the skin and mucous membranes. The severity of EB blister burden varies by disease subtype. Studies have shown that patients with generalized severe epidermolysis bullosa simplex (EBS), a variant characterized by extreme fragility, develop blisters in the setting of overproduced, mutated K14 protein, a component of the intermediate filament integral in keratinocyte stability, and constitutive activation of interleukin (IL)-1, a pro-inflammatory cytokine that promotes the hyperproliferation of keratinocytes. Diacerein, a rhein prodrug and anthraquinone, has been shown to reduce expression of K14 and inhibit IL-1 converting enzyme. In clinical trials, topical 1% diacerein was shown to be an effective and safe, non-invasive treatment for patients suffering from EBS. This review examines the clinical trials of topical diacerein and its role in EBS. Diacerein ointment was granted US FDA Rare Pediatric Disease designation in May 2018 and Fast Track development designation in August 2018.

Key Words:
blistering, diacerein, epidermolysis bullosa, treatment

Introduction

Epidermolysis bullosa (EB) is a group of rare genetic diseases that causes fragile blistering of the skin.¹ EB presents most commonly in infancy and early childhood, but in some cases it can present later in adolescence.² Painful skin blisters often manifest spontaneously or secondary to friction against the skin, minor injury, or even from heat.³ Patients with EB are often called “Butterfly Children,” as their skin is as fragile as the wings of a butterfly.⁴ This inherited disease not only causes blister formation of the skin, but also can occur within mucosal membranes such as the oral cavity and the respiratory, gastrointestinal, and genitourinary tracts.^5,6 The severity of EB varies with the type and inheritance pattern of the disease.⁴ Milder forms commonly resolve with time, but severe forms are associated with more painful and often disabling blistering, scarring, and deformation that can lead to life-threatening health complications.¹

Pathogenesis of Epidermolysis Bullosa

EB often results from either an autosomal dominant (AD) or autosomal recessive (AR) genetic defect.⁶ Mutations of genes encoding integumentary proteins are the most common causes of poor integrity and skin fragility that lead to blistering in patients with EB.⁵ EB has been categorized into 4 major types, the most common of which is epidermolysis bullosa simplex (EBS) with an incidence of about 1 in every 25,000-50,000 people.⁷ EBS is usually inherited in an AD pattern. Defects frequently occur in the keratin filament genes, KRT5 and KRT14, and these mutations lead to destabilization of keratinocyte cytoskeletons within the epidermis. EBS presents with blisters affecting the hands and feet, normally resolving without signs of scarring.⁵

The major risk factor for this disease is a family history of EB. Prevalence may be found in every racial and ethnic group worldwide and affects both sexes equally.²

Current Treatments

Currently, EBS treatment is limited to caring for blisters through wound care, symptomatic relief, and alleviating secondary complications such as infection.⁸ Pain management involves the combined use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids depending on the severity of pain, as well as tricyclic antidepressants if the pain is neuropathic in origin. Pruritus can be treated with antihistamines. If the blisters become infected, antibiotic use is indicated but only for short periods of time and in rotation to prevent resistance.⁹ Corrective gene therapy is currently being researched, as EBS is a monogenic disease.⁶

Phase Trials

Studies have demonstrated that patients with generalized severe epidermolysis bullosa simplex (EBS-gen/sev) (formerly EBS Dowling-Meara/EBS-DM), a variant of EBS with extreme intolerance to mechanical stress, heat shock, and osmotic shock, develop painful blisters and injury after even minor disruption to the skin and/or mucous membranes.¹⁰ EBS-gen/sev pathology involves the overproduction of mutated K14 protein, a component of the intermediate filament integral in keratinocyte stability, and the constitutive activation of interleukin (IL)-1β, a proinflammatory cytokine that promotes the hyperproliferation of keratinocytes.¹¹ Diacerein, a rhein prodrug and anthraquinone, has been shown to reduce expression of K14, inhibit IL-1 converting enzyme, and exert a protective effect on cartilage matrix destruction in patients with osteoarthritis when administered orally.^{12, 13}

Thus, Wally et al. (2013) developed a topical formulation of diacerein with the aim of providing relief for patients suffering from EBS-gen/sev.¹⁴ This double-blind, randomized, placebo-controlled pilot study employed ultraphil^® as the base for a 1% diacerein treatment cream, with ultraphil^® alone as placebo. The study recruited 5 patients diagnosed with EBS-gen/sev and mutated K14 protein. Phase 1 (P1) of the study was open label, with all patients receiving 1% diacerein cream to apply on both axillae in the evening for 6 weeks. Blisters were documented every other day by the patient and every other week by a study nurse. Patients also took photos of their axillae with a tape measure in the frame for computerized calculation of blister area. In phase 2 (P2), the second 6-week period, patients applied 1% diacerein to one axilla and placebo to the other in a blinded, randomized fashion. The primary endpoint was designated as time to half the effect of P1 results, namely time to loss of efficacy. This study showed a statistically significant reduction in blistering in the first 2 weeks of P1, which remained stable throughout the phase. The examiners missed their primary endpoint in P2, as no loss of efficacy was noted; researchers proposed this result could be secondary to carryover from the P1 arm of the study. This pilot study suggested that a reasonably sustained reduction in blistering can be noted within 2 weeks of initiating 1% diacerein treatment.¹⁴

Wally et al. (2018) completed the only phase 2/3 randomized, placebo-controlled, double-blind clinical trial to date.⁸ Of the 15 EBS-gen/sev-diagnosed patients initially enrolled, 8 were randomly assigned to the diacerein treatment group and 7 to the placebo group for the first 4 weeks. One patient left the placebo group after the first visit and was replaced; a second placebo patient became ill during the first 4-week period and was replaced for the first 4-week period only, returning for the second treatment period. Both events were considered not treatment-related. After the first 4 weeks, the patients completed a 3-month follow-up phase and mean washout period of 5.6 months. After this time, the groups crossed over, with patients previously in the diacerein group now in the placebo group and vice versa. The 1% diacerein treatment cream was made in ultraphil^® as described above. The placebo cream was composed of 0.005% tartrazine in ultraphil^® to mimic the yellow hue of the treatment cream. The primary endpoint was designated as the percent of patients with a reduction in blister number from baseline to over 40% within treatment areas in each of the 4-week periods. Researchers also identified and analyzed two secondary endpoints: continued reduction of blister count from baseline to over 40% at the end of the follow-up period and recurrence of baseline blister count plus/minus 10% at the end of each 4-week period. Blisters counts were conducted by 3 independent, blinded raters from photographs taken at each visit; the raters arrived at a consensus count, which was used for statistical analyses.⁸

Among all patients, 39 skin areas were treated, including the arms/axillae, legs, trunk, buttocks, and feet. Throughout both 4-week treatment periods, 102 blisters were counted at baseline in the placebo group, and 97 blisters were counted at baseline in the diacerein group. Researchers noted that blisters healed without scarring or obvious adverse effects. Upon evaluation of the primary endpoint after the first 4-week period, 86% of diacerein-treated and 14% of placebo-treated patients had reduced blister counts of greater than 40%. After the follow-up period, all diacerein-treated patients and only 57% of placebo-treated patients achieved a reduction in blister count of over 40%. In the second 4-week period, 37.5% of diacerein-treated and 17% of placebo-treated patients achieved greater than 40% reduction in blister counts. And at the end of the second follow-up period, 75% of diacerein-treated versus 17% of placebo-treated patients exhibited a greater than 40% decrease in blister number. The mean change in blister counts from start to end in the 4-week treatment periods as well as the mean change from start to end in follow-up periods was significantly different only in diacerein-treated groups, not in placebo-treated groups. Blister counts were also significantly different between diacerein- and placebo-treated groups after both 4-week treatment periods and follow-up periods. Lastly, diacerein-treated groups saw a significant decrease in blister number from the end of treatment periods to the end of follow-up periods.⁸

Upon evaluation of the secondary endpoint, 1 diacerein-treated patient versus 4 placebo-treated patients reached blister numbers greater than or equal to 90% of baseline. There was no significant difference between diacerein and placebo group recurrence in the first 4-week period; however, after follow-up, significantly more patients in the placebo group achieved 90% or more of their original blister counts.⁸

Patient-Reported Outcomes

Patients who completed both arms of the Wally et al. (2018) study were asked to answer an 8-question quality of life assessment following each 4-week treatment period and follow-up period.⁸ Interestingly, although the study nurse did not note any significant change in pain and/or pruritis in the study subjects across time or between study groups, the question “Has your skin been itching recently, or have you had pain?” elicited a statistically significant difference between diacerein- and placebo-treated patients.⁸ Thus, a positive effect of diacerein treatment, according to patients, was reduction in pain and pruritus of treatment areas, though this finding was not confirmed objectively. The other 7 quality of life assessments did not yield significance between diacerein and placebo; still, trends were generally similar and could perhaps become significant with increased power.⁸

Safety

Oral administration of diacerein is associated with gastrointestinal issues; however, topical use is not postulated to induce such effects.¹⁵ In the phase 2/3 trial published by Wally et al. (2018), 13 adverse events were recorded, none of which were determined to be severe or treatment-related. Additionally, none of these adverse effects were reported in the treated skin area(s).⁸ Topical 1% diacerein resulted in blister healing without scarring or other noted side effects. Overall, topical diacerein appears to be a safe and tolerable therapy for patients suffering from EB.⁸

Future Trials

For EBS, topical 1% diacerein ointment was recently granted Rare Pediatric Disease designation in May 2018 and Fast Track development designation in August 2018. Additional clinical trials are still underway.

Conclusion

Topical diacerein, a rhein prodrug, has made a promising impact as an effective treatment for patients with generalized severe EBS. Its mechanism of blocking key inflammatory pathways, as well as its protective effects against collagen destruction, have been shown in clinical trials to result in improved healing and reduction of blister formation. Although diacerein treatment does not correct the underlying genetic defects associated with EBS, it does target the burdensome symptoms accompanying this chronic disorder and can potentially improve the quality of life in affected patients. Therefore, topical diacerein ointment is poised to be an efficacious treatment of EBS, with clinical trials demonstrating reduction in blister severity and improvement in blister healing, in addition to its low-risk side effect profile.

Updated on May 23, 2019. 

¹Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
²Texas A&M University College of Medicine, Dallas, TX, USA
³Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract
Hyperhidrosis is a condition characterized by excessive sweat production beyond which is physiologically necessary for thermal regulation. Affecting over 4.8% of the United States population, studies have shown that severe primary hyperhidrosis interferes with daily activities and can be considered intolerable, negatively impacting a patient’s quality of life. Glycopyrronium tosylate is a topical anticholinergic agent that reduces sweat production by blocking the activation of acetylcholine receptors in peripheral sweat glands. In clinical trials, topical glycopyrronium tosylate, a pre-moistened cloth containing 2.4% glycopyrronium solution, was shown to be an effective, safe and non-invasive treatment for patients suffering from primary hyperhidrosis. This review examines the clinical trials of topical glycopyrronium tosylate and its role in primary hyperhidrosis. Glycopyrronium tosylate was recently US FDA-approved (as of June 2018) to manage patients with primary axillary hyperhidrosis.

Key Words:
anticholinergic, axillary hyperhidrosis, glycopyrronium tosylate, Qbrexza, sweat, treatment

Introduction

Hyperhidrosis is a condition characterized by sweat production beyond which is physiologically necessary for thermal regulation. A recent study estimates the prevalence of hyperhidrosis in the United States to be 4.8%, with over 70% of sufferers experiencing severe sweating that is considered intolerable or interfering with daily activities.¹ Hyperhidrosis has been shown to correlate with anxiety, depression and diminished quality of life.^2-5 Patients often report frustration with the length of time until diagnosis, as well as the cost and efficacy of treatments once a diagnosis is established.^4,5

Pathogenesis of Hyperhidrosis

The pathogenesis of primary hyperhidrosis is not well-delineated. The condition is thought to be the result of a dysregulated autonomic nervous system and has a clear genetic component.^6,7 Hyperhidrotic skin regions do not exhibit increased number or size of sweat glands; rather, the grossly normal sweat glands hyperfunction.⁸ Whether or not this hyperfunctioning is secondary to an increased sensitivity to specific stimuli, emotional, sensory, or otherwise, remains a topic of debate.

Current Treatments

Several treatment options exist for patients with primary hyperhidrosis. First-line agents include topical antiperspirants containing aluminum chloride hexahydrate that obstruct eccrine glands, and glycopyrrolate, which works by competitively binding muscarinic acetylcholine receptors. Oral anticholinergics, such as glycopyrrolate, oxybutynin, and bornaprine, are also effective in treating hyperhidrosis. Other oral medications have shown some benefit in treatment as well. Beta-blockers and benzodiazepines are particularly effective if the patients have anxiety triggers, and methanthelinium bromide and clonidine work well for axillary hyperhidrosis and cranial hyperhidrosis, respectively. In addition to topical and oral treatments, an injectable method utilizing botulinum toxin is available. This toxin works as an acetylcholine release inhibitor causing a neuromuscular blockade. Different types of the toxin are effective for different forms of primary hyperhidrosis, including axillary, palmar, and plantar. The use of medical devices through iontophoresis and microwave thermolysis have also shown benefit in reducing sweat production through unclear mechanisms.⁹

When pharmacological measures are exhausted, surgery may be performed. Surgeons have utilized endoscopic thoracic sympathectomy (ETS) in treating primary hyperhidrosis of the face, extremities, and axillae.10 Pharmacological and surgical treatments have demonstrated substantial success in patients with hyperhidrosis, but adjunctive therapies tailored for individualized treatment plans are recommended. Specialized clothing and bedding to prevent moisture can provide relief as well.⁹

Phase Studies

Glycopyrronium tosylate (GT, Qbrexza™), formerly DRMO4, is a topical competitive inhibitor of acetylcholine receptors that targets cholinergic peripheral tissues including sweat glands.¹¹ Blockade of acetylcholine receptors that activate sweat glands leads to the reduction in sweat production, an essential component in the treatment of primary axillary hyperhidrosis. Glycopyrronium tosylate is administered topically as a single-use, pre-moistened cloth containing 2.4% glycopyrronium solution.¹¹

The first Phase 2b clinical trial, DRM04-HH01, enrolled 198 patients with severe hyperhidrosis. The study was conducted as a randomized, double-blind, vehicle-controlled trial evaluating dose dependence and statistical significance in the reduction of signs and symptoms of primary axillary hyperhidrosis. Patients were randomized to receive either the topical agent at one of the four concentrations (1%, 2%, 3% and 4%) or the vehicle wipes for 4 weeks.¹² Results in the DRM04-HH01 study demonstrated dose dependence and statistically significant improvement in the topical GT group compared to the vehicle group.¹²

Due to the significant clinical results in DRM04-HH01, the second Phase 2b study, DRM04-HH02, was designed to gain clinical experience with DRM04 prior to Phase 3 investigations.¹³ Accordingly, the DRM04-HH02 study was not powered to demonstrate statistical significance but did support advancement into Phase 3 clinical development.¹³ DRM04-HH02 was conducted in a similar fashion as the first Phase 2b trial (randomized, double-blind, vehicle-controlled), but differed in that this second trial would aid in assessing the efficacy, safety, and pharmacokinetics of topical glycopyrronium wipes. In this study, 105 patients were recruited and instructed to apply either the topical agent or vehicle product to each axilla once a day for 4 weeks. Sweat production measurement tools used to establish baseline sweat production and analyze post-treatment changes included gravimetrically measured sweat production and the Hyperhidrosis Disease Severity Scale (HDSS). DRM04-HH02 also explored a new patient-reported outcome instrument, the Axillary Sweating Daily Diary (ASDD) [see “Patient-Reported Outcomes” below]. Results of the study showed an average reduction in sweat production from baseline to week 4 ranging from 67.7% to 79.8% in patients receiving topical GT cloth compared to 48.7% reduction in patients who received the vehicle only.¹³ Patients who achieved at least a 2-grade improvement in HDSS score after week 4 ranged from 40.9% to 50% with DRM04 use compared to 27.3% in patients who received vehicle only.¹³ ASDD data demonstrated that patients who received DRM04 experienced greater improvements in disease severity compared with vehicle treatment. At the end of the trial, ASDD data was still being validated during the publication of this review.

In both DRM04-HH01 and DRM04-HH02 clinical trials, the GT treatment was well-tolerated and displayed a low incidence of manageable side effects, with the most common being dry mouth, application site pain, and headache.¹³

Glaser et al. published the only Phase 3 trial data to date. The clinical trials ATMOS-1 and ATMOS-2 were replicated, randomized, double-blinded, vehicle-controlled, parallel-group 4 week trials conducted to further assess the efficacy and clinical significance of GT in hyperhidrosis. Each trial had an overall sample size of 330 to provide at least a 95% power at a significance level of 0.05 in efficacy assessment.¹⁴ Patients were randomized within two treatment groups, glycopyrronium tosylate 3.75% (equivalent to 2.4% glycopyrronium) or a matched vehicle group. Participants were instructed to apply their assigned product once daily to a clean and dry axilla, and were assessed at weekly clinical visits for 4 weeks. The participant population included male and non-pregnant females aged 9 years and older who presented with primary axillary hyperhidrosis for more than 6 months, sweat production of >50 mg/5 min in each axilla on at least 1 of 3 gravimetrically performed measurements, ASDD sweating severity score >4, and HDSS grade 3 or 4 (based on a 4-point scale).¹¹ At week 4, a statistically significant change from baseline sweat production was observed in ATMOS-2 (p<0.001) but not in ATMOS-1 (p=0.065).⁹ In these trials, GT application was generally well tolerated with the most common side effects being dry mouth, headache, sore throat, and mydriasis, occurring in only 2% of patients.¹⁵

Patient-Reported Outcomes

Patients treated with GT or vehicle in the ATMOS-1 and ATMOS-2 Phase 3 trials were asked to complete Axillary Hyperhidrosis Patient Measures (AHPM) on a nightly basis, including the ASDD if aged 16 or over, or the Axillary Sweating Daily Diary-Children (ASDD-C) if under 16. Patients aged 16 and over were also asked Weekly Impact Items, to determine the effect and bother of hyperhidrosis on daily activities, as well as one Patient Global Impression of Change (PGIC) item at the end of the study.¹⁴ These measures gave patients the opportunity to express the impact of treatment on their perceived sweat burden.

Item 2 of the ASDD/ASDD-C asked participants to rate their worst sweating over the past 24 hours on a scale from 0 to 10. At the 4-week point, the proportion of patients who reported improvements of greater than or equal to 4 points from baseline was statistically significant between GT- and vehicle-treated patients in ATMOS-1 (53% versus 28%) and in ATMOS-2 (66% versus 27%), with p<0.001 in both.¹⁴

ATMOS-1 and ATMOS-2 also utilized the 4-point Hyperhidrosis Disease Severity Scale (HDSS) to screen patients. Patients were determined to be grade 3 or 4 at baseline. A greater than or equal to 2-grade improvement was noted in GT versus vehicletreated patients as early as week 1. By week 4, ATMOS-1 showed an improvement in 57% versus 24% of patients and ATMOS-2 an improvement in 62% versus 28% (both with p<0.001).¹⁴

Efficacy and Safety

In addition to the subjective efficacy endpoints evaluated in the previous section on patient-reported outcomes, sweat production was measured gravimetrically weekly throughout both ATMOS-1 and ATMOS-2. In ATMOS-2, a statistically significant difference favoring GT in mean absolute change from baseline in sweat production was noted compared to vehicle (p<0.001).¹⁴ Mean absolute change seen in ATMOS-1 at week 4 was not statistically significant (p=0.065). However, when ATMOS-1 data was adjusted via pre-specified sensitivity analysis and an identified outlier focus was eliminated, ATMOS-1 also showed a significant change from baseline in GT- versus vehicle-treated patients.¹⁴ Ultimately, ATMOS-1 and ATMOS-2 were able to demonstrate a significant reduction in axillary sweat production in participants, meeting both co-primary efficacy endpoints of ASDD-Item 2 response rate and mean absolute change from baseline in axillary sweat production.¹⁴

Treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs), along with laboratory testing results, vital signs, ECG results, and physical exam findings were used to assess safety. Adverse events were mostly mild to moderate, and the incidence remained consistent across trials.¹⁴ Approximately one-third (33.9%) of TEAEs were treatment-related in the GT group in ATMOS-1, similar to the 44% observed in ATMOS-2.¹⁴ Dry mouth and mydriasis were the most commonly reported anticholinergic-related TEAEs, and led to discontinuation in less than 4% of patients. A decreased percentage of TEAEs was noted in vehicle-treated groups in both trials. TEAEs of special interest, such as blurry vision, mydriasis, and urinary hesitancy and/or retention, were seen in 11% and 15.5% of GT-treated patients in ATMOS-1 and ATMOS-2 trials, respectively.¹⁴ The onset of all TEAEs occurred in week 1 but decreased throughout the trials. One serious TEAE of treatment-related unilateral mydriasis was noted in ATMOS-1, and another serious TEAE of treatmentunrelated moderate dehydration was noted in ATMOS-2.¹⁴ TEAE differences between GT and vehicle treatment groups were unremarkable in regards to laboratory and physical exam findings, ECG results, and vital signs. LSRs were mostly absent and, if observed, were mild and comparable in incidence in both GT- and vehicle-treated groups for both trials.¹⁴

Future Trials

Future trials for glycopyrronium tosylate include a long-term, open-label extension of the Phase 3 randomized controlled trials (ATMOS-1 and ATMOS-2) to assess the long-term safety and efficacy of GT for primary hyperhidrosis management. Notably, in the studies published by Glaser et al., patients with a history of prior surgical intervention for hyperhidrosis or treatment with botulinum toxin within 1 year of baseline were excluded from the Phase 3 trials.¹⁴ Including these patient cohorts in future trials may provide additional comparative data to augment the current safety and efficacy profiles of GT. Furthermore, hyperhidrosis can be generalized or focal, most often affecting the face, axillae, palms, and soles. Future trials could include an analysis of efficacy in the treatment of non-axillary hyperhidrosis.

Conclusion

Glycopyrronium tosylate, a topical anticholinergic therapy, has been shown to be effective in the treatment of primary axillary hyperhidrosis. Primary hyperhidrosis is a condition with the potential to significantly affect patients’ quality of life. Thus, optimal management is a priority. The clinical trials described here have shown GT to be clinically effective in reducing excess sweat production in the axillae as well as presenting a low side effect risk, garnering the drug recent US FDA approval as the first and only topical agent indicated to treat primary hyperhidrosis. Though further investigation is needed to confirm the longterm safety and efficacy of glycopyrronium tosylate, it should be considered in the treatment algorithm for hyperhidrosis.

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