¹Department of Dermatology, McGovern Medical School at The University of Texas Health Sciences Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Houston, TX, USA

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

Abstract:
The ichthyoses, also termed the disorders of keratinization, are a heterogenous group of skin diseases in which a distinctive horny layer arises secondary to excessive transepidermal water loss. Although occasionally acquired, the majority of ichthyoses are inherited and can be pinpointed to characteristic genetic mutations. Management depends on disease severity and includes topical agents and lifestyle modifications with or without oral retinoids. Genetic counseling is also an important consideration. This review aims to highlight advances in our understanding of disease pathogenesis as well as the holistic approach necessary to adequately manage ichthyosis patients.

Key Words:
ichthyosis, keratinization, lifestyle, management, pathogenesis, treatment

Introduction

Ichthyoses are an inherited group of skin disorders in which cornified layer accumulation leads to characteristic phenotypic features including xerosis, hyperkeratosis, excessive scaling, keratosis pilaris, and palmar and plantar hyperlinearity.¹ The common manifestations of this heterogeneous group of diseases arise due to abnormal skin barrier function that causes increased transepidermal water loss and a resultant compensatory hyperproliferation.² The clinical symptoms of ichthyosis typically present at birth or within the first few years of life.² With limited treatment regimens and no current cure, it is important to acknowledge the associated impaired quality of life that patients with lifelong ichthyosis experience.³ A recent study demonstrated that adults affected with this disorder report diminished quality of life regarding their physical health (impaired appearance of skin and mobility), daily life (cost of disease), and relationships with others and oneself (negative reaction of others to disease).³ In the following brief review, we aim to update advances in understanding the pathophysiology and management of ichthyosis.

Pathogenesis

As previously mentioned, the ichthyoses, or disorders of keratinization, are characterized by hyperproliferation triggered by increased transepidermal water loss.² The distinctive horny layer can be localized or diffuse and may be complicated by hypohidrosis, erythema, and infection. Although occasionally acquired, ichthyosis is largely an inherited condition with over 50 genes implicated in its pathogenesis. These genes influence a variety of cellular functions from DNA repair to adhesion, with the end result being a dysfunctional epidermal barrier.² The common ichthyoses are ichthyosis vulgaris and X-linked recessive ichthyosis, both of which are caused by well-characterized genetic mutations.^2,4 Ichthyosis vulgaris occurs due to autosomal dominant mutations in the filaggrin gene (FLG), and X-linked recessive ichthyosis results from alterations in the STS gene, which encodes steroid sulfatase.^2,4 Harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma all result from autosomal recessive mutations.² Harlequin ichthyosis is associated with homozygous loss of function mutations in ABCA12, which encodes an ATP-binding cassette transporter.² Lamellar ichthyosis, congenital ichthyosiform erythroderma, and others exist on a spectrum of autosomal recessive congenital ichthyoses characterized by mutations in TGM1, NIPAL4/ ICHTHYIN, ALOX12B, ALOXE3, CYP4F22, ABCA12, PNPLA1, CERS3, LIPN, SDR9C7, and SULT2B1.^2,5-7 Understanding the impact of genetics in the pathogenesis of the ichthyoses gives perspective as to why these diseases often present in infancy or childhood, why they are lifelong burdens to those affected, and why finding a cure presents a challenge.

Management

Topical Agents

Ichthyosis management should incorporate hydration and lubrication with the addition of keratolytics and modulators of keratinocyte differentiation depending on scale severity.⁸ Hydration can be accomplished with creams and ointments containing low concentrations of salt, urea, or glycerol. Such topical therapies are employed to increase the water-binding capacity of the stratum corneum. Hydrophobic ointments such as petroleum jelly are effective for adequate lubrication. Of note, evidence does not support the use of skin-lipid-containing creams over the aforementioned plain creams and ointments in ichthyosis. When disease is characterized by markedly thickened stratum corneum, topical keratolytics such as alpha-hydroxy acids (lactic acid, glycolic acid), salicylic acid, N-acetylcysteine, propylene glycol, and high-dose urea allow for desquamation while keratinocyte differentiation modulators such as the retinoids (tretinoin, adapalene, tazarotene) and calcipotriol limit epidermal proliferation.⁸

Oral Medications

Although generally not necessary in the management of the common ichthyoses (ichthyosis vulgaris and X-linked recessive ichthyosis), oral retinoids are a mainstay in the systemic management of severe disease.⁸ Patients suffering from lamellar ichthyosis, epidermolytic hyperkeratosis, or congenital ichthyosiform erythroderma can benefit from retinoids as the drug’s keratolytic effects allow shedding and prevent further hyperproliferation. It is recommended that these agents be administered in low, effective doses as their use could be lifelong in ichthyosis patients.⁸ Additionally, retinoids are well-known teratogens.⁹ Retinoic acid plays a significant role in transcription regulation by binding retinoic acid response elements (RAREs) that are located proximally to numerous genes. RAREs have been found to inhibit Fgf8, homeobox genes, and other genes integral to neuron and organ development, thereby causing major craniofacial, thymic, cardiac, and central nervous system malformations in addition to spontaneous abortion.^9,10 In an effort to increase awareness and reduce birth defects associated with isotretinoin use, US-based physicians prescribing isotretinoin should be certified in and patients taking the medication should be registered with the iPLEDGE Program.¹¹ For female patients of child-bearing potential, this program mandates regular pregnancy tests and requires two forms of contraception.¹¹ Providers and patients in other countries should adhere strictly to local pregnancy avoidance programs and policies. In a patient considering pregnancy, isotretinoin may actually be preferred to acitretin due to its shorter half-life and resultant shorter washout period.⁸ At this time, data suggest oral retinoids are safe to use in reproductively active men.¹²

While retinoids share many features, some agents may be more effective than others situationally.⁸ For example, isotretinoin and aromatic retinoids (such as etretinate, acitretin) appear equally efficacious in the treatment of lamellar ichthyosis, whereas the propensity of acitretin to act on volar skin makes it the preferred therapy in palmoplantar hyperkeratosis.⁸

Lifestyle Considerations

The majority of ichthyosis therapies aim to improve the barrier function of the skin. Important aspects of an ichthyosis patient’s daily routine include bathing and proper application of the bland creams and ointments discussed previously.¹³ Daily bathing with water or mild cleanser and the application of plain emollients directly after bathing, as well as frequently throughout the day, help to seal in moisture.¹⁴ It is thought that bathing aids to hydrate and promote shedding of the stratum corneum, therefore reducing the thickness of scaling and improving overall skin appearance.¹³ Many emollients are not covered by insurance; in addition, patients self-report applying topical agents as time-consuming.³ Thus, it is important to be aware of the possible financial and lifestyle stresses with which these therapies may burden the ichthyosis patient population.

In addition, patients diagnosed with ichthyosis should be aware of the lifelong course of this group of disorders, as there is currently no cure. Patients who are carriers of the FLG gene mutation may be at increased risk of developing atopic disorders, such as atopic dermatitis and asthma.¹ To decrease potential risks for the development of atopic disorders, individuals diagnosed with ichthyosis vulgaris should be advised to avoid certain environmental risk factors including professions involving wet work or excessive metal and contact irritant exposure.¹ Smoking tobacco should also be discouraged as an interaction between FLG mutations and tobacco smoking has been shown to favor the development of asthma in patients with ichthyosis vulgaris.^1,15

Finally, it is important to acknowledge lifestyle factors that commonly influence the quality of life in ichthyoses patients. Patients self-report suffering from altered skin and eye appearance, including pain, pruritus, and “smelly” skin, that worsen in relation to environmental and psychological changes.³ To accommodate these changes, most patients refrain from activities that risk exacerbating their condition by avoiding hot atmospheres and activities in which they cannot hide their skin.³ As affected patients consistently express dissatisfaction with their medical care, it is prudent for physicians to advocate for the development of strategies and therapeutic programs targeted at improving the care and quality of life of these individuals.³

Genetic Counseling

Gene therapy is not yet a reality in ichthyosis therapy; however, genetic counseling remains an integral aspect of disease management. As mentioned previously, the most common forms of ichthyosis are ichthyosis vulgaris and X-linked recessive ichthyosis, which are inherited in autosomal (pseudo-) dominant and X-linked recessive patterns, respectively, via well-characterized genetic mutations. Although the diagnosis of ichthyosis vulgaris in particular may be evident from biopsy alone, the diagnosis of X-linked recessive ichthyosis requires polymerase chain reaction analysis, Southern blot, or fluorescent in situ hybridization analysis.^4,8 A positive male-only family history of scaly skin, the detection of low estriol on the prenatal triple screen, and/or low estrogen and nonhydrolyzed sulfated steroids in maternal urine can point toward a diagnosis of X-linked recessive ichthyosis, thus prompting analysis of chorionic villi or amniotic fluid using the aforementioned techniques.⁴ Additionally, a recent case report suggests that a rare and extreme form of fetal ichthyosis, harlequin ichthyosis, can be detected on ultrasonography as early as the second trimester with subsequent genetic screening to elucidate mutations in ABCA12.^2,16 A referral to a genetic counselor can serve to answer questions and alleviate anxiety regarding the diagnosis of a congenital ichthyosis as well as assist parents in consideration of future pregnancies.

Future Considerations

Topical therapy is necessary in the management of ichthyosis; thus, consideration should be given to the cosmetic appeal and fragrance of treatment creams and ointments. A recent case report found preliminary success utilizing carbocysteine cream in the treatment of ichthyosis.¹⁷ Carbocysteine is a molecule similar to N-acetylcysteine except that it contains a bound sulfhydryl group rather than a free one.¹⁷ As the sulfhydryl group cannot be liberated, this cream lacks the rancid egg smell of N-acetylcysteine cream, a major barrier to treatment compliance.¹⁷ Further research dedicated to such creams, ointments, and even cosmetic products has the potential to improve the quality of life in patients suffering physical discomfort and social stigmata due to their condition. In addition, development of gene therapy has tremendous potential in treating patients with these disorders and should be explored further.

Conclusion

The ichthyoses are typically inherited conditions exhibiting disordered keratinization secondary to excessive transepidermal water loss, with the most common variants being ichthyosis vulgaris and X-linked recessive ichthyosis. Ichthyosis management requires a multimodal approach, including topical and oral agents in addition to lifestyle modifications. Topical creams and ointments are the mainstays of treatment utilized to achieve adequate hydration and, when applicable, keratolysis, while more severe phenotypes benefit from the use of oral retinoids. Patients should also be educated regarding bathing practices and avoidance of topical irritants and tobacco, as well as be actively supported by their clinician, as ichthyosis patients often report decreased quality of life.

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¹Texas A&M University College of Medicine, Dallas, TX, USA
²Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, 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:
Methotrexate (MTX), an agent originally intended for anti-neoplastic use, has been successfully employed in the treatment of a variety of dermatologic conditions. In addition to its multiple clinical indications, variable dosing and modes of administration make it a viable option for patients of all ages and most comorbidities. MTX is a folate analog that antagonizes dihydrofolate reductase, thus inhibiting thymidylate synthesis and, ultimately, the production of pyrimidine. Depending on dosage, MTX can function as an anti-inflammatory agent, immunomodulator, or antimetabolite. Patients suffering from psoriasis have benefited from MTX in addition to those with atopic dermatitis, chronic urticaria, pemphigus vulgaris, bullous pemphigoid, cutaneous lupus erythematosus, cutaneous sarcoidosis, and mycosis fungoides. Although patients with these conditions can benefit from MTX treatment, the drug can cause adverse sequelae, including hematologic, pulmonary, gastrointestinal, and hepatic side effects. Therefore, the drug should be administered under careful physician supervision.

Key Words:
atopic dermatitis, methotrexate, psoriasis, psoriasis treatment

Introduction

Methotrexate (MTX), an agent originally intended for antineoplastic use, has been successfully employed in the treatment of a variety of dermatologic conditions. It can be administered orally, subcutaneously, or intramuscularly, and depending on its clinical indication, MTX can be given once weekly or on a triple-dose schedule at 12-hour intervals. The drug is a folate analog that antagonizes the enzyme dihydrofolate reductase. Inhibition of dihydrofolate reductase obstructs thymidylate synthesis and, ultimately, inhibits production of pyrimidine, an important nucleic acid base that gives rise to cytosine, thymine, and uracil. At a low dose, MTX acts as an anti-inflammatory agent and immunomodulator. At high doses, it acts as an antimetabolite. Given its mechanism of action, MTX can lead to many adverse events and should be used with caution. Along with nausea, anorexia, fatigue, and malaise, other systemic toxicities can occur, including hematologic, gastrointestinal, reproductive, pulmonary, cardiac, and neurologic complications. It is safe to use low-dose MTX in children, but it should be avoided in pregnant women. Drug interactions may occur and can increase the likelihood of MTX toxicity. For this reason, the American Academy of Dermatology (AAD) strongly recommends folate supplementation with MTX therapy.¹ This review aims to briefly delineate established clinical indications for, as well as recent research regarding the utility of MTX in dermatology.

Clinical Indications

Psoriasis

One of MTX’s primary uses is in the treatment of moderate to severe psoriasis and psoriatic arthritis, as the drug acts as an antiinflammatory agent.¹ In one randomized, double-blind, placebo-controlled study, 75% improvement was seen in the Psoriasis Area and Severity Index (PASI) score in 40% of patients treated with MTX.² PASI 75 in 45.2% of patients treated with MTX was also reported by a meta-analysis of 11 studies.³ Based on several randomized, controlled trials (RCTs), a starting dose of 15 mg/ week and maximum dose of 25 mg/week is recommended in patients with psoriasis.⁴ In addition to monotherapy, MTX can be administered in combination with betamethasone, ultraviolet B (UVB) phototherapy, and etanercept to treat psoriasis. Pustular variants of psoriasis have also been treated with combination therapy of MTX with retinoids and colchicine. Due to decreased renal clearance in the elderly, lower doses are effective in treating this patient population. A dose of only 2.5 mg/week is adequate in controlling psoriasis for patients over 80 years of age.¹

Chronic Urticaria (CU)

A recent retrospective review of 16 patients with steroid-dependent CU treated with MTX demonstrated improvement in 12 patients, with complete clearance of CU in 2 patients. A dose of 10-15 mg/week was administered to achieve a steroid-sparing effect.^1,5 In a different study involving 45 patients with chronic idiopathic urticaria, of which 12 tested positive for autoantibodies, MTX was given in 10 mg/week doses to these patients, all of whom improved clinically.^1,6 A different study performed in 2014 for the treatment of H1-antihistamine resistant chronic spontaneous urticaria involved 14 patients over the course of 12 weeks. Only 10 out of 14 patients completed the 12-week treatment, and no statistically significant difference in efficacy was observed between MTX treatment group and placebo group.⁷ Despite this finding, MTX is still commonly used to treat patients with CU, with several studies supporting its efficacy. However, additional confirmatory studies should be pursued. Serious side effects of MTX in patients with CU include bone marrow suppression and hepatitis.⁸

Atopic Dermatitis (AD)

MTX is an effective second- or third-line treatment option for AD in both adults and children.⁹ However, it has been shown to be more effective in adult-onset compared to childhood-onset AD.¹ In one randomized, controlled trial that compared the efficacies of MTX versus azathioprine (AZA) in adults with severe AD, a SCORAD (SCORing Atopic Dermatitis) reduction of 42% was seen in patients treated with 10-22.5 mg/week of MTX. In a randomized clinical trial for children aged 8 to 14 years, a SCORAD reduction of 49% was demonstrated in those treated with 7.5 mg/week of MTX compared to a 45% reduction in those treated with cyclosporin A. MTX was usually well-tolerated, and the most common side effect in these studies was nausea.⁹ An open-label prospective study demonstrated that 8 out of 12 patients with AD achieved clinical improvement through a starting dose of 10 mg and incremental increase of 2.5 mg/week until a therapeutic effect was observed.^1,10 Long-term risks include pulmonary fibrosis and hepatotoxicity.⁹

Blistering Disorders

Pemphigus Vulgaris

A retrospective chart review evaluated 23 patients with pemphigus vulgaris who were initially treated with prednisone before starting treatment with MTX.¹¹ Results of this study revealed that 21 of the 23 patients (91%) experienced clinical improvement in blistering after MTX initiation.¹¹ In addition to clinical improvement, these patients were able to reduce their dosage of prednisone, with 16 patients (70%) weaning off prednisone completely.¹¹ It was reported that MTX had to be discontinued in 2 patients due to adverse effects.

Bullous Pemphigoid (BP)

MTX has been shown to be effective in controlling BP when combined with systemic steroids.¹² A retrospective study was conducted to evaluate the efficacy and safety of MTX with standard prednisone treatment. Of the 138 participants included in the study, 98 were treated with MTX and received a median weekly dosage of 5-6 mg.¹² Treatment groups included MTX only, MTX plus prednisone, prednisone only, and topical betamethasone gel. After 24 months, an estimated remission rate among treatments groups was 43%, 35%, 0% and 83%, respectively (p < 0.001).¹² The adverse effects observed in this study, which resulted in cessation of MTX, included gastrointestinal (GI) irritation, anemia, transient alveolitis, and increased liver enzyme levels.¹² Another study suggested a marked therapeutic effect with MTX use in BP patients suffering from secondary diseases such as diabetes and active peptic ulcers.^13,14

Localized Scleroderma

Although the treatment selection for localized scleroderma is still controversial, MTX has been observed as an effective treatment modality.^1,15 A comparative study was performed between two treatment groups: MTX and MTX plus corticosteroids with statistically significant (p = 0.02) differences in duration of sclerotic disease between treatment groups, 22-25 months and 12 months, respectively.¹⁵ Both groups received a median weekly dosage of 15 mg of MTX.¹⁵ Clinical assessment revealed that 81% of patients treated with MTX and all patients treated with MTX plus steroids showed clinical improvement of sclerotic skin.¹⁵ An additional study that evaluated juvenile patients specifically supported the efficacy and safety of MTX as a monotherapy.¹⁶ MTX was well-tolerated in these studies with reported side effects including infections, GI disturbance, and elevated liver enzymes.^15,16

Cutaneous Lupus Erythematosus (CLE)

MTX is commonly used as a second-line treatment in patients with CLE who have contraindications or resistance to first-line agents and in patients with refractory subacute CLE, as well as discoid lupus erythematosus.^1,17 A retrospective study was performed to analyze 12 patients refractory to first-line therapy who received MTX treatment.¹⁸ A median dosage of 10-25 mg of MTX was administered weekly.¹⁸ Ten of the 12 patients showed improvements of their cutaneous lesions within 6 weeks.¹⁸ Another study of 43 patients with recalcitrant CLE treated with MTX demonstrated improvement of cutaneous lesions in 98% of patients, with the best clinical improvement seen particularly in patients with subacute CLE.¹⁸ Discontinuation of treatment occurred in 7 patients who displayed severe side effects, however, the side effects resolved after cessation of MTX.¹⁸ Both studies supported the use of low dose MTX for management in refractory patients.^17,18

Cutaneous Sarcoidosis (CS)

MTX is a widely employed second-line agent in the treatment of CS along with antimalarial drugs and tetracyclines.^1,19 Secondline agents are useful especially if the patient needs to avoid or is resistant to glucocorticoids. However, studies evaluating the efficacy of MTX for CS are uncontrolled and small, with one study demonstrating efficacy in 80% of participants.^1,19 MTX is given in doses of 10-25 mg/week for CS; once improvement is noted, the dose can be tapered to as low as 2.5 mg/week.^1,20,21 Another study suggested that low-dose MTX (7.5 mg/week) as monotherapy for sarcoidosis was more effective for cutaneous than pulmonary lesions with no patients experiencing serious adverse events.²²

Mycosis Fungoides (MF)

Literature regarding the use of MTX in treating cutaneous T-cell lymphoma has expanded in recent years. Low-dose MTX (up to 30 mg/week orally) is a viable first-line agent for advanced MF, with low toxicity compared to multiagent chemotherapy regimens and a mean period of 5 months until repeat treatment is required.²³ Additionally, the combination of MTX with other systemic agents such as interferon-alpha and bexarotene may enhance efficacy in the treatment of advanced MF.²⁴

Safety Considerations

Hepatotoxicity

One of the main concerns of MTX use in patients is hepatotoxicity. Several studies have shown that patients treated with MTX are at increased risk for developing hepatic adverse events such as elevated transaminase levels and fibrosis. The exact pathogenesis for this phenomenon is unclear, but it has prompted transaminase monitoring and use of liver biopsies to monitor patients at risk for hepatotoxicity through the Roenigk classification system, which progressively classifies changes from early fatty infiltration to varying degrees of fibrosis. Transaminase levels should be monitored every 2 weeks when initiating treatment or adjusting doses, and every 12 weeks once a stable dose is achieved. If transaminases are elevated, administration of MTX should be reduced, and further evaluation is needed to determine the source of elevation. In this case, a liver biopsy might be indicated; however, liver biopsies are rarely clinically indicated, due to its high sampling error rate of 20-30% and risk of morbidity and mortality.²⁵ A relatively new non-invasive technology known as transient elastography (TE) has been more recently utilized to monitor liver fibrosis. TE uses an ultrasound transducer in order to measure shear wave speed to approximate stiffness in hepatic tissue.²⁶ A study of 24 patients treated with a median dose of 1,635 mg of MTX for psoriasis who previously underwent liver biopsy showed that TE had good negative predictive value and accurately identified 88% of those without significant fibrosis.²⁷ It has also been found that a higher prevalence of non-alcoholic fatty liver disease (NAFLD) exists in psoriatic patients treated with MTX compared with the general population. This can be explained by risk factors of NAFLD, including obesity and type II diabetes mellitus. The development of NAFLD in this population is the hepatic manifestation of metabolic syndrome, and treating these patients with MTX puts them at an even higher risk for hepatotoxicity.²⁸ A possible explanation for MTX hepatotoxicity is a reduction of folate stores in the liver due to a local folate deficiency. For this reason, the AAD recommends 1-5 mg of daily folic acid supplementation for all MTX-treated patients.^25,29 Although it was once thought that MTX use should be limited over one’s lifetime, if there are no signs of hepatotoxicity or bone marrow failure with regular monitoring, MTX therapy should not be withheld regardless of cumulative dose.³⁰

Drug Interactions

MTX administration can pose a high risk for drug-drug interactions. Sulfa drugs such as trimethoprim-sulfamethoxazole (TMP-SMX) can interact with MTX and cause severe adverse effects by potentiating the inhibition of dihydrofolate reductase.³¹ This further impairs folate production, thus increasing risk for myelosuppression.³² A systemic analysis revealed that concurrent MTX and TMP-SMX use, occurring at remarkably low doses (5-15 mg/week), is a risk factor for pancytopenia.³³ In addition, TMP-SMX and MTX are both nephrotoxic agents, and their combinative effects impair renal excretory function, which can lead to elevated drug levels. Caution is advised in patients with preexisting renal conditions.³²

Concurrent use of nonsteroidal anti-inflammatory agents (NSAIDs) and MTX results in a proposed mechanism of competitive renal tubular excretion, leading to increased serum MTX levels.³² The use of high dose MTX with NSAIDs has been documented to cause adverse effects including myelosuppression, transaminitis and acute kidney injury. NSAIDs that commonly have the propensity to interact with MTX include indomethacin, diclofenac, ibuprofen, and high dose aspirin.^32,33

When MTX is co-administered with antibacterial agents such as penicillin, there is a prolonged delay in clearance, causing increased serum MTX levels that can place a patient at risk of adverse effects including neutropenia, renal failure and mucositis.³⁴ While administration of low dose MTX (7.5- 25 mg/day) poses a lower risk than dosing at antineoplastic levels (500 mg-1.2 g/m²/week), it is recommended that an alternate antibiotic be used to prevent these risk factors.^34,35

Pregnancy

MTX, as a folate antagonist, disrupts DNA synthesis, DNA damage repair, and cellular replication.³⁶ These properties can cause devastating birth defects for a developing fetus, including heart malformations, cleft palate, hypospadias, congenital diaphragmatic hernia, craniosynostosis, and even death.^36,37 In fact, MTX is used for medical termination of pregnancy. A recent meta-analysis found that two doses of MTX was more effective than either one or multiple doses in the treatment of ectopic pregnancy.³⁶ Therefore, MTX should be stopped at least 3 months prior to becoming pregnant and should not be used at any point during the pregnancy.³⁷

Risk of Lymphoma

MTX, aside from being immunosuppressive, is also cytotoxic and can lead to a loss of cellular immune control of tumor proliferation.³⁸ One prospective cohort study involving 1,380 patients treated for psoriasis found that high-dose exposure, defined as at least 36 months of MTX treatment, led to an increased risk of lymphoma. Patients in the cohort treated with MTX had a 7 times greater risk of lymphoma compared to those in the cohort with less exposure to MTX (IRR, 7.77).³⁹

Conclusion

MTX has been an important agent in the management of dermatologic conditions for decades. Although first indicated for the treatment of psoriasis, MTX has been shown to be a successful treatment option for a wide array of skin diseases. As biologics become more widely prescribed and available, monitoring the combination of these drugs with MTX will be relevant; for example, etanercept and MTX co-administration has shown increased efficacy without an increase in adverse events when compared to etanercept alone in the treatment of psoriasis.⁴⁰ Additionally, a recent study found that rates of non-basal cell skin cancers were 3 times higher in rheumatic patients treated with prolonged low-dose MTX versus placebo, an observation that warrants caution and further investigation.⁴¹

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¹Texas A&M University College of Medicine, Dallas, TX, USA
²Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, 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
Herpes zoster (HZ), also known as shingles, results from reactivation of the latent varicella-zoster virus (VZV), which commonly causes chickenpox in childhood. Greater than 90% of adults are infected with this virus, putting them at risk for reactivation. HZ presents as a painful, vesicular rash distributed in a unilateral and dermatomal pattern along dorsal root or cranial nerve ganglia. The rash often presents with prodromal symptoms and progresses to include clear vesicular clusters, evolving through stages of pustulation, ulceration, and crusting. HZ therapy currently involves the use of antiviral agents and pain management; however, HZ prophylaxis has been strongly recommended in older adults through vaccination with a live attenuated vaccine, Zostavax^®. A new recombinant subunit vaccine, HZ/su (Shingrix^®), is the subject of this review. In clinical trials, HZ/su demonstrated an overall vaccine efficacy of 97.2% among participants 50 years of age or older, indicating a significantly reduced risk of HZ in these individuals. Shingrix^® was approved by the US FDA in October 2017 as HZ prophylaxis.

Key Words:
herpes zoster, rash, recombinant subunit vaccine, shingles, Shingrix, treatment, vaccine, varicella zoster virus

Introduction

Herpes zoster (HZ), also known as shingles, results from reactivation of the latent varicella-zoster virus (VZV), which commonly causes chickenpox in childhood. HZ presents as a painful, vesicular rash distributed in a unilateral and dermatomal pattern along dorsal root or cranial nerve ganglia.¹ This painful rash negatively affects patients’ quality of life (QoL) by impairing physical, emotional, and social functioning.² Greater than 90% of adults are infected with this virus, putting them at risk for reactivation. Reactivation often occurs in adults over the age of 50 due to immunosenescence but can occur at any age, especially in those who are immunocompromised.¹ Complications of HZ include postherpetic neuralgia, which occurs in 10-20% of patients and increases in frequency and severity with age.^1,2

Pathophysiology

HZ is one of the two distinct syndromes caused by VZV. Primary disease is known as varicella infection or chickenpox, a contagious, frequently benign illness occurring predominantly among susceptible children.³ Upon resolution of primary infection, VZV establishes a lifelong latency within the cranial or dorsal root ganglia.⁴ Major risk factors for reactivation include older age, family history of zoster, immunosuppression, and in utero or early infancy primary varicella infection, with older age being the most significant risk factor.⁴ As the virus-specific T cell-mediated immune response declines or becomes impaired, the subsequent reactivation of latent VZV in the root ganglia results in a dermatomal and localized maculopapular eruption known as shingles.⁴ Shingles often presents with prodromal symptoms such as headache, malaise, photophobia, and skin sensations ranging from itching to tingling to severe pain.³ The erythematous maculopapular rash progresses to include clear vesicular clusters, evolving through stages of pustulation, ulceration, and crusting.³ Cutaneous healing occurs within 2 to 4 weeks of rash onset. Scarring, hypo/hyperpigmentation, and postherpetic neuralgia are common sequelae.³

Current Treatments

Current HZ therapies consider both disease prevention and acute outbreak management. Antiviral agents including acyclovir, valacyclovir, and famciclovir are FDA-approved for the treatment of active HZ.³ Valacyclovir and famciclovir are preferred to acyclovir, but all three oral drugs have been shown to reduce the duration of pain secondary to postherpetic neuralgia when compared to placebo.³ HZ is often accompanied by significant pain and discomfort; thus, acute management should include symptom control.³ Analgesia can be achieved by neural blockade, oral or transdermal narcotics, and topical anesthetics.³ Pain caused specifically by postherpetic neuralgia can also be managed with gabapentin, pregabalin, tricyclic antidepressants, and opioids.^3,5 Gabapentin or pregabalin, however, are most effective when initiated during acute zoster.⁶

In addition to acute treatment, HZ prophylaxis is an important public health consideration. As shingles results from reactivation of latent VZV, prevention of primary varicella infection can be considered the first step in HZ prevention. Often, two doses of the live attenuated single-antigen varicella virus vaccine (Varivax^®) is administered to children over 12 months of age.^7,8 At the age of 50, patients can receive a live, attenuated, single-dose vaccine specifically targeted at HZ (Zostavax^®).^9,10 This vaccine reduces the incidence and duration of shingles and postherpetic neuralgia.⁹ Alternatively, a two-dose shingles vaccine was recently brought to market; it is a non-live, recombinant glycoprotein E vaccine.^1,11 The virus glycoprotein is combined with an adjuvant (AS01B) and is available to adults aged 50 or older.¹ This newer vaccine (Shingrix^®) is the subject of this review.^1,11

Phase Trials

Shingrix^®, a recombinant subunit vaccine also known as HZ/su, contains the VZV glycoprotein E and the AS01B adjuvant system.¹ VZV glycoprotein E is involved in viral replication and cell-to-cell spread and, for this reason, was selected as the vaccine antigen in combination with the AS01B adjuvant system, which strongly promotes humoral and CD4+ T cell-mediated immunity against recombinant proteins. Phase I and II clinical trials were previously performed in older adults and those who were immunosuppressed and demonstrated that the vaccine stimulated an immune response that persisted for at least 3 years with an adequate safety profile. Because of the positive outcomes, researchers began the ZOE-50 phase III trial to evaluate the efficacy of two doses of HZ/su in reducing the risk of HZ in adults 50 years of age or older.¹

ZOE-50 was a randomized, placebo-controlled study conducted in several countries around the world. Adults who were 50 years of age or older were eligible to participate in the study unless they met certain exclusion criteria, including history of HZ, previous vaccination against VZV or HZ, or current immunosuppressive condition. The patients were randomly assigned to receive either the vaccine or placebo in a 1:1 ratio and were stratified according to region and age group. Although the appearances of the vaccine and placebo differed, those who administered the injections were not involved in any study assessment. Therefore, the study remained double-blinded. Between August 2010 and July 2011, 16,160 participants were enrolled, but 749 were excluded due to deviations from Good Clinical Practice (GCP) standards. Of the remaining participants, 95.8% (14,759) were included in the modified vaccinated cohort. The modified vaccinated cohort excluded participants who did not receive the second dose of HZ/su or who had confirmed cases of HZ within 1 month after the second dose of the vaccine. In addition, 8,926 participants were assigned to the reactogenicity subgroup (4,460 in the HZ/su group and 4,466 in the placebo group).¹

The vaccine, containing 50 μg of recombinant VZV glycoprotein E, is also made up of the liposome-based AS01B adjuvant system, containing 50 μg of 3-O-desacyl-4′-monophosphoryl lipid A (MPL) and 50 μg of Quillaja saponaria Molina, fraction 21 (QS21, a purified extract from the bark of the Quillaja saponaria tree).¹ MPL specifically causes activation of innate immunity resulting in cytokine production. QS21 causes stimulation of CD4+ and CD8+ T cells and antigen-specific antibody responses.¹² The vaccine and placebo (0.9% saline solution) were administered as two 0.5 mL doses into the deltoid muscle at months 0 and 2. Participants were followed for a minimum of 30 months starting 1 month after the second dose.¹

In total, 408 participants reported suspected HZ, of which 244 (59.8%) were confirmed through PCR assay and the ascertainment committee. Suspected cases were defined as unilateral rashes with pain which had no alternative diagnoses. Any suspected case of HZ was examined by study investigators within 48 hours of emergence and samples were taken for virus confirmation via real-time polymerase chain reaction. Efficacy was calculated using the Poisson method. In the modified vaccinated cohort, 216 cases out of 7,344 participants of HZ were confirmed after a mean follow-up of 3.2 years, with 6 in the HZ/su group and 210 in the placebo group. Overall, the incidence of HZ per 1000 person-years was 0.3 in the HZ/su group and 9.1 in the placebo group, which demonstrated a significant overall vaccine efficacy of 97.2% among participants 50 years of age or older (p<0.001). No significant difference in vaccine efficacy was seen among the three age groups (96.6% to 97.9%).¹

Safety

A subgroup designated the “reactogenicity” subgroup of participants was formed to monitor the occurrence of adverse events.¹ The subgroup was made up of all participants over the age of 70, as well as a random assortment of patients aged 50-69. These patients recorded injection-site reactions including pain and swelling as well as systemic reactions including gastrointestinal upset and headache for 7 days following each dose of the recombinant vaccine. Each symptom was also graded on a scale of 0 (not present) to 3 (interfering with daily activities). Any additional adverse events were monitored for 30 days after each dose. Lastly, serious adverse events were recorded in all patients for at least 1 year after the second vaccine dose.¹

Within the reactogenicity subgroup, 84.4% of HZ/su-group patients versus 37.8% of placebo-group patients reported symptoms within 7 days of vaccination. Although most symptoms were of mild-to-moderate severity, 17% of HZ/sugroup patients and 3.2% of placebo-group patients experienced grade 3 symptoms. Injection site reactions were noted in 81.5% of patients who received HZ/su and in 11.9% of patients who received placebo. Systemic reactions were recorded in 66.1% of HZ/su patients and in 29.5% of placebo patients. The most commonly reported injection site reaction was pain (79.1% of HZ/su versus 11.2% of placebo), and the most commonly reported systemic reaction was myalgia (46.3% of HZ/su versus 12.1% of placebo). Reactions had median durations ranging from 1 to 3 days, and grade 3 systemic reactions were statistically more common after the vaccine’s second dose (8.5% after second dose versus 5.9% after first dose, with non-overlapping 95% confidence intervals).¹

Among all study participants, 231 serious adverse events were recorded within 30 days of vaccine administration, 103 in HZ/su-group and 128 in placebo-group patients. Adverse events were evaluated, and 4 such events (1 in an HZ/su recipient and 3 in placebo recipients) were considered related to vaccination – hypotension with syncope, mononeuritis, neurosensory deafness, and musculoskeletal chest pain. At publication, with a mean of 3.5 years of follow-up, no major safety concerns related to the vaccine were identified by either the investigators or independent monitors.¹

Future Trials and Considerations

Future trials for the HZ/su vaccine included ZOE-70, a sister study to ZOE-50 that would further investigate the vaccine in subjects only ≥70 years of age, as the ZOE-50 trial was not intended to definitively assess the efficacy of the vaccine within the ≥70 age group.¹ When the ZOE-70 trial was completed (September 2016), trial endpoints in the ZOE-50 trial were further analyzed and evaluated.¹³ The results revealed that the adjuvanted HZ/su was efficacious in reducing the risk of HZ and also postherpetic neuralgia in adults ≥70 years of age.¹³ In addition, the vaccine displayed similar efficacy between the two age groups studied (70-79 years of age and ≥80 years of age), indicating that there was no decline in efficacy with increasing age and that an age-independent immune response is the most likely protective mechanism of this vaccine.¹³ This greatly differed with the approved live attenuated vaccine (Zostavax^®), which was found to decline in efficacy with increasing age.¹³

Further trials of the adjuvanted subunit HZ/su vaccine include current ongoing clinical trials examining the vaccine immunogenicity and safety in renal transplant recipients and evaluating HZ/su efficacy in autologous hematopoietic stem cell transplant (HSCT) recipients.¹⁴ In addition, a direct head-to-head comparison study between Zostavax^® and HZ/su in the older adult population (ages 50-85) is currently underway to compare the age effect and persistence of both vaccines’ immune responses.¹⁴

Conclusion

Shingrix^®, a new recombinant subunit vaccine, has shown a great deal of promise in the prevention of HZ in adults over the age of 50. The combination of zoster viral glycoprotein E and the AS01B adjuvant system make it a safe, efficacious option for the elderly as well as immunosuppressed individuals. In addition, by preventing HZ, individuals can avoid postherpetic neuralgia, a long-term, debilitating complication associated with HZ. Due to its demonstrated efficacy and safety, Shingrix^® is now considered the first-line prophylactic vaccine for those at risk of HZ.

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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