Use of Topical Glycolic Acid Plus a Lovastatin-Cholesterol Combination Cream for the Treatment of Autosomal Recessive Congenital Ichthyoses

This case series evaluates the use of topical glycolic acid plus a lovastatin-cholesterol combination cream to treat autosomal recessive congenital ichthyoses.

Key Points

Question

Could a therapeutic regimen of glycolic acid cream plus a lovastatin-cholesterol combination cream be used to treat treatment-refractory autosomal recessive congenital ichthyosis (ARCI)?

Finding

In this case series involving 15 patients with treatment-refractory ARCI, treatment with the study drug for 3 months was associated with an average reduction in disease severity score of 33.7% at 2 months and 57.5% at 3 months.

Meaning

This therapeutic regimen may be used in difficult-to-treat ARCI as well as other dermatoses involving a defective skin barrier.

Abstract

Importance

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders caused by defects in signaling pathways involved in epidermal proliferation and differentiation, leading to a wide range of skin manifestations. Therapeutic options are limited and often unsatisfactory. Topical cholesterol and statin as a combined formulation has proven successful in the treatment of patients with CHILD syndrome (congenital hemidysplasia ichthyosis and limb defects).

Objective

To assess change in disease severity score after a 3-month therapeutic regimen consisting of a glycolic acid, 10% to 20%, cream and a combination cream of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI.

Design, Setting, and Participants

This case series of 15 patients with ARCI was conducted at the American University of Beirut, a referral center in the Middle East region for genodermatoses, between May 2017 and January 2018. No age groups were excluded; all patients were from the Middle East area; and all were initially not responsive to treatment with hydrating creams in combination with urea creams, 30% to 40%, or glycolic acid, 10% to 20%. Excluded were patients who had been taking systemic retinoids within 3 months before the start of the study.

Interventions

A 3-month therapeutic regimen of glycolic acid, 10% to 20%, cream and a combination of lovastatin, 2%, with cholesterol, 2%, cream.

Main Outcomes and Measures

Percentage change in disease severity scores following 2 and 3 months of study treatment.

Results

Of the 15 patients included in the study, 10 were male (mean age, 11.2 years; age range, 2-38 years). The average percentage reduction in the disease severity score was 33.7% at 2 months (from 60.8 to 40.2) and 57.5% at 3 months (from 60.8 to 21.9). Adverse effects were mild and consisted mainly of irritation and burning.

Conclusions and Relevance

These findings suggest a benefit from a treatment regimen consisting of glycolic acid, 10% to 20%, and a combination of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI. This combination of creams might also prove to be beneficial in other types of ichthyoses and other dermatological diseases with a defective skin barrier.

Introduction

Ichthyosis refers to a set of inherited and acquired disorders of keratinization in which the skin is covered by an excessive amount of scales, resulting in a thick yet dysfunctional skin barrier. Among the most commonly encountered inherited nonsyndromic ichthyoses in Lebanon is a subgroup referred to as autosomal recessive congenital ichthyosis (ARCI).¹ The mainstay of treatment involves the use of hydrating agents and keratolytics, including topical glycolic acid, urea, salicylic acid, and retinoids, among others. Systemic retinoids can also be used in select cases.²

The formation of the physiologic skin barrier and its normal differentiation rely on the normal production of lipids, particularly cholesterol. Disturbances in cholesterol production and metabolism are involved in the pathogenesis of many skin diseases, including ichthyosis.³

Topical cholesterol replacement has been previously used, with variable success, in the management of x-linked ichthyosis caused by mutations in the steroid sulfatase gene.^4,5 Our research group and others^6,7,8,9 have used a combination of lovastatin, 2%, and cholesterol, 2%, cream for the treatment of cutaneous manifestations in a rare ichthyosiform condition known as CHILD syndrome (congenital hemidysplasia ichthyosis and limb defects). The lovastatin serves to inhibit local 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme activity and thus the production of toxic metabolites, and the cholesterol compensates for the endogenous cholesterol normally produced in the skin.^6,7,8,9

In the present study, we assess the clinical value of a combination topical therapy for the treatment of 15 treatment-resistant cases of ARCI: glycolic acid, 10% to 20%, plus the combination cream lovastatin, 2%–cholesterol, 2%.

Methods

The Department of Dermatology at the American University of Beirut Medical Center maintains a large database of genodermatosis cases among Lebanese and Middle Eastern families. From this database, we recruited 15 patients with topical treatment–resistant lamellar ichthyosis who had undergone no oral treatment for at least 3 months. All participants had consanguineous parents and were clinically and genetically diagnosed with ARCI. The study was approved by the institutional review board at the American University of Beirut, and all patients provided their written informed consent.

Treatment consisted of 3 different components: glycolic acid, statin, and cholesterol. Glycolic acid, 10%, was applied on the face; glycolic acid, 15% or 20%, was applied on the body. The frequency of application varied from nightly application to every other night, depending on tolerability. The combination cream of lovastatin, 2%, and cholesterol, 2%, was applied every morning on all affected areas. All patients were asked if they would be willing to participate in a smaller left sided vs right sided trial, and those who agreed were asked to apply the combination lovastatin-cholesterol cream on 1 side of the body only (eg, right arm and right leg) to assess the additive effects of the combination cream.

Patients were scheduled for monthly visits, for up to 3 months, during which they were provided with the study creams, and the ARCI was assessed for improvement. The primary outcome was clinical improvement after 3 months of treatment.

Scoring System

Each patient was given a severity score based on 5 criteria: (1) skin thickness and/or scaling; (2) pain, pruritus, and/or discomfort; (3) erythema; (4) impact of the condition on the ability to perform daily functions; and (5) the patient’s subjective severity scoring, ie, the patient’s own assessment of the severity of the condition. The degree of improvement at follow-up was assessed by the percentage reduction in the severity score compared with baseline. A reduction of 0% to 9.9% was considered a poor response; 10.0% to 24.9%, a fair response; 25.0% to 49.9%, good response; 50% to 74.9%, very good response; and 75% to 100%, excellent response.

Results

A total of 15 patients with ARCI were enrolled in the study. The average patient age was 11.2 years (range, 2-38 years); 10 (67%) were male, and 5 (33%) were female. More information about the study participants and outcomes is available in the Supplement.

Primary Outcome

The average severity scores at baseline and 2- and 3-month follow-up evaluations were 60.8, 40.2, and 21.9, respectively. The average percentage reductions in the severity scores were 33.7% at 2 months (mild response) and 57.5% at 3 months (good response). Overall, at 2 months, 7 patients had achieved a mild response; 2 patients, a good response; and 6 patients, a very good response. At 3 months, 2 patients had achieved a mild response; 2 patients, a good response; 9 patients, a very good response (Figure 1); and 2 patients, an excellent response (Figure 2).

Figure 1. Clinical Manifestation in Patient 4 of Autosomal Recessive Congenital Ichthyosis.

Patient 4 before (A) and 3 months after (B) treatment with the study medication. A very good response was noted, ie, 72.7% improvement from baseline in the disease severity score.

Figure 2. Clinical Manifestation in Patient 11 of Autosomal Recessive Congenital Ichthyosis.

Patient 11 before (A) and 3 months after (B) treatment with the study medication. An excellent response was noted, ie, 79.3% improvement from baseline in the disease severity score.

Secondary Outcomes

Five patients applied the combination cream of lovastatin and cholesterol on the right side of the body only, while the glycolic acid was applied to both sides (patients 1, 2, 3, 4, and 6). As detailed in eTable 4 of the Supplement, in all 5 of these patients, a better response was noted on the sides where the combination cream was applied compared with the sides where it was not. This points to a potentially significant role for the lovastatin-cholesterol combination in the treatment of ARCI. However, owing to the small number of patients, definite conclusions cannot be drawn.

Adverse effects reported by patients were mild erythema, scaling, and burning. These effects were transient and resolved rapidly after altering the frequency of application.

Discussion

Cholesterol is an integral component of all cell membranes. It contributes to the barrier function of the epidermis. The “cholesterol sulfate cycle” is also essential for the development and maturation of keratinocytes. In the lower epidermis, cholesterol is sulfated by the enzyme cholesterol sulfotransferase (SULT2B1b) to form cholesterol sulfate, which is then de-sulfated by the enzyme steroid sulfatase in the outer epidermis.³ Studies suggest that cholesterol sulfate is not only a marker of differentiation but also a signaling molecule involved in the regulation of keratinocyte differentiation.^10,11 While many of the ichthyoses are associated with inherited disorders of lipid metabolism, the particular importance of the cholesterol cycle is highlighted in patients with x-linked ichthyosis due to loss-of-function mutations in the steroid sulfatase gene. In the past, studies evaluating the therapeutic role of cholesterol in x-linked ichthyosis have failed to recognize the role of generated toxic metabolites in the pathogenesis of the disease. This explains, in part, the inconsistent results obtained after treatment with topical cholesterol.^4,5 Adding a topical statin to the treatment regimen allows the inhibition of endogenous cholesterol production, thus preventing the accumulation of toxic metabolites that may disrupt skin differentiation. Although the direct role of the cholesterol metabolic pathway is most clear in x-linked ichthyosis, we believe that this pathway also plays an important role in ARCI. Many of the genes that are mutated in ARCI are involved in lipid metabolism (SULT2B1, ALOX12B, ALOXE3, PNPLA1, CERS3, LIPN) and are either directly or indirectly linked to the cholesterol pathway.

We evaluated the therapeutic efficacy of a treatment regimen consisting of a glycolic acid, 10% to 20%, cream and a combination cream of lovastatin, 2%, with cholesterol, 2%, in the treatment of 15 patients with ARCI who had responded poorly to other topical medications. Glycolic acid was used as a keratolytic agent to allow for better penetration of the lovastatin-cholesterol combination cream. Interestingly, the average percentage reductions in the disease severity scores were 33.7% at 2 months (mild response) and 57.5% at 3 months (good response). Nine patients had very good responses, and 2 had excellent responses; ie, at least 75% of the patients had more than 50% improvement. Among the 5 patients who applied the lovastatin-cholesterol combination cream only on the right side of the body, we observed significant improvement when compared to the left side. Adverse effects were mild and transient and were limited to irritation and burning secondary to the glycolic acid.

Limitations

Limitations of our study include the small number of patients, the subjective nature of some of the scoring criteria, and the use of a nonvalidated scoring system.

Conclusions

In conclusion, our study points to potential benefits of a treatment regimen consisting of glycolic acid, 10% to 20%, cream and a combination cream of lovastatin, 2%, with cholesterol, 2%, in the treatment of patients with ARCI.

Supplement.

eFigure. The cholesterol metabolic pathway and the cholesterol sulfate cycle

eTable 1. Scoring criteria

eTable 2. Baseline patient characteristics

eTable 3. Severity score before, 2 months and 3 months after treatment

eTable 4. Response in patients who applied the combination of statin with cholesterol on the right side of the body only