A New Case of Allergic Contact Dermatitis to Topical Simvastatin Used for Treatment of Porokeratosis

Topical statins (primarily simvastatin and lovastatin) have recently been introduced as a pathogenesis-directed treatment for disseminated actinic porokeratosis and other related forms of porokeratosis. We report a new case of allergic contact dermatitis following the use of a compounded preparation containing simvastatin and cholesterol in this context. A 74-year-old patient with no significant medical history presented with linear porokeratosis on the right lower limb, which developed a few days after a total hip prosthesis implantation. The diagnosis of porokeratosis was confirmed histologically through a skin biopsy. Several topical treatments, including high-potent corticosteroids, calcipotriol and 5-fluoro-uracil ointments, were ineffective. He was subsequently treated with a compounded topical preparation containing 2% simvastatin and 2% cholesterol in a cold cream base (paraffinum liquidum, cera alba, cetyl palmitate and water) applied twice daily, which resulted in significant improvement of the skin lesions. Two months later, the patient received a second magistral preparation with the same concentration of simvastatin and cholesterol but in a different cream base, which included other excipients such as cetyl alcohol, propylene glycol, pentylene glycol and chlorphenesin. A few days after using this second preparation, the patient developed large, pruritic, erythematous, vesicular, crusted and/or squamous lesions over the porokeratotic areas of the right lower limb, with extension to the left calf, ankle and buttocks (Figure 1). The topical treatment was discontinued, and a high-potent corticosteroid cream was applied, leading to an improvement in the inflammatory lesions. Patch tests were conducted on the upper back using IQ Ultra chambers (Chemotechnique Diagnostics, Vellinge, Sweden) occluded for 2 days with Opertape (Iberhospitex, Innovative Health Technologies, Barcelona, Spain). The European baseline series was tested along with additional haptens recommended by the REVIDAL-GERDA network (Réseau de Vigilance en Dermato-Allergologie du Groupe d'Etude et de Recherche en Dermato-Allergologie), 1% simvastatin in petrolatum (pet.) and 1% cholesterol in pet. from our hospital pharmacy. The patient's personal products (both preparations containing simvastatin and cholesterol) were tested ‘as is’ along with some of the ingredients from the second preparation such as propylene glycol 30% in water (aq.), pentylene glycol 10%aq., chlorphenesin 0,3% aq. and cetyl alcohol 5% in pet. The haptens were supplied by Chemotechnique Diagnostics except for pentylene glycol (Dipta, Aix-en-Provence, France) and chlorphenesin (provided by a cosmetic manufacturer). Patch tests were read on days 2 (D2) and 4 (D4) according to the ESCD recommendations [1]. All tests were negative except for simvastatin 1%pet. + on D2 and ++ on D4, and both preparations containing simvastatin ++ on D2 and D4, resulting in a final diagnosis of allergic contact dermatitis to topical simvastatin (Figure 2). Five controls tested with simvastatin 1% pet showed negative results. Subsequently, patch tests with other available statins (only on a tablet form), such as pravastatin, fluvastatin (both from Arrow, Lyon, France), rosuvastatin (Téva Santé, La Défense, France) and atorvastatin (EG Labo, Issy les Moulineaux, France) in 30%pet. and aq. according to the guidelines for performing skin tests with drugs were carried out in our patient with negative results on D2, D4 and D7 [2]. Porokeratosis is a heterogeneous group of cutaneous disorders characterised by abnormal keratinization secondary to somatic genetic alterations in the mevalonate pathway in some subsets, resulting in a reduction of skin cholesterol content and an accumulation of toxic metabolites (i.e., mevalonate) in these cases. Accordingly, topical cholesterol/statin therapy has recently been proposed as a pathogenesis-directed treatment for various forms of porokeratosis to prevent the accumulation of mevalonate in the skin (via statins) while compensating for cholesterol deficiency and has proven to be effective [3]. Topical statin treatment is usually considered safe although the follow-up in most reports has been brief (< 12 weeks) [4]. To our knowledge, only one case of allergic contact dermatitis to simvastatin in a compounded preparation has been reported in a patient concurrently receiving oral rosuvastatin for hypercholesterolemia without any notable side effects [5]. In our case, chronic intermittent application over a prolonged period may have promoted sensitisation. Additionally, the potential for enhanced skin penetration of simvastatin due to the presence of glycols, such as propylene glycol and pentylene glycol in the second preparation cannot be ruled out, leading also to an increased risk of cutaneous sensitisation. Interestingly, simvastatin has already been identified as a skin sensitiser, with a few cases of airborne sensitisation, most often considered as an occupational allergic contact dermatitis [6-8]. Another statin, lovastatin (which is not available in France) is also used in compounded preparations for similar indications but no cases of allergic contact dermatitis have been reported with this molecule to date [9]. Cross-reactions with other commercially available oral statins, particularly pravastatin (which shares a naphthalene ring structure with simvastatin and lovastatin) were not observed in our patient (Figure S1). Nadia Raison-Peyron: conceptualization, methodology, investigation, supervision, visualization, project administration, writing – original draft, writing – review and editing. Céline Girard: methodology, investigation, writing – review and editing. Manon Girod: methodology, investigation, writing – review and editing. Olivier Dereure: project administration, resources, supervision, writing – review and editing. The authors declare no conflicts of interest. Figure S1. Chemical classification of statins. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.