Introduction
Granuloma annulare (GA) is an inflammatory dermatosis that clinically presents as erythematous papules or plaques arranged in an annular configuration on the upper extremities; the lesions may be isolated or generalized and atypical presentations with perforating, subcutaneous lesions or unusual localization (genitals) have been described [1].
The diagnosis of GA may be established clinically in typical cases, whereas skin biopsy and clinicopathological correlation are particularly useful in atypical, disseminated, or diagnostically uncertain presentations. Differential diagnoses include erythema nodosum, erythema annulare centrifugum, elastosis perforans serpiginosa, foreign body granuloma, insect bite, lichen planus, necrobiosis lipoidica diabeticorum, sarcoidosis, and others. Histopathologically, GA is characterized by histiocytes arranged in either a palisaded granulomatous or interstitial pattern, associated with dermal mucin, degenerated collagen, and occasionally, multinucleated giant cells.
Although the exact pathogenesis is unknown, the disease is linked to a delayed‐type hypersensitivity reaction. Specifically, a Th1 response involving IFN‐gamma‐stimulated macrophages triggers the release of matrix metalloproteinases, ultimately resulting in connective tissue degradation [1].
Topical and intralesional corticosteroids are commonly used, but responses are variable, especially in disseminated disease. The inflammatory target lies within the dermis, and topical efficacy may be limited by the barrier function of the stratum corneum. Ethoxydiglycol, also known as diethylene glycol monoethyl ether or DEGEE, is a hydrophilic solvent used in topical formulations as a solubilizer and penetration/retention modifier [2, 3].
Case History
We report two patients with biopsy‐confirmed disseminated granuloma annulare who showed only a partial response to clobetasol propionate (CPO) 0.05% ointment in a petrolatum‐based vehicle containing propylene glycol, both of whom improved after switching to clobetasol propionate 0.05% topical solution in DEGEE.
The first patient was a 29‐year‐old woman with a history of Graves' disease. She presented with a 3‐month history of mildly pruritic disseminated papules involving the trunk (Figure 1A) and upper limbs, including the hands. The second patient was a 75‐year‐old man with a 5‐month history of disseminated papulo‐annular lesions involving the trunk (Figure 1C).
Methods
Histopathological examination showed a palisading pattern of GA in the first patient and an interstitial pattern in the second patient, with an inflammatory infiltrate involving the superficial and mid‐reticular dermis in both cases (Figure 2A,B).
Both patients had previously shown an unsatisfactory response to a commercially available CPO 0.05% ointment (Clobesol; GlaxoSmithKline S.p.A., Verona, Italy), applied once daily for 15 days, with partial resolution of the lesions and recurrence after treatment discontinuation. As they declined intralesional and systemic treatment options, treatment with a compounded CPO was initiated at the next follow‐up visit, 4 weeks later. The compounded formulation was prepared by dissolving clobetasol propionate powder in diethylene glycol monoethyl ether (DEGEE) under continuous stirring to obtain a final concentration of 0.05% w/v (0.5 mg/mL).
DEGEE served as both the solvent and the vehicle, producing a clear liquid topical solution. The formulation was applied without occlusion once daily for 15 days as induction therapy, then on alternate days for the following 15 days, and twice weekly for a further month.
Results
Complete clinical clearance was achieved by the end of the 15‐day induction phase. At the 3‐month assessment from treatment initiation, both patients remained free of active lesions (Figure 1B,D). No local adverse events were detected.
Discussion
The management of disseminated GA remains challenging because no standardized treatment algorithm is supported by high‐quality evidence, and most reported therapies, including topical, intralesional, and systemic corticosteroids, phototherapy, and systemic agents, are based primarily on case reports and small series [4].
GA may follow a relapsing course, with recurrence frequently occurring after treatment discontinuation [5]. In both our patients, complete clinical clearance was achieved during the induction phase and was maintained while treatment frequency was progressively reduced, with no recurrence. Although the relative contributions of the vehicle and treatment schedule cannot be separated, this regimen may have supported sustained disease control.
Strategies used to optimize drug delivery include physical methods, vesicular systems, drug–vehicle interactions, and chemical penetration enhancers [6, 7]. Since the stratum corneum is the main barrier to percutaneous absorption, chemical enhancers are intended to modify drug partitioning and/or diffusion across this layer [6]. Our compounded preparation used the same active ingredient as the commercial ointment used as the initial treatment but is integrated with DEGEE, a hydrophilic solvent that may enhance drug solubilization and cutaneous retention.
DEGEE is a low‐viscosity ether alcohol with marked cosolvent and skin‐penetration‐enhancing properties [2]. Compared with the commercial petrolatum‐based formulation containing propylene glycol, the DEGEE‐containing vehicle may have altered clobetasol propionate solubilization and its partitioning between the formulation and the skin [2, 7]. Experimental studies suggest that DEGEE can increase solubility within the stratum corneum [8] and, depending on the active compound and formulation, promote cutaneous accumulation without a corresponding increase in transdermal permeation [9].
In corticosteroid formulations, DEGEE has also been associated with increased skin retention and the formation of an intracutaneous drug depot [10]. These effects could have increased the local cutaneous availability of clobetasol propionate, thereby providing a plausible pharmacotechnical explanation for the improved clinical response observed after switching formulations.
The two predominant histopathological patterns of granuloma annulare are the interstitial and palisading patterns [11]. In the interstitial pattern, observed in Patient 2, histiocytes are dispersed between collagen bundles, usually within the superficial‐to‐mid dermis, whereas the palisading pattern, observed in Patient 1, is characterized by histiocytes surrounding foci of altered or necrobiotic collagen at variable dermal depths. Since the inflammatory target may therefore lie at different distances from the skin surface, the depth and distribution of the infiltrate could plausibly influence the response to topical therapy.
This possibility may be particularly relevant to topical treatment because a more superficially located infiltrate could be more readily reached by an optimized formulation. In our two cases, the relatively superficial dermal distribution observed histologically may have facilitated corticosteroid penetration and delivery to the inflammatory target. However, given the limited number of observations, this interpretation should be regarded as hypothesis‐generating and not as evidence of an established predictor of treatment response.
Conclusion
The response observed after the change in formulation supports the potential relevance of vehicle optimization in selected patients with GA.
These cases suggest that optimization of the vehicle may enhance the therapeutic performance of topical corticosteroids in GA. The possible influence of histological depth on treatment response remains a hypothesis‐generating observation that requires evaluation in larger studies.
Author Contributions
Alexandre Raphael Meduri: writing – original draft, writing – review and editing, conceptualization. Giorgia Sbarra: conceptualization, investigation, data curation. Giulia Ciccarese: writing – review and editing.
Paolo Danza: writing – review and editing. Vincenzo Scarano: writing – review and editing. Francesca Ambrogio: writing – review and editing.
William Andrew Rosato: writing – review and editing. Gerardo Cazzato: writing – review and editing, writing – original draft, supervision. Mario Della Mura: writing – review and editing, writing – original draft.
Giuseppe Demichele: writing – review and editing. Caterina Foti: methodology, writing – review and editing, supervision, conceptualization, investigation.
Funding
The authors have nothing to report.
Ethics Statement
The study was conducted in accordance with the principles of the Declaration of Helsinki.
Consent
Written informed consent was obtained from both patients for the publication of their clinical information and accompanying images.
Conflicts of Interest
The authors declare no conflicts of interest.