Abstract
Subcorneal pustular dermatosis (SPD) is a rare neutrophilic dermatosis characterized by pustules on the trunk and intertriginous areas. While oral dapsone is the first-line treatment for SPD, alternative options are necessary for patients with glucose-6-phosphate dehydrogenase deficiency, drug hypersensitivity reactions, or refractory disease. To date, no consensus exists regarding next-best agents for SPD. In this report, we present a patient with significant SPD who developed dapsone hypersensitivity syndrome and then was successfully treated with colchicine and adalimumab. We propose that colchicine should be considered as a second-line treatment for SPD and present a therapeutic algorithm for clinicians to utilize when patients are not candidates for dapsone, have side effects requiring drug discontinuation, or have refractory disease.
1. Introduction
Subcorneal pustular dermatosis (SPD) is a rare neutrophilic dermatosis characterized by pustules on the trunk and intertriginous areas [1, 2]. It is most common in middle-aged women and may be associated with underlying systemic disorders such as rheumatoid arthritis and monoclonal gammopathy [3]. SPD presents similarly to IgA pemphigus clinically and histopathologically but can be differentiated by negative direct immunofluorescence studies [3].
Dapsone is the established first-line treatment for SPD but may not be appropriate for all patients due to refractory disease or serious potential side effects such as hemolytic anemia, agranulocytosis, or dapsone hypersensitivity syndrome (DHS) [2, 4]. To date, no consensus exists regarding next-best agents for SPD. In this report, we present a patient with SPD who developed an acute drug reaction from dapsone and then was successfully treated with colchicine and adalimumab. We review the case report literature to summarize successful treatments of SPD and propose a novel treatment algorithm with second-line and third-line treatments to consider for SPD when dapsone fails or is not tolerated.
2. Case
A 67-year-old female with no pertinent past medical history presented to a university dermatology clinic in December 2021 with four years of a tender and pruritic rash on her legs, trunk, breasts, and arms. The rash was refractory to clobetasol 0.05% cream, betamethasone diproprionate 0.05% cream, intralesional triamcinolone acetonide-10, and halobetasol 0.05% cream.
Physical exam in December 2021 revealed multiple annular pink plaques studded with occasional pustules on the trunk and upper and lower extremities (see Figure 1). Repeat punch biopsies of the skin of the right breast and right thigh revealed subcorneal pustules filled with neutrophils and negative direct immunofluorescence studies. This was consistent with a diagnosis of subcorneal pustular dermatosis (also known by the eponym Sneddon–Wilkinson syndrome). Serum protein electrophoresis and serum immunofixation did not show evidence of a monoclonal gammopathy. Rheumatologic studies including ANA and rheumatoid factor were negative.
2.1. Treatment Course
The patient was started on dapsone 50 mg daily, up-titrating after ten days to 100 mg daily with topical corticosteroids. Glucose-6-phosphate dehydrogenase enzyme activity was within normal limits. At her one-month follow-up, her lesions showed dramatic improvement with absence of pustules and interim resolution of the patches on the abdomen.
Two days later, the patient noticed a new, pruritic erythematous macular eruption on her thighs and arms, fever with chills, but denied any facial swelling. She self-discontinued the dapsone. Laboratory studies performed three days later showed elevated liver function tests from the baseline including an aspartate aminotransferase of 191 U/L, alanine transaminase of 262 U/L, total bilirubin of 1.4 mg/dL, and alkaline phosphatase of 246 U/L. Her hemoglobin was 8.5 g/dL, and white blood cell and eosinophil count were within normal limits (7.0 × 109/L and 0.4 × 109/L, respectively). Given fever, transaminitis, and morbilliform eruption, there was clinical concern for dapsone hypersensitivity syndrome (DHS), a variant of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [5]. Oral prednisone 40 mg daily was initiated, followed by a 10-week taper. Liver function tests showed improvement with this course, and the new eruption cleared within 2 weeks of drug discontinuation.
Unfortunately, around one month after dapsone discontinuation and while still on 30 mg of oral prednisone daily, the patient’s SPD rash returned on the upper and lower extremities. Phototherapy with narrow-band ultraviolet-B light was denied by her insurance, so two weeks after the recurrence of rash, she was placed on acitretin 10 mg for 30 days. The acitretin helped the pruritus but failed to demonstrate improvement of skin lesions even with up-titration to 20 mg daily for an additional 60 days. Subsequently, adalimumab initiated at 40 mg every two weeks with improvement in pruritus but without change in skin lesions.
After 3 months, oral colchicine 0.6 mg daily was added. Within three weeks of starting colchicine, the patient experienced rapid significant improvement of her SPD rash and noted almost complete clearance of her trunk and upper extremity lesions; the lesions on her legs resolved within 6 weeks (see Figure 2). Because the patient had experienced an increase in mild upper respiratory infections while on adalimumab, approximately three months after starting colchicine, she attempted discontinuation of adalimumab with concomitant increase of colchicine to 1.2 mg daily, but within two weeks of her last dose of adalimumab, she began to experience recrudescence of the lesions on the legs. As a result, she resumed every-other week adalimumab injections and continued colchicine 1.2 mg daily, with significant improvement.
3. Discussion
This is a case of a 67-year-old female with SPD who, despite excellent disease resolution on dapsone, required discontinuation of the medication due to an acute drug reaction. Although dapsone is the established first-line treatment for SPD, it carries serious potential side effects such as hemolytic anemia, agranulocytosis, or dapsone hypersensitivity syndrome (DHS) [2, 4]. No consensus exists regarding next-best agents for SPD.
3.1. Colchicine for SPD
Colchicine is a low-risk medication that may be considered in neutrophilic dermatoses. It is an antineutrophilic drug that has demonstrated efficacy in neutrophilic dermatoses such as Sweet’s syndrome and palmoplantar pustulosis [6]. It is relatively affordable and well tolerated, with the most common side effects being diarrhea and vomiting; however, these side effects are seen less frequently at lower doses [6]. Additionally, colchicine is considered safe to use long-term based on studies that examine its use in gout and cardiovascular disease [7].
To our knowledge, data on the efficacy of colchicine for SPD have not been summarized. We performed literature review to identify published case reports of SPD treated with colchicine. The results of our findings are summarized in Table 1. Four case reports describe colchicine leading to the resolution of symptoms, [8–11] whereas 13 case reports report no improvement on the drug. Even so, due to colchicine’s low risk and ability to completely clear skin lesions in some patients, it presents significant promise as a dapsone-alternative therapy for a subset of patients with SPD. Insufficient data were included in the case reports to draw conclusions about what patient characteristics may be associated with positive response to colchicine.
3.2. Proposing a Treatment Algorithm
Due to dapsone’s side effect profile, we argue for early consideration of dapsone-alternatives such as colchicine in patients at risk for dapsone intolerance. This includes patients with pre-existing anemia, G6PD deficiency, or sulfa allergy or sensitivity [4]. A multitude of case reports published in the last 25 years describe success with oral retinoids, small-molecule inhibitors, phototherapy, biologics, and various topicals (Table 2). These case reports were gathered with a Boolean search on PubMed using the phrase “(“subcorneal pustular dermatosis” OR “Sneddon-Wilkinson disease”) AND (“case” OR “treatment”).” Case reports were not included in the table if they were not in English, were published before 1998, included dapsone as the primary successful treatment, and/or did not describe a successful treatment. From review of these data, we propose a novel treatment algorithm for SPD (Figure 3).
Overall, there is significant work to be done in determining safe and efficacious treatments for SPD. Our algorithm is based on case reports which are subject to publication bias and overinterpretation [56]. Further, our case describes a patient on colchicine and adalimumab simultaneously, without evaluating colchicine alone. However, given the rarity of this condition, it is unlikely that randomized controlled trials of treatments for SPD using existing agents such as dapsone, colchicine, oral retinoids, and TNF-alpha inhibitors are on the horizon. Thus, this algorithm provides a reasonable starting point for shared clinical decision-making with patients.
Data Availability
The data used to support the findings of this study can be obtained from the corresponding author upon request.
Consent
Written informed consent to publish the patient’s clinical information and photographs was obtained.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors’ Contributions
The authors Brittney Schultz and Amrita Goyal contributed equally. Brittney Schultz and Amrita Goyal are senior coauthors.