Treatment of Subcorneal Pustular Dermatosis without Dapsone: A Case Report and Review of the Literature

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.


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 diferentiated by negative direct immunofuorescence studies [3].
Dapsone is the established frst-line treatment for SPD but may not be appropriate for all patients due to refractory disease or serious potential side efects 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.

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.Te 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 flled with neutrophils and negative direct immunofuorescence studies.Tis was consistent with a diagnosis of subcorneal pustular dermatosis (also known by the eponym Sneddon-Wilkinson syndrome).Serum protein electrophoresis and serum immunofxation did not show evidence of a monoclonal gammopathy.Rheumatologic studies including ANA and rheumatoid factor were negative.

Treatment Course.
Te 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 selfdiscontinued 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 × 10 9 /L and 0.4 × 10 9 /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.Te 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 signifcant improvement of her SPD rash and noted almost complete clearance of her trunk and upper extremity lesions; the lesions on her legs resolved within   Case Reports in Dermatological Medicine    [50] "Early 20s"-year-old male with mycoplasma pneumoniae infection Topical steroids: complete remission in 1 week

Vitamin B derivatives
Ribofavin + nicotinamide Yamaguchi et al. [54] 62-year-old male Vitamin B2 ribofavin low dose and subsequent 1500 mg/day oral nicotinamide: gradual improvement with clearance at 2 months

Xanthine derivatives Pentoxifylline
Falcone et al. [55] "20s"-year-old female Pentoxifylline 400 mg TID: remission for 7 years, only one fare which was treated with prednisone Case Reports in Dermatological Medicine 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 signifcant improvement.

Discussion
Tis 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 frst-line treatment for SPD, it carries serious potential side efects such as hemolytic anemia, agranulocytosis, or dapsone hypersensitivity syndrome (DHS) [2,4].No consensus exists regarding next-best agents for SPD.

Colchicine for SPD.
Colchicine is a low-risk medication that may be considered in neutrophilic dermatoses.It is an antineutrophilic drug that has demonstrated efcacy in neutrophilic dermatoses such as Sweet's syndrome and palmoplantar pustulosis [6].It is relatively afordable and well tolerated, with the most common side efects being diarrhea and vomiting; however, these side efects 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 efcacy of colchicine for SPD have not been summarized.We performed literature review to identify published case reports of SPD treated with colchicine.Te results of our fndings are summarized in Table 1.Four case reports describe colchicine leading to the resolution of symptoms, [8][9][10][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 signifcant promise as a dapsone-alternative therapy for a subset of patients with SPD.Insufcient data were included in the case reports to draw conclusions about what patient characteristics may be associated with positive response to colchicine.

Proposing a Treatment Algorithm.
Due to dapsone's side efect profle, we argue for early consideration of dapsonealternatives such as colchicine in patients at risk for dapsone intolerance.Tis includes patients with pre-existing anemia, G6PD defciency, 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).Tese 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,

First line Dapsone
Established efficacy, however high risk and requires laboratory monitoring.

Topical steroids
Low risk, and efficacious alone or in combination with other medications.

Colchicine
Low risk, however published case reports suggest mixed efficacy.

Retinoids
Efficacy demonstrated in multiple case reports, however high risk and requires laboratory monitoring.

Third line Phototherapy
Low risk, with three case reports demonstrating efficacy.However, may be logistically difficult for patients to obtain, especially long-term.

Systemic steroids
A multitude of case reports demonstrate their efficacy alone or in combination with other medications, however not a good long-term treatment.

TNF Inhibitors
Three case reports demonstrate their efficacy, however not an ideal treatment due to immunosuppression.

Apremilast
Low risk, however only one published case report demonstrating efficacy.

Doxycycline
Low risk, however only one published case report demonstrating efficacy.8 Case Reports in Dermatological Medicine 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 signifcant work to be done in determining safe and efcacious 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.Tus, this algorithm provides a reasonable starting point for shared clinical decision-making with patients.

Table 1 :
Colchicine therapy for subcorneal pustular dermatosis.Colchicine 0.5-1.5 mg/day: started when patient had PPP eruption, not SPD (although had a recent history of SPD previously controlled with dapsone).At 12 month follow-up after starting colchicine and discontinuing dapsone, patient did not have relapse