Combined dapsone and sulfapyridine for the treatment of therapy-resistant linear IgA bullous dermatosis: Two case reports

Linear IgA bullous dermatosis (LABD) is a rare autoimmune vesiculobullous disease causing blistering lesions of the skin and mucosa.1Venning V.A. Linear IgA disease: clinical presentation, diagnosis, and pathogenesis.Immunol Allergy Clin North Am. 2012; 32: 245-253,vihttps://doi.org/10.1016/j.iac.2012.04.004Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar LABD typically presents in either early childhood or adulthood.2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,3Genovese G. Venegoni L. Fanoni D. Muratori S. Berti E. Marzano A.V. Linear IgA bullous dermatosis in adults and children: a clinical and immunopathological study of 38 patients.Orphanet J Rare Dis. 2019; 14: 115https://doi.org/10.1186/s13023-019-1089-2Crossref PubMed Scopus (21) Google Scholar The pathogenesis is characterized by a linear deposition of IgA at the dermoepidermal junction.2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar LABD can be idiopathic or drug-induced (typically by vancomycin, β-lactam antibiotics, or nonsteroidal anti-inflammatory drugs).4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar Children frequently present with widespread annular blisters, with predilection of the lower portion of the abdomen, genital areas, and thighs.5Wojnarowska F. Marsden R.A. Bhogal B. Black M.M. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap.J Am Acad Dermatol. 1988; 19: 792-805https://doi.org/10.1016/s0190-9622(88)70236-4Abstract Full Text PDF PubMed Google Scholar,6Mintz E.M. Morel K.D. Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood.Dermatol Clin. 2011; 29: 459-462,ixhttps://doi.org/10.1016/j.det.2011.03.022Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar In adults, the clinical presentation varies and annular lesions are less common.5Wojnarowska F. Marsden R.A. Bhogal B. Black M.M. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap.J Am Acad Dermatol. 1988; 19: 792-805https://doi.org/10.1016/s0190-9622(88)70236-4Abstract Full Text PDF PubMed Google Scholar,7Guide S.V. Marinkovich M.P. Linear IgA bullous dermatosis.Clin Dermatol. 2001; 19: 719-727https://doi.org/10.1016/s0738-081x(00)00185-1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The reported incidence of LABD varies from <0.5 to 2.3 cases per 1 million population/year.2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Dapsone is often reported the most effective drug of choice and is frequently used as first-line therapy. Other treatment options include sulfonamide drugs, such as sulfapyridine/sulfamethoxypyridazine, corticosteroids, colchicine, and other immunosuppressive agents.2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar,7Guide S.V. Marinkovich M.P. Linear IgA bullous dermatosis.Clin Dermatol. 2001; 19: 719-727https://doi.org/10.1016/s0738-081x(00)00185-1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,8Benbenisty K.M. Bowman P.H. Davis L.S. Localized linear IgA disease responding to colchicine.Int J Dermatol. 2002; 41: 56-58https://doi.org/10.1046/j.1365-4362.2002.01321.xCrossref PubMed Scopus (20) Google Scholar Herein, we present 2 case reports of patients with LABD successfully treated with a combination of dapsone and sulfapyridine. A 2-year-old, otherwise healthy girl presented with vesiculobullous lesions on the extremities, neck, abdomen (Fig 1, A) and, especially, the vulva and buttocks. Complaints of itching and sleep deprivation were reported. The lesions were on an erythematous base and with a rosette-like pattern. Before onset, the patient had diaper dermatitis, treated with oral amoxicillin. Microbiologic test results were negative for herpes and bacteria. Histopathology (including immunofluorescence) confirmed the diagnosis of LABD, revealing a linear IgA deposit at the epidermal basal membrane zone as well as a dermal infiltration of neutrophils. Treatment with 10 mg/day of oral dapsone was initiated (1 mg/kg/day), and the patient initially responded well. However, after a few weeks of treatment, the disease progressed, with the development of new vesiculobullous lesions in the same regions (Fig 1, B). The lesions were painful and pruritic. The treatment was supplemented with 10 mg/day of prednisone as well as a topical steroid treatment and potassium permanganate baths. During the following 6 months, the dapsone dose was slowly increased to 20 mg/day, with varying prednisone dosing, but the disease was never fully controlled by this regimen. Sulfapyridine (250 mg/day; 23 mg/kg/day) in combination with prednisone was then attempted and later increased to 500 mg/day (44 mg/kg/day). This treatment regimen led to temporary prednisone-related growth suppression and excessive hair growth, and the patient again developed several new bullae. Eventually, a combination of dapsone (10 mg/day) and sulfapyridine (500 mg/day) was initiated.9Hardman C. Leonard J. Sulphapyridine and sulphamethoxypyridazine.in: Wakelin S.H. Systemic Drug Treatment in Dermatology. 1st ed. CRC Press, 2002: 201-208https://doi.org/10.1201/b16367Google Scholar After a few weeks, the patient responded significantly to the treatment combination (Fig 1, C). Over the next 6 weeks, the prednisone was tapered off, and no new vesicles or bullae occurred after the introduction of the combination therapy. A 55-year-old man presented to our clinic with a highly itchy rash located on the abdomen, neck, back, and extremities (Fig 2, A and B). The lesions were annular, with a characteristic rosette-like pattern. The patient reported earlier bullae formations. The patient’s comorbidities included hypertension, diabetes, and obesity. Regular medications were thoroughly reviewed, and no new medication had been initiated within the 6 months prior to the disease presentation. Histopathologic investigations revealed bullae formation and infiltration by neutrophils, and immunofluorescence revealed linear IgA deposits at the dermoepidermal junction compatible with LABD (Fig 2, E). Treatment with dapsone (50 mg/day) was started, in combination with topical steroids and potassium permanganate baths. Initially, the patient experienced a partial response. However, after 1 month, progression occurred, and the dapsone dose was increased to 100 mg/day. After 3 months, the patient developed several new bullae, and the dapsone dose was further increased (150 mg/day), together with a prednisone course (40 mg/day for 2 weeks and then tapered off). In the following 2.5 years, the disease control was maintained by dapsone treatment and a few courses of prednisone. However, the patient then experienced moderate-to-severe progression, especially involving the hands (Fig 2, C) and buttocks, and the treatment regimen was changed from dapsone to sulfapyridine (1000 mg/day, increasing to 1500 mg/day). After a couple of weeks, the patient experienced severe progression, and dapsone (150 mg/day) was reintroduced. On this treatment combination, the patient quickly recovered (Fig 2, D), and the skin lesions completely cleared, with only postinflammatory hyperpigmentation remaining. To date, no relapse has occurred on the treatment combination. LABD is a rare vesiculobullous skin disease characterized by the linear deposition of IgA at the dermoepidermal junction. LABD often has an abrupt onset, with new blister formation, with an annular appearance resembling rosettes.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar The gold-standard diagnostic method is skin biopsy including direct immunofluorescence, revealing the linear IgA deposits (Fig 2, E).2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,10Shin L. Gardner 2nd, J.T. Dao H.J. Updates in the diagnosis and management of linear IgA disease: a systematic review.Medicina (Kaunas). 2021; 57: 818https://doi.org/10.3390/medicina57080818Crossref PubMed Scopus (1) Google Scholar The evidence for the current treatment of LABD is limited and based on case reports and case series, and larger controlled trials are lacking.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar,10Shin L. Gardner 2nd, J.T. Dao H.J. Updates in the diagnosis and management of linear IgA disease: a systematic review.Medicina (Kaunas). 2021; 57: 818https://doi.org/10.3390/medicina57080818Crossref PubMed Scopus (1) Google Scholar Dapsone is generally well tolerated and is often used as a first-line therapy.2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,3Genovese G. Venegoni L. Fanoni D. Muratori S. Berti E. Marzano A.V. Linear IgA bullous dermatosis in adults and children: a clinical and immunopathological study of 38 patients.Orphanet J Rare Dis. 2019; 14: 115https://doi.org/10.1186/s13023-019-1089-2Crossref PubMed Scopus (21) Google Scholar The dose range for the treatment of LABD in adults is 50 to 150 mg/day, while the dose range for children has been reported at 0.5 to 2 mg/kg/day.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar Hematologic parameters should be monitored, since hemolysis (especially in patients with glucose-6-phosphate dehydrogenase deficiency), methemoglobinemia, and agranulocytosis are potential adverse effects.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar Sulfonamides have been reported as an effective treatment for LABD.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar However, the availability of these agents is limited in some countries. The sulfapyridine dose for the treatment of LABD in adults is 1000 to 1500 mg/day, while the dose range for children has been reported at 15 to 60 mg/kg/day.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar Adverse effects, including agranulocytosis, hemolysis, and elevated liver enzymes, may occur but are generally well tolerated.2Fortuna G. Marinkovich M.P. Linear immunoglobulin A bullous dermatosis.Clin Dermatol. 2012; 30: 38-50https://doi.org/10.1016/j.clindermatol.2011.03.008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,3Genovese G. Venegoni L. Fanoni D. Muratori S. Berti E. Marzano A.V. Linear IgA bullous dermatosis in adults and children: a clinical and immunopathological study of 38 patients.Orphanet J Rare Dis. 2019; 14: 115https://doi.org/10.1186/s13023-019-1089-2Crossref PubMed Scopus (21) Google Scholar Recommendations for the treatment of therapy-resistant LABD are lacking, although various options, including intravenous immunoglobulin, rituximab, tumor necrosis factor-α inhibitors, omalizumab, and a combination therapy of dapsone and sulfapyridine, have been suggested.4Hall RP, Rao CL. Linear IgA bullous dermatosis. In: Post TW, ed. UpToDate. 2020.Google Scholar,9Hardman C. Leonard J. Sulphapyridine and sulphamethoxypyridazine.in: Wakelin S.H. Systemic Drug Treatment in Dermatology. 1st ed. CRC Press, 2002: 201-208https://doi.org/10.1201/b16367Google Scholar We present 2 cases with histologically verified LABD. In both cases, initial monotherapy with dapsone or sulfapyridine was not sufficient to treat the skin lesions. However, the combination of dapsone and sulfapyridine effectively resulted in full, lasting remission in both patients. In conclusion, in LABD cases where both dapsone and sulfapyridine monotherapy have been attempted, combination therapy with dapsone and sulfapyridine should be considered. None disclosed. The authors thank the patients for their consent to participate in this study.