Dapsone or sulfapyridine is the treatment of choice for CBDC. Dapsone is a sulfone antibiotic approved for the treatment of dermatitis herpetiformis and leprosy in pediatric patients (lower age limit not specified). Sulfapyridine is a sulfonamide antibiotic that is no longer available in the United States, but is available in other countries. Although there are no controlled or comparative studies, there is ample anecdotal evidence in the form of case reports and case series to support the use of dapsone or sulfapyridine as monotherapy for the treatment of CBDC [7, 11, 13, 15, 16]. The response to treatment is usually rapid, with resolution of blisters within 2 weeks of starting therapy. Kenani et al. [10] performed a retrospective review of 25 children with CBDC. Nineteen children were treated with dapsone alone (1–2 mg/kg) and 11 of 19 patients achieved disease control after 8–15 days of therapy. Eight patients required the addition of systemic corticosteroids (0.5–1 mg/kg) to control their disease. The duration of treatment ranged from 3 to 60 months. Seventeen patients had achieved remission at the time of publication. Four patients developed methemoglobinemia that necessitated a reduction in dose or withdrawal of medication for a few days, but no other adverse effects were seen. Wojnarowska et al. [1] studied a series of 25 children with CBDC. All children were treated with either dapsone (20–200 mg) or sulfapyridine (0.5–2 g) and all had a response to treatment within 72 hours with relapses when the drug was withdrawn. Sixteen of 25 patients achieved remission over a variable time period of 6 months to 16 years (mean 5.3 years). Eight children were also treated with low dose systemic corticosteroids. Detailed treatment information and side effects were not provided. Marsden et al. [15] reported 20 children with CBDC treated with either dapsone (20–200 mg) or sulfapyridine (0.25–3 g); 12 of 20 children were well controlled with monotherapy and eight children required the addition of corticosteroids.

Again the evidence is anecdotal, but it is apparent from the literature that systemic corticosteroids are useful as adjunctive therapy for disease that is resistant to first line treatment and severe disease presentations (e.g., extensive blistering and erosions, severe pruritus, symptomatic mucous membrane involvement), but should be avoided as monotherapy due to the long-term side effects in children [3, 7, 10, 17, 18]. The most frequently used dose is 0.5–1 mg/kg (prednisone/prednisolone). The corticosteroids are continued until the disease is controlled, then they are tapered off, usually over a 3–6 week period. They can then be used intermittently for severe exacerbations if necessary. Wojnarowska et al. [1] used low dose systemic steroids (<10 mg; weight-based dosing not provided) in 8 of 25 children not controlled on dapsone or sulfapyridine and concluded that the value of the addition of low dose systemic corticosteroids is difficult to determine as the effect was neither rapid nor dramatic. If systemic corticosteroids are to be used, it appears at least moderate doses (0.5–1 mg/kg) are necessary.

Medium-potency topical corticosteroids have been reported to be useful as monotherapy for controlling very limited and mild disease [7]. Topical corticosteroids are frequently used as adjunctive therapy with systemic agents for symptom control.

The semisynthetic penicillins (oxacillin, cloxacillin, dicloxacillin, and flucloxacillin), macrolide antibiotics (erythromycin) and sulfonamides (trimethoprim-sulfamethoxazole) have all been reported to be useful for the treatment of CBDC [3, 10, 19–26]. Alajlan et al. [19] conducted a prospective observational study of seven children with confirmed CBDC treated with flucloxacillin (similar to dicloxacillin). Four of seven patients had a complete response to flucloxacillin and the medication was stopped after 2.5–4 months of therapy with no relapses. The remaining three patients had a complete response, but relapsed when flucloxacillin was stopped and have remained on treatment for 3–6 years. Interestingly, the patients treated within 1 month of disease onset responded better to flucloxacillin then patients with longstanding disease. Periodic monitoring of complete blood count (CBC) and liver function was done and no laboratory abnormalities or adverse effects were seen. An additional nine patients treated with semisynthetic penicillins have been reported with similar results [10, 20–22]. Erythromycin was first reported as an effective treatment by Cooper et al. [23]. A 5-year-old girl with CBDC with + IgA and IgG on DIF and IIF was treated with erythromycin with complete control of her disease within 2 weeks. Discontinuation of erythromycin led to a relapse of blisters and therefore she was on continuous therapy at least 24 months. Other authors have reported similar results [3, 10, 21]. A survey of members of the British Society for Pediatric Dermatology detailed 13 patients treated with erythromycin; used as monotherapy in five children and in combination with other agents (dapsone, prednisolone, nicotinamide, sulfamethoxypyridazine) in eight children. One patient had complete resolution, three had good improvement but relapsed, five patients had some improvement and four patients had minimal response. This data suggests that erythromycin alone is unlikely to produce a sustained remission [24]. Two patients cleared with trimethoprim-sulfamethoxazole within 1 week with no relapse and one cleared within 2 years [3, 25]. Pulimood et al. [26] reported a 2-year-old boy who continued to develop blisters despite dapsone 2.5 mg/kg for 3 weeks. The addition of trimethoprim-sulfamethoxazole led to resolution of blisters in 4 days and complete resolution of disease in 10 months. It is hypothesized that antibiotics are effective due to inherent anti-inflammatory and not antimicrobial properties. Antibiotics have a more favorable side effect profile than dapsone and systemic corticosteroids, require less frequent laboratory monitoring and may be a good alternative in select patients with mild to moderate disease.

Colchicine is an anti-inflammatory drug that is FDA approved in children 4 years and older for the treatment of familial Mediterranean fever. Colchicine appears to be a well-tolerated and effective treatment for CBDC and can be considered an alternative therapy in children with glucose-6-phosphate dehydrogenase deficiency (G6PD) or who develop intolerable side effects from dapsone [27–29]. Banodkar and Al-Suwaid [27] treated eight children with G6PD deficiency or steroid-dependent disease with colchicine 0.5 mg twice a day. Within 4–6 weeks of colchicine therapy, five patients showed a complete response without the need for corticosteroid therapy. Three patients had a good response, but still required corticosteroids, although at lower doses, to maintain remission. Two additional patients were reported with similar responses. One patient developed diarrhea, but overall colchicine was very well tolerated with no other adverse effects. No abnormalities on CBC or liver and renal function tests were seen.

Mycophenolate mofetil is an immunosuppressive agent that preferentially inhibits T-lymphocytes and has been reported to be an effective steroid-sparing agent in adults with immunobullous disease [30]. It is approved in infants and children for the prevention of renal allograft rejection. There is a single case report describing its use in a child with severe CBDC resistant to dapsone and requiring repeated pulses of corticosteroids for disease control [31]. Mycophenolate mofetil 310 mg/m², later decreased to 155 mg/m² due to lethargy and decreased oral intake, was initiated and she showed rapid improvement within a few days and was almost clear after 6 weeks of therapy with mycophenolate mofetil and dapsone without the need for additional corticosteroids.

Nicotinamide (30 mg/kg) plus dapsone was helpful in controlling CBDC in a 4-year-old girl who had not responded to high-dose dapsone and systemic corticosteroids over 3 months. Within 2 weeks she had complete resolution of her blisters and was successfully tapered over 12 weeks [32].

Tacrolimus ointment 0.03 % was reported to be helpful in a 4-year-old girl with CBDC who experienced a flare of blisters while on dapsone. The addition of tacrolimus ointment 0.03 % resulted in resolution of blisters within 2 weeks and was used periodically to control flares [33].

Thalidomide was reported in an 8.5-year-old boy with severe CBDC who required systemic steroids for disease control [34]. The patient developed iatrogenic Cushing syndrome after 1 year on corticosteroids. The disease responded to dapsone, but dose-limiting anemia developed. The patient failed to respond to cefadroxil, erythromycin, methotrexate, and azathioprine. Cyclosporine 4 mg/kg induced remission, but was cost prohibitive. Thalidomide 3 mg/kg was started with resolution of disease in 1 month. The thalidomide had to be withdrawn after 1 year of therapy because of the development of leg pain. This patient continues to have disease as an adult.

Intravenous immunoglobulin (IVIG) was reported in a 3-year-old boy with CBDC that initially responded well to dapsone and oral corticosteroids, but due to the development of diabetic ketoacidosis other treatments were sought [35]. His disease was difficult to control despite dapsone 2.5 mg/kg. Erythromycin was not helpful. IVIG 1 mg/kg was given monthly with a reduction in blistering and corticosteroid requirements. He remained clear except for episodic exacerbations during the next year.

Like CBDC, dermatitis herpetiformis (DH) is an IgA-mediated disease that in certain populations may be more common than CBDC. DH is rare before puberty, but in one analysis of childhood onset the mean age was 7.5 years [15]. DH has been reported to occur as young as 8 months of age [38]. DH is more common in Europe and unusual in Africa and Asia [39]. Without treatment, the disease usually persists indefinitely. All children with DH have an underlying gluten-sensitive enteropathy.

The disease classically presents with symmetrically-distributed, intensely pruritic, grouped urticarial papules and vesicles; due to the intense pruritus erosions and excoriations may be the most abundant sign. DH most frequently involves the elbows, knees, scapulae, shoulders, sacrum, buttocks, hairline and scalp. Acral petechiae or purpura have been reported more frequently in children [40]. The mucous membranes are generally spared.

Histology of an intact vesicle shows subepidermal clefting with a predominantly neutrophilic infiltrate and dermal papillary microabscesses. DIF from perilesional skin shows the presence of a granular deposition of IgA within the dermal papillae, which is diagnostic for DH.

The diagnosis of suspected DH in children should be confirmed with histology and DIF. If confirmed, referral to a gastroenterologist is warranted. A gluten-free diet is the treatment of choice and should be attempted in all patients. Dapsone is indicated for the rapid relief of pruritus and treatment of skin lesions. Once the patient is on a gluten free diet and skin lesions are controlled, dapsone should be tapered gradually to the lowest possible dose that controls the disease. In patients compliant with a gluten-free diet it can eventually be discontinued. If the patient is not controlled or cannot adhere to a gluten-free diet and is intolerant of dapsone, sulfapyridine or sulfasalazine can be tried. Moderate to high potency topical steroids can be used adjunctively on localized lesions.

Bullous pemphigoid (BP) is another one of the more common immunobullous disease to occur in children. According to the cases reported in the literature it is much more common in Caucasians (61 % white versus 17 % black, 17 % Asian, 6 % Hispanic) and slightly more common in females (60 % of reported cases) [44]. There are two peaks of incidence in childhood BP: before age one (infantile BP) and again at 8 years of age [45]. A subtype of BP in children has been labeled localized vulval pemphigoid [46, 47]. Childhood BP has a very good prognosis, with remission occurring in most patients several weeks to a year after onset, with infrequent relapses. Despite the good prognosis, generalized disease can be life-threatening and should be treated appropriately [48, 49]. Childhood bullous pemphigoid has been reported to occur a few hours to 3 weeks after vaccination with DPT/polio alone or in conjunction with vaccines against pneumococcus, H. influenza, hepatitis B, or meningococcus. There are three cases that recurred with subsequent vaccinations, although the recurrence was less severe than the initial outbreak [50].

BP presents with the abrupt onset of large, tense bullae on normal-appearing, red or urticarial skin, frequently accompanied by erosions and crusting (Fig. 12.3). Infantile BP more commonly involves the palms, soles, and face while childhood BP more commonly involves the genital region. Localized vulval pemphigoid involves only the vulva or scrotum [46, 47]. Mucous membranes are involved in approximately half of patients [51]. The blisters can be localized or disseminated. Pruritus is frequently present. The lesions heal without scarring.

Nemeth et al. [52] proposed the following criteria for diagnosis: (1) onset prior to 18 years of age; (2) tense blisters with typical histology (subepidermal blister with eosinophils); (3) DIF from perilesional skin showing a linear deposition of IgG and/or C3 as the major immunoreactant at the BMZ or a positive IIF showing circulating IgG antibodies directed against the BMZ. IIF on salt split skin reveals binding of IgG autoantibodies to the epidermal side and can be used to differentiate BP from epidermolysis bullosa acquisita (EBA); although rare cases with epidermal and dermal as well as pure dermal patterns have been reported [53]. Immunoblot assay or ELISA reveals circulating IgG autoantibodies directed against BP180/230 and can be useful for confirmation of diagnosis in uncertain cases. Eosinophilia is a frequent finding on CBC and may provide an early clue to diagnosis [54].