Childhood Linear IgA Dermatosis Successfully Treated with the Combination of Dapsone and Sulfasalazine Open Access

Linear IgA dermatosis (LAD) is a rare acquired autoimmune blistering disease caused by IgA autoantibodies against antigens in the basement membrane zone. It primarily affects young children and older adults. Clinical presentation can be similar in the different age groups, but children are more likely to have perioral involvement and typical “string of pearls” arrangement of lesions [1].

Due to rarity of disease there is an absence of randomized, controlled trials on the treatment of LAD, and the best documented systemic therapy is dapsone while other sulfonamides are considered the second-line treatment [2]. There is some data published on use of sulfapyridine in childhood LAD [3, 4], while there are so far, no published paediatric reports on the use sulfasalazine in LAD. We present a case on a 1-year-old child who did not respond adequately to conventional therapies for LAD (dapsone and topical therapies) but showed complete response after the addition of oral sulfasalazine.

A 15-month-old boy presented to our tertiary hospital with a 1-month history of a generalized bullous eruption. The prior medical history was significant for diagnosed vesicoureteral reflux, treated with trimethoprim prophylaxis. There was no family history of dermatological disease. Rash started as small red papules in the perioral area that spread to the truncus, extremities, and genital area. Rash had initially diagnosed as impetigo but showed no effect of conventional antimicrobial therapies. Shortly thereafter the skin erupted in generalized vesicles and bulla. Local paediatric department and family doctor attempted oral erythromycin and thereafter oral clindamycin with progression of the rash. Swabs from vesicles were negative for herpes simplex, varicella, and monkey pox. Bacteriological swabs from a lesion showed growth of gram-negative rods, considered not of clinical significance.

Upon presentation at our department, there were widespread vesicles and bullae to the face with large confluent erosions and crusts. There were similar findings to the body, particularly acral accentuation to hands and feet (Fig. 1). The perianal area and genitalia were also affected, but not other mucosal surfaces.

The initial presentation gave a clinical suspicion for LAD, and this was confirmed with direct immunofluorescence biopsy from the child’s upper back, showing a linear IgA depositional on the basement membrane. LAD can be drug-induced, and several reports in the literature documents LAD induced by trimethoprim-sulfamethoxazole [2]. Our patients only received trimethoprim, and this had been initiated more than 6 months prior to onset of rash. Drug was discontinued and replaced with another prophylactic antibiotic (nitrofurantoin), but without any clinical improvement over several months. Drug-induced LAD was thus considered unlikely in this case.

Patient was initially treated with topical steroids (hydrocortisone butyrate and mometasone) with no effect. After diagnostic verification of LAD, systemic treatment with dapsone 0.5 mg/kg in addition to prednisolone 0.5 mg/kg was initiated. Glucose-6-phosphate dehydrogenase deficiency was ruled out by biochemical testing prior to initiation of dapsone. The dose of dapsone was increased on a weekly basis, with parallel reduction of prednisolone. In the span of 1 month, dapsone was increased to 2 mg/kg and prednisolone discontinued, and there was observed clinical improvement with fewer vesicles and bulla, but still not complete remission. Initial laboratory monitoring showed slight reduction in haemoglobin levels (10.5 g/dL) and methaemoglobin of 5%.

After several months with partial remission, the dapsone dose was reduced to 1.5 mg/kg due to worsening anaemia and reported lethargy. The anaemia and lethargy improved but with increase in skin activity. The patient subsequently underwent a surgical procedure for an inguinal hernia and experienced a further rebound of LAD. Supplementary topical steroids and calcineurin inhibitors had little to no effect.

Sulfonamides other than dapsone have been used in the treatment of LAD, and a case report of the combination treatment with dapsone and sulfapyridine in a child had recently been published [3]. Sulfapyridine was not available in Norway and attempts to import the drug from abroad were futile.

Sulfasalazine is another sulfonamide more readily available. It is a prodrug composed of 5-aminosalicylic acid (5-ASA) and sulfapyridine linked by an azo bond. In the colon, the drug is metabolized to 5-ASA and sulfapyridine, where sulfapyridine is mostly absorbed systemically. Although less commonly used now, there is a long experience with his drug in paediatric inflammatory bowel and rheumatic diseases with a beneficial safety profile in children. There are some published reports on the use of sulfasalazine in adult LAD, but we found no published data in the paediatric population.

In agreement with the patient’s parents, we attempted the combination of oral sulfasalazine with dapsone. Patients were at that time 2 years old, weighing approximately 15 kg. Sulfasalazine suspension was initially dosed at 13 mg/kg in combination with dapsone at a reduced dose of 1 mg/kg. After close clinical and laboratory monitoring showing no side effects the dose was increased to 25 mg/kg (200 mg × 2). The drug combination was well tolerated. Laboratory monitoring was performed every other week initially, then every second month. It revealed a mild isolated neutropenia (1.2–1.6 10⁹/L) which persisted but was not considered clinically important. Total leucocyte count (4.4–5.8 10⁹/L) and lymphocyte count (2.6–3.8 10⁹/L) were within normal ranges, and liver function tests remained normal throughout the follow-up.

Within a few weeks after initiation of combination treatment no new blisters developed. The patient has been in complete clinical remission for more than 16 months after addition of sulfasalazine (Fig. 2a, b). Dapsone dose was eventually reduced to 0.5 mg/kg while keeping the sulfasalazine dose at 200 mg × 2. During two attempts at stopping dapsone, parents reported development of erythematous papules on the extremities which led to re-introduction of low dose dapsone. At the time of submission of the case report, the dose of dapsone has been reduced to 0.35 mg/kg. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546155).

Childhood LAD is a rare disease and recommended treatment options are mainly empirical, with no published randomized controlled trials. Dapsone is considered effective in inducing complete remission for the majority of patients. In recalcitrant cases, the recent updated S2k European guidelines recommend sulfonamides (sulfapyridine, sulfasalazine, and sulfamethoxypyridazine) as the second-line therapy [2]. For childhood LAD, successful combination of dapsone and sulfapyridine is described in a previously published case report [3]. While three previous reports have described an effect of sulfasalazine monotherapy in adolescents and adults [5‒7], to our knowledge this is the first reported case of combined dapsone and sulfasalazine in a paediatric case.

Sulfasalazine is safe and more readily available than sulfapyridine, making it a viable treatment option. In our case the dose of 25 mg/kg oral suspension divided in two daily doses was given, as recommended in treatment for juvenile arthritis. In European guidelines for LAD as well as in recommendations for paediatric IBD, more frequent administration is recommended [2, 8], likely due to more stable absorption with this dosing. Nevertheless, our patient had a remarkable effect of treatment with few side effects.

Paediatric LAD usually goes into spontaneous remission within months to years [2]. Because systemic treatment can mask spontaneous remission, periodic attempts of withdrawing or reducing dose of medications should be performed. We are currently performing a new attempt at stopping dapsone with continuing sulfasalazine monotherapy. If no relapse occurs, gradual tapering of sulfasalazine will be attempted.

The mechanism of action of sulfonamides is not completely understood, but likely involves inhibition of neutrophil activity as well as other immunomodulatory effects perhaps through modulation of nuclear factor kappa-B (NF-kB), arachidonic acid metabolism and several other inflammatory pathways [8]. Dapsone and sulfasalazine, both being sulphonamides, have similar mechanism of action and the exact differences between them and to what extent they have non-overlapping synergistic or additive biological effects is unclear. Whether the 5-ASA component of sulfasalazine, which mainly acts locally in the bowel, has any effect at all on bullous disorders is not a known, but for RA it is thought that sulfapyridine is the main active moiety [9]. Interestingly, there is also a report of drug-induced LAD due to sulfasalazine, putting this drug both as a culprit and treatment in this rare inflammatory skin disease [10].

In conclusion, this is the first report on the successful use of sulfasalazine in recalcitrant childhood LAD. Although this is a single case, it provides a rationale for considering sulfasalazine as a second-line option in paediatric LAD, particularly when sulfapyridine is unavailable.

We acknowledge the Medical Photography and Illustration Service at University of Oslo and Oslo University Hospital for providing clinical photographs.

Written informed consent was obtained from parents for publication of the details of the medical case and the accompanying images. This is a case report and ethical approval is not required in accordance with local or national guidelines.

Ashley S. Kim has participated in an advisory board for Almirall. Olav Sundnes is a primary investigator for clinical trials on behalf of Moonlake Therapeutics, Boehringer-Ingelheim and Abbvie. He has also participated in advisory board and given talks for Novartis. All payments for industry collaboration have gone to employer, and there are no financial conflicts of interests.

This study was not supported by any sponsor or funder.

A.S.K. and O.S. both contributed with clinical data, writing and critically revising the manuscript.

The data that support the findings of this case report are cited in the reference list. Further information is available from the corresponding author upon request.