Dapsone-induced photodermatitis in a patient with linear IgA dermatosis

ARTICLE

Dapsone (4, 4' diaminodiphenylsulfone) is currently the drug of choice for the treatment of dermatitis herpetiformis Duhring. After the initiation of therapy in most cases the sulfone results in a prompt decrease in pruritus and control of skin lesions. Moreover, dapsone is used as a therapy in several inflammatory dermatological diseases, such as bullous pemphigoid, linear IgA dermatosis, pyoderma gangrenosum, relapsing polychondritis and SWEET-syndrome [1]. Because dapsone is also characterized by antibacterial activity it is used for prophylaxis and treatment of pneumocystis carinii pneumonia and toxoplasma gondii encephalitis in HIV-infected individuals [2-4]. So far the mechanism of action of dapsone in inflammatory dermatoses has not been fully elucidated. Several experimental studies indicate that N-hydroxylated metabolite of dapsone is more active than the parent compound [5-7]. On the other hand the property of the sulfone to cause adverse effects is well-known and has been the subject of much concern. The most frequent side effects are dose-related methemoglobinemia and hemolytic anemia (Table I). A broad range of other, less frequent dapsone-associated reactions has been reported, e.g. phototoxic and photoallergic reactions [8]. The first case in a patient suffering from bullous skin disease is presented here.

Case report

In April 1998 a 76 year-old woman presented on admission an annular, urticarial exanthema with marginal blistering, several erosions and crusts. No alterations of the oral, ocular and genital mucosa were seen. A skin biopsy was performed. The specimen showed a subepidermal blister with a subepidermal infiltrate of neutrophilic and eosinophilic leukocytes. The cell accumulation at the base of the blister consisted of lymphocytes, histiocytes and plasma cells. The direct immunofluorescence revealed linear deposition of IgA and granular deposition of C3 at the basal membrane. IgG and IgM could not be detected. The indirect immunofluorescence demonstrated IgA-antibodies against the basal membrane with a titer of 1:160 at the roof of the blister (salt split skin). Staining for IgG was negative. A linear IgA dermatosis was diagnosed and a combined treatment with 100 mg dapsone and 70 mg prednisolone daily was started. Since an efficient clinical amelioration was seen, prednisolone dosage was gradually reduced and stopped after one month. The patient showed no side effects of dapsone therapy.

In June 1998, after about one hour's exposure to sunlight the patient developed an acute superficial confluent erythema in association with itching in the face, neck, lower neckline, forearms and lower thighs. A limited swelling of the face with blepharedema was also observed (Fig. 1). Shaped, grey-blue, partly livid maculae were apparant on the upper arms and thighs as residues of the IgA dermatosis. The general condition of the patient was not affected. She had no fever, no lymphadenopathy or any abdominal complaints. She had not used any skin care or sun blockers. The complete blood cell count, electrolytes, liver and kidney function as well the serum electrophoresis were normal. Methemoglobin level and the activity of glucose-6-phosphate dehydrogenase were also in the normal range.

A skin biopsy revealed parakeratotic areas with nuclear fragments in the stratum corneum, isolated necrotic keratinocytes in the oedematous connective tissue stroma of the epidermis and multiple lymphohistiocytic infiltrates without eosinophilic leukocytes in the upper corium. Focal invasion of lymphocytes into the epidermo-dermal junction and into the lower stratum spinosum as well as a slight spongiosis in these areas were seen.

After clearing of skin lesions patch tests with dapsone, monoacetyldapsone (MADDS), hydroxylamine dapsone (DDS-NOH) (0.1% in acetone), trimethoprim-sulfamethoxazole (co-trimoxazole) and sulfasalazine (1:1 in petrolatum) and standard tests according to HERMAL were negative (chemical structures see Fig. 2). Photopatch tests with dapsone, MADDS and DDS-NOH were positive while trimethoprim-sulfamethoxazole, sulfasalazine and standard tests revealed no reaction in the photopatch test (Fig. 3). A skin biopsy specimen of the positive photopatch test area with DDS-NOH (after 48 hrs) showed a perivascular lymphohistiocytic infiltrate, focal weak spongiosis and isolated necrotic keratinocytes. The epidermis was regular. A superficial, perivascular lymphocytic infiltration was observed.

Because the sulfone in association with sunlight was suspected to cause the skin reaction dapsone therapy was discontinued. Daily systemic treatment with 100 mg of prednisolone intravenously was initiated. This dosage could be reduced quickly and thereafter changed to oral application. Finally, the maintenance dosage was 10 mg prednisolone once a day. Additionally, antihistamine (loraditine 1 x 1/d) and skin care with Excipial U Lipolotio^® were administered. The patient was also advised to use an emoillent for sun protection (Daylong 16^®).

Discussion

Dapsone is a non-steroidal antiphlogistic agent that is widely used in the treatment of several pathogen-caused diseases (e.g. leprosy) as well as inflammatory conditions (e.g. dermatitis herpetiformis, rheumatoid arthrithis) [4]. Following oral administration dapsone is almost completely absorbed from the gastrointestinal tract and peak serum concentrations are generally attained within 2-8 hrs [9]. Dapsone appears to undergo enterohepatic circulation. By the oral route dapsone is acetylated in the liver by N acetyltransferase (NAT I) to monoacetyldapsone as the major metabolite of acetylation [10]. The rate of acetylation in man is genetically determined by a bimodal polymorphism (rapid and slow acetylator phenotype). Because phenotyping with dapsone has been shown to give results comparable to those using isoniazid, dapsone has been used recently as a rapid, specific and sensitive method for determing acetylator phenotype. Mediated by another main pathway the drug is also hydroxylated by hepatic enzymes to hydroxylamine dapsone (DDS-NOH) and other hydroxylated metabolites [11]. It has been suggested that the N-hydroxylated sulfones play a role in drug-related toxicity, especially in hematotoxicity [4]. Thus, the incidence of adverse reactions of dapsone has to be related to the rate of acetylation and consecutively of hydroxylation. Therefore reducing the hematological toxicity by pharmacological modulation (e.g. additional dose of cimetidine) has been recently tried to inhibit the generation of DDS-NOH [12]. Usually skin reactions due to dapsone result from sensitization, from hematological side effects such as methemoglobinemia and anemia or as a symptom of hypersensitivity syndrome. They include a broad range of cutaneous manifestations. HIV-infected individuals develop a rash more frequently than patients treated for dermatological diseases. In AIDS-patients receiving dapsone concomitantly with trimethoprim a rash occurs in about 30-40% of cases but less frequently in those receiving dapsone alone [8]. In our patient the diagnosis of a hypersensitivity syndrome with cutaneous involvement could be excluded by medical history, clinical examination and laboratory values. The patient did not demonstrate fever, lymphadenopathy, hepatitis or arthralgia. Laboratory investigation revealed no increase in leukocytes, eosinophils or atypical lymphocytes. Moreover, patients with hypersensitivity syndrome usually recover rapidly when dapsone therapy is stopped.

In our case we diagnosed a non dose-related side effect of dapsone, that has only been described to date in a small number of leprosy patients [13-15]. The incidence of photosensitivity induced by dapsone is extremly low. Dapsone-induced photosensitivity was first described by Joseph in 1987 in a female leprosy patient in whom re-challenge with dapsone in addition to sunlight confirmed the skin reaction [13]. In some cases no skin test or re-challenge with dapsone and UV was performed. Thus, the real causality remains unclear (Table II). In our patient the positive photopatch test to dapsone, MADDS and DDS-NOH reveals for the first time that the two most important dapsone metabolites are also able to induce side effects. Sulfonamides and sulfasalazine which chemically belong to a different class of compounds than dapsone elicited no positive reaction in the photopatch test. We therefore conclude that the characteristic sulfone group -C-SO₂-C is responsible for the observed dapsone-induced photosensitivity. Our observation also shows that dapsone-induced photosensitivity generally is not only related to leprosy but also to non-pathogen caused inflammatory conditions. The mechanism of dapsone-induced photosensitivity is not known so far. The exploration of the mechanism is complicated by the fact that dapsone and its main metabolites are able to act as radical scavenger [16], as inhibitior of arachidonic acid cascade [17] and as erythema-suppressive agent [7].

Whether the photosensitivity in our patient is of photoallergic or phototoxic origin is hard to decide. Features in favour of a photoallergy include the positive photopatch test and the biopsy of those skin areas in which we reproduced skin reaction. In addition, the pattern of the photopatch test in point of time (so-called crescendo reaction), argues more for an allergic pathway. Therefore, we speculate that the photosensitivity adverse reaction to dapsone in our patient is probably based on an immunological pathway.

If a patient experiences severe adverse effects related to dapsone as in our case, dapsone should be discontinued from the regimen and substituted by alternative therapeutic approaches. In linear IgA dermatosis systemic glucocorticosteroids offer most promise beside immunosuppressive agents. Whether sulfapyridine, one action moiety of sulfasalazine tested, is useful in such a situation has yet to be addressed.

CONCLUSION

In summary dapsone-induced photoallergic or phototoxic effects have to be considered as rare, not dose-dependent adverse reactions to the sulfone. Physicians should be alert to this potential side-effect in patients taking dapsone who develop a rash especially after UV or sunlight exposure. Furthermore, our case suggests that dapsone has to be added to the list of drugs that may induce photosensitivity also in non-leprosy patients. The general characteristics of such reactions need further investigation.

Acknowledgements

We are indepted to Mrs. Katharina Blümlein for her helpful technical assistence. We are grateful to Mr. Axel Freyberger for preparing the photographic documentation. The authors additionally wish to thank Jacobus Pharmaceutical Co., NJ, USA, for providing DDS-NOH and MADDS.

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