Cutaneous rash and dapsone-induced hypersensitivity syndrome a common manifestation in adult immune thrombocytopenia. Presentation and outcome in 16 cases
Authors: GaËtan Sauvetre, Matthieu MahÉvas, Nicolas Limal, Constance Guillaud, Mehdi Khellaf, Philippe Bierling, Laetitia Languille, Florent Delbos, France Noizat‐Pirenne, Marc Michel, Bertrand Godeau
Journal: American Journal of Hematology (2015)

The successful use of dapsone for primary or secondary immune thrombocytopenia (ITP) was first reported 25 years ago 1, 2. Although the mechanism of action remains poorly understood, several uncontrolled studies have assessed the efficacy of dapsone for ITP 1-4 with an overall response rate of 40%. Dapsone is proposed as possible second-line treatment for ITP as suggested by international consensus in the guidelines recently published by the American Society of Haematology. A multitude of drug hypersensitivity definitions exist in the literature. Dapsone-induced hypersensitivity syndrome (DHS), sometimes called dapsone or sulfone syndrome, was originally described in leprosy and combines a generalized skin eruption with one or more of the following: (1) fever, (2) lymphadenopathy, or (3) hepatitis 5. DHS prevalence is estimated to be about 1.4% (95% confidence interval, 1.2–1.7%) 5. Prognosis can be severe, with life-threatening visceral involvement and high mortality (9.9%) 5. A recent genome-wide association study in China demonstrated a strong association of HLA-B*13:01 polymorphism and risk of DHS among patients of Indian origin receiving dapsone for leprosy 6. As the incidence and clinical outcome of DHS in ITP patients receiving dapsone have never been reported, we report our experience in a large monocentric study. Over an 11-year period (2002–2013), we identified 231 patients with ITP who received dapsone in our institution. In total, 17 (7.3%) presented a dapsone-induced cutaneous reaction. One patient was excluded from the final analysis because of missing data or lost to follow-up. Baseline characteristics of the 16 patients with primary ITP are summarized in Supporting Information Table 1. All patients, except two Asians, were of Caucasian or African origin. The median platelet count at the onset of dapsone treatment was 21 g/L (range, 2–50 g/L). In all, 14 patients also received steroid therapy (prednisolone: 1 mg/kg) as second-line therapy. No other drugs had been newly introduced in the previous 3 months. Overall, the response rate to dapsone was 62.5% (10/16), that is, 7/16 (44%) CR and 3/16 (18%) R. All 16 patients presented generalized skin rash within 3 months after dapsone initiation (median, 24 days; range, 2–52 days) (Table 1). The skin rash was usually described as urticated erythematous papules and plaques (Supporting Information Fig. 1). The median platelet count at the time of skin rash was 112 g/L (range, 23–293 g/L). In all 16 cases, dapsone was withdrawn within 48 hr. No severe hemolysis was observed (median decrease in hemoglobin level, 1.35 g/dL, n = 7). Skin rash was associated with fever in five patients (31%), hepatitis in three patients (18.7%), and lymphadenopathy in one patient (6.3%). In all, 6 out of the 231 patients fulfilled the DHS criteria (2.6%); three were referred to the hospital. One patient met DHS criteria and presented moderate cytolysis hepatitis (with no liver failure). Two other patients did not fulfill DHS criteria; one presented generalized rash; a skin biopsy showed an inflammatory infiltrate. At the time of skin eruption, 14 patients were still on a short course of steroids. Steroids were discontinued during the week after the skin manifestations in all patients. After daspone discontinuation, cutaneous and systemic manifestations disappeared in all patients, without any treatment. Two patients showed sustained CR after the discontinuation of treatment, at 5- and 8-month follow-up. The other patients showed relapse and required therapy. The 11 patients with a DNA sample did not show HLA-B*13:01 polymorphism. Dapsone is an inexpensive therapeutic option for treating ITP in children and adults but has not been well studied as compared with other more costly alternatives. The drug is largely used in France, Italy, Turkey, and India, with an overall response rate of 40% 1-4. DHS is the most severe adverse event with the treatment, but until now, its incidence in ITP was not reported. In our analysis of 16 patients with ITP, cutaneous reaction to dapsone was a common adverse event (7.3%) and occurred in the weeks after the start of treatment. In 40% of these patients, skin rash was associated with systemic manifestations consistent with the diagnosis of DHS, and hence the incidence of definite DHS (2.6%) was similar to that in other diseases 5. We found a good prognosis with dapsone-induced reactions in ITP. In contrast with the severe outcomes reported for DHS in other settings, with a mortality of almost 10%, we observed no life-threatening visceral involvement, no systemic symptoms, or biological manifestations (hepatitis, eosinophilia) in most patients; only three had to be referred to the hospital but showed rapid recovery. One hypothesis to explain this good prognosis is that a short course of steroids (<3 weeks) was almost systematically combined with dapsone. The anti-inflammatory and/or immune modulation induced by steroid therapy may attenuate the systemic manifestations. In view of the potential severity of DHS, our practice is now to systematically associate a short course of steroid therapy (<3 weeks) with the initiation of dapsone. An alternative explanation could be the rapid withdrawal of dapsone in all cases. The physicians in our group are aware of dapsone-related adverse events. Patients are systematically informed that dapsone should be immediately stopped if any skin symptom occurs. The pathophysiological mechanism and risk factors of dapsone-related skin and systemic symptoms remain unknown. A strong association of HLA-B*13:01 polymorphism and risk of DHS (odds ratio, 20.53) has been reported earlier 6. We confirm that this haplotype is largely absent in European and African patients. All of our patients, who were tested, including two Asians, were negative for the polymorphism. At least in Europe, HLA genotyping is not useful before dapsone treatment. To conclude, skin rash is a common manifestation of dapsone treatment for ITP. However, the incidence of DHS does not differ from that with other indications. Conversely, DHS in ITP is characterized by good prognosis, possibly because of concomitant steroid therapy. In this cohort, the risk of hypersensitivity reaction did not limit the use of dapsone in ITP. However, physicians should be aware of this potential severe manifestation. Rapid discontinuation of treatment is mandatory with skin manifestations. GaËtan Sauvetre,1 Matthieu MahÉvas,1,2* Nicolas Limal,1 Constance Guillaud,1 Mehdi Khellaf,1 Philippe Bierling,2 Laetitia Languille,1 Florent Delbos,2 France Noizat-Pirenne,2 Marc Michel,1 Bertrand Godeau1 1Service De Médecine Interne, Centre De Référence Des Cytopénies auto-Immunes De L'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux De Paris, Université Paris Est Créteil, Créteil, France; 2Etablissement Français Du Sang Ile De France, Inserm U955, Créteil, Hôpital Henri Mondor, Paris, France Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.