Alternative procedure to allow continuation of dapsone therapy despite serious adverse reaction in a case of dapsone-sensitive erythema elevatum diutinum

Dapsone has potent anti-inflammatory effects and remains an effective therapy in a variety of skin disorders: cutaneous vasculitis, neutrophilic dermatoses and blistering disorders. However it may cause a severe idiosyncratic reaction compatible with drug-induced DRESS (drug reaction with eosinophilia and systemic symptoms) leading to the discontinuation of the treatment despite its effectiveness. We report a 68-year-old woman who was successfully treated with dapsone for erythema elevatum diutinum. However she developed a hypersensitivity syndrome compatible with DRESS with fever, skin rash and acute hepatitis confirmed in vitro by the presence of circulating dapsone- specific T cells. Dapsone therapy was suspended, leading to a relapse of erythema elevatum diutinum. While alternative therapies were totally ineffective in our patient to improve her skin condition, we proposed a tolerance induction protocol to dapsone with excellent results.     

Dapsone and sulfapyridine

Dapsone and sulfapyridine are structurally related compounds with anti-microbial and anti-inflammatory effects. Dapsone remains the most important drug for leprosy and is useful in the prophylaxis of Pneumocystis pneumonia in patients with HIV disease. The medical treatment of choice for dermatitis herpetiformis is dapsone; and sulfapyridine also can be used for those patients who are intolerant of dapsone. Other neutrophilic disorders also may respond to these drugs. Toxic side effects of both dapsone and sulfapyridine are mediated through the hydroxylamine metabolite. These include hemolysis, methemoglobinemia, and agranulocytosis. Careful monitoring for possible adverse reactions includes frequently performing complete blood counts and regular blood chemistry profile determinations.     

Efficacy of Dapsone in the Treatment of Pemphigus and Pemphigoid

Dapsone is a chemotherapeutic agent primarily used in treating leprosy, Pneumocystis jiroveci(previously carinii) pneumonia, and malaria. It is also used as an adjuvant in the treatment of pemphigus and pemphigoid. To assess the role of dapsone in the treatment of pemphigus and pemphigoid, a retrospective review of reports in the English-language literature was conducted. Information on the number of patients treated, their average age, prior therapies, indications for use, protocol (dose and interval) used, concomitant therapies, reported adverse effects, and clinical outcomes were analyzed. There were 35 case reports/series published describing the use of dapsone in a total of 427 patients. Data on 55 pemphigus patients were obtained from several case reports and some case series and one randomized controlled trial. Of these, 32 patients with pemphigus vulgaris and 14 patients with pemphigus foliaceus responded to dapsone. Data from 13 case series, each including at least five patients, accounted for 372 patients with pemphigoid. The overall response rates to dapsone, when given either alone or in combination with corticosteroids or immunosuppressive agents, were 84% in mucous membrane pemphigoid, and 81% in bullous pemphigoid. Hemolysis was the most common adverse effect observed. Dapsone is a promising and useful agent in patients with autoimmune mucocutaneous blistering diseases, especially in mucous membrane pemphigoid. It can be used as a corticosteroid-sparing agent. Therefore, its combined use with oral corticosteroids may be useful in pemphigus vulgaris and bullous pemphigoid. Adverse effects of dapsone are dose dependent and usually reversible. Hemolysis and concomitant anemia secondary to hemolysis are expected in most patients. In the opinion of the authors, dapsone is underutilized in the treatment of autoimmune mucocutaneous blistering diseases.     

Dapsone induced acute photosensitivity dermatitis; a case report and review of literature

Dapsone is one of the main constituents of anti-leprosy treatment and has been in use for various dermatological and non-dermatological indications since the 1940s. Dapsone-induced photosensitivity is a rare complication. Only 11 cases seem to have been reported in the literature. We report a case of dapsone-induced photosensitivity in an Indian patient with leprosy, and briefly review the literature. Dapsone (diaminodiphenyl sulphone or DDS) is the most commonly used anti-leprosy drug since the 1940s. Apart from leprosy, it is used for various other infectious and non- infectious dermatoses as well as for prevention of Pneumocystis carinii pneumonia in HIV infected patients. It is one of the main constituents of multidrug therapy (MDT) in leprosy by virtue of its anti-mycobacterial properties. It acts by interference with folate metabolism. Because of its inhibitory effect in neutrophil chemotaxis and neutrophilic oxygen burst, it acts as a potent anti-inflammatory agent. Documented cutaneous adverse effects of dapsone include generalised maculopapular rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, pustular and acneiform skin eruptions. Photosensitivity dermatitis is a very rare side-effect of dapsone and to the best of our knowledge, only 11 cases have been reported in the literature to date.     

A century of the synthesis of dapsone: its anti-infective capacity now and then

BACKGROUND: Although dapsone was first synthesized in 1908, a quarter of a century was to pass before it was used in the treatment of bacterial infections. Dapsone was, however, too toxic for humans (because of the excess dosage which was administered at that time) and was thus considered to be of no value in the treatment of common bacterial infections. Since the early 1950s, dapsone has been recognized as being uniquely effective against a number of noninfectious, inflammatory diseases and, today, this is its main indication. Thus, the reason why dapsone was first introduced into medicine, namely the treatment of bacterial infections, has been set aside and its main current applications are the treatment of noninfectious, inflammatory, autoimmune, and bullous diseases. OBJECTIVE: To study the anti-infective capacity of dapsone against common bacterial infections. As many patients who receive dapsone for the treatment of noninfectious, inflammatory diseases have a concomitant bacterial infection or a superinfection of their skin disease, we thought that, if dapsone proved to be effective against common bacterial infections, it may obviate the need for an additional antimicrobial drug in these patients. METHODS: Three bacterial ATCC> strains (Streptococcus pyogenes, Staphylococcus aureus, and Escherichia coli) were tested by a macrodilution minimal inhibitory concentration (MIC) test for dapsone. Dapsone concentrations were between 0.06 and 1125 microg/mL. RESULTS: Even the highest concentration of dapsone of 1125 microg/mL did not inhibit bacterial growth. CONCLUSIONS: Our results indicate that dapsone has no antibacterial effects whatsoever. Even at very high concentrations, it does not suppress the growth of most susceptible strains of bacteria. The story of dapsone (i.e. the long time that elapsed between its synthesis to its use for the chemotherapy of infectious diseases) will not repeat itself this time.     

Dapsone-induced photodermatitis in a patient with linear IgA dermatosis

Dapsone (4, 4' diaminodiphenylsulfone) is an efficient antiinflammatory agent. Its therapeutic use may result in a variety of adverse effects. The most frequent unwanted reactions are hemolytic anemia and methemoglobinemia. By oral route dapsone is mainly metabolized to monoacetyldapsone (MADDS) and hydroxylamine dapsone (DDS-NOH). We report a 76-year-old female patient with linear IgA dermatosis who developed a dapsone-induced photosensitivity 8 weeks after initiation of sulfone therapy. She showed a widespread erythematous eruption in UV-exposed skin area. After clearing of skin lesions the photopatch test revealed positive reactions to dapsone, MADDS and DDS-NOH. Dapsone-induced photosensitivity to date has been described only in leprosy patients. We demonstrate for the first time that this adverse reaction is not restricted to leprosy and that dapsone metabolites may also contribute to the mechanism of photosensitivity like the parent sulfone. Dapsone-induced photosensitivity is a rare, not dose-related adverse effect of the sulfone and can also occur in patients with inflammatory skin disorders.     

Pentoxyfilline as a treatment for subcorneal pustular dermatosis

Subcorneal pustular dermatosis (SPD) is a rare pustular neutrophilic dermatosis in which groups of sterile pustules appear in the superficial (subcorneal) skin. This chronic condition can be associated with significant morbidity and decreased quality of life. Dapsone is the first‐line therapy for SPD, but some patients fail to respond or cannot tolerate it. In these instances, patients may be treated with second‐line therapies such as phototherapy, topical corticosteroids, or systemic agents including glucocorticoids, acitretin, immunosuppressive, or biologic medications. These therapies may not always be efficacious and can be associated with intolerable adverse effects. Here, we report a case of a patient who sustained long‐term remission and no side effects with the novel use of pentoxifylline, a tumor necrosis factor‐alpha inhibitor, as monotherapy. Pentoxifylline should be considered as a possible therapy in patients with SPD intolerant to dapsone.     

Treatment of Pemphigus Vulgaris

Background: Pemphigus vulgaris is a rare, chronic, autoimmune mucocutaneous blistering disease. The disease can progress to involve the skin and multiple mucosae. Pemphigus vulgaris can be associated with a high morbidity and significant mortality rate. Treatment of the condition can be challenging. Conventional therapy primarily consists of systemic corticosteroids and immunosuppressant agents. In some patients with pemphigus vulgaris, these agents fail to provide an effective clinical response or have significant adverse effects. Methods: We evaluated data on 792 patients with pemphigus vulgaris retrieved from PubMed, covering the period 1973–2004. Only patients reported in the English literature were included in this review. Recently, several new therapeutic agents and treatment modalities have been described for the treatment of patients with pemphigus vulgaris. Some therapeutic agents that were used in the past and abandoned have recently regained favor. This review focuses on the therapeutic uses of dapsone, methotrexate, mycophenolate mofetil, chlorambucil, dexamethasone-cyclophosphamide pulse therapy, immunoablative therapy with cyclophosphamide, plasmapheresis, and extracorporeal photochemotherapy. Newer agents, such as intravenous immunoglobulin (IVIg) therapy and rituximab (an anti-CD20 chimeric monoclonal antibody), are also discussed. Results and conclusions: Among the oral agents, dapsone may be considered a first-line agent. This is primarily because the risk of potentially fatal adverse effects with this drug is lower than that associated with other available chemotherapeutic agents. In patients who are refractory to oral agents, alternative treatments have been used to prevent further disease progression. Recently, the use of IVIg therapy, with a defined protocol, has been reported to be beneficial. This therapy is promising since it may allow for discontinuation of all other therapies and is safe. The adverse effects from IVIg therapy are minimal. Furthermore, compared with other therapies, it provides a better quality of life.     

Epidermolysis Bullosa Acquisita Responsive to Dapsone Therapy

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal blistering disease that is frequently resistant to therapy. OBJECTIVE: A 58-year-old man who had a one-year history of a bullous eruption involving the hands, forearms, trunk, scalp, and oral mucosa. Histopathology revealed a subepidermal bulla, and direct and indirect immunofluorescence studies were consistent with EBA. The patient failed respond to niacinamide and tetracycline and oral prednisone 40 mg per day. METHODS: Complete control of his blistering was achieved within two months of initiating oral dapsone, 150 mg per day. CONCLUSION: Dapsone may be an effective agent for some patients with EBA.     

Dapsone treatment of folliculitis decalvans

BACKGROUND: Folliculitis decalvans consists of recurrent patchy painful folliculitis of the scalp causing scarring alopecia. The physiopathology of this condition is still unclear, but is likely a manifestation of chronic neutrophilic bacterial folliculitis. Numerous topical and systemic treatments (corticosteroids, antistaphylococcal antibiotics) have been used with variable results. Based on the dapsone antimicrobial activity and its anti-inflammatory action especially directed to the neutrophil metabolism, we treated two patients with severe folliculitis decalvans with this drug. CASE REPORTS: The patients were treated with dapsone at a daily dose of 75 and 100 mg, respectively for 4 to 6 months. After 1 and 2 months, pustular folliculitis progressively cleared, leaving a residual non inflammatory cicatricial alopecia. When maintaining a dapsone dosage at 25 mg/day no relapse occurred during 3 years and 1 year, respectively. No important adverse effect to dapsone was evidenced. After dapsone withdrawal, a moderate relapse of the disease with pruritus and folliculitis occurred after a few weeks in both cases. The disease relapse rapidly cleared after dapsone reintroduction at a daily dose of 25 mg. COMMENTS: Dapsone at moderate dosage was well tolerated and rapidly effective in treating the two cases of folliculitis decalvans. A long term and low dose (25 mg daily) maintenance treatment avoided disease relapses.     

Dapsone hypersensitivity syndrome with circulating 190‐kDa and 230‐kDa autoantibodies

Dapsone has potent anti‐inflammatory effects, and is used in the treatment of leprosy, cutaneous vasculitis, neutrophilic dermatoses, and dermatitis herpetiformis and other blistering disorders. However, it may cause severe adverse reactions such as hypersensitivity syndrome, which is characterized by fever, skin rash, hepatitis and lymphadenopathy. We report a 44‐year‐old female Korean patient with dapsone hypersensitivity syndrome (DHS) that presented as a bullous skin eruption. The patient had a 1‐year history of urticarial vasculitis, treated with antihistamines, prednisolone and dapsone. Although the skin lesions improved, she reported fever, nausea, abdominal pain, jaundice, fatigue and skin rashes. On physical examination, there were generalized erythematous macules and purpura with facial oedema that developed into vesicles on the upper limbs. Histological examination of a skin biopsy of a vesicular lesion found subepidermal oedema with a mixed inflammatory cell infiltrate, including eosinophils in the dermis. Indirect immunofluorescence testing using normal foreskin as substrate revealed IgG deposits in the basement membrane zone. Circulating autoantibodies against antigens of 190 and 230 kDa were found by immunoblotting analysis using epidermal extracts. This case illustrates DHS with the formation of circulating autoantibodies.     

Agranulocytosis caused by dapsone therapy for granuloma annulare

Dapsone has been suggested as a useful drug in the treatment of granuloma annulare; however, adverse reactions include a potentially life-threatening agranulocytosis. We report the case of a 50-year-old woman in whom agranulocytosis and septicemia developed after 7 weeks of therapy with dapsone for granuloma annulare. Full recovery followed cessation of this drug, but caution is advised in prescribing dapsone for relatively benign skin conditions.     

Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner

BACKGROUND: Dapsone (4,4'-diaminodiphenyl sulphone) is a powerful therapeutic tool in many skin diseases including neutrophilic dermatoses. The drug has an outstanding therapeutic efficacy against many skin diseases characterized by neutrophil-rich infiltrates; however, mechanisms of its action are poorly understood. OBJECTIVES: We investigated the effects of dapsone on respiratory and secretory functions of human neutrophils triggered by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), the physiological agonist C5a, and phorbol myristate acetate (PMA). METHODS: Human neutrophils were isolated from venous blood obtained from healthy donors. We detected extracellular production of superoxide (O(2) (-)) by cytochrome C reduction assay, and intracellular production of O(2) (-) by flow cytometry. Neutrophil elastase release was measured by the cleavage of the specific elastase substrate N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide. Measurement of cytosolic free calcium concentration was performed using the calcium-reactive fluorescence probe, Fluo-3. RESULTS: Dapsone suppressed intra- and extracellular production of O(2) (-) and elastase release triggered by fMLP and C5a, but not by PMA. Both fMLP and C5a signalled the above pathways by inducing calcium influx, but PMA functions bypassed calcium influx. Dapsone was capable of antagonizing the induction of calcium influx. CONCLUSIONS: These findings suggest that one mechanism of the anti-inflammatory action of dapsone is inhibition of calcium-dependent functions of neutrophils including release of tissue-damaging oxidants and proteases in the affected skin.     

Dapsone hypersensitivity syndrome: a clinico-epidemiological review

Diaminodiphenyl sulphone (dapsone) is a drug of choice in the treatment of leprosy. It is also useful for the treatment of many neutrophilic and other dermatoses. Dapsone hypersensitivity syndrome is a rare but well recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepato-splenomegaly. Twenty-six patients with dapsone hypersensitivity syndrome were studied for clinical profile, outcome, and prognosis. The male:female ratio was 2.2:1, and the mean age was 33.19 years (range 13 to 64 years). The interval between start of dapsone therapy and appearance of symptoms varied from 2-7 weeks (mean 29.82 days). Twenty-four patients received dapsone as a part of multi-drug therapy for leprosy; the other two patients received dapsone for lichen planus and acne vulgaris. Exfoliative dermatitis was the most common cutaneous manifestation followed by erythematous maculo-papular eruption and Stevens-Johnson syndrome-like lesion. The other common systemic manifestations were: fever (26 cases), itching (22 cases), lymphadenopathy (21 cases), jaundice (21 cases), pallor (20 cases), hepatomegaly (19 cases), and pedal edema (14 cases). Investigation profile revealed elevated levels of serum liver enzymes in 100% of patients, elevated erythrocyte sedimentation rate in 92.3%, raised bilirubin in 84.6%, leucocytosis in 69.23%, low hemoglobin (<9 gm/dl) in 46.15% and hypoproteinemia in 42.3%. Eosinophilia, hemolytic anemia, and reticulocytosis count were found in 4 patients each. All the patients had favorable outcomes except three who died due to hepatic failure. Medical personnel must be aware of this potentially fatal syndrome, because it can cause considerable morbidity and mortality.     

Dapsone in dermatology and beyond

Dapsone (4,4′-diaminodiphenylsulfone) is an aniline derivative belonging to the group of synthetic sulfones. In 1937 against the background of sulfonamide era the microbial activity of dapsone has been discovered. Shortly thereafter, the use of dapsone to treat non-pathogen-caused diseases revealed alternate antiinflammatory mechanisms that initially were elucidated by inflammatory animal models. Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs. The latter capabilities primarily were used in treating chronic inflammatory disorders. Dapsone has been investigated predominantly by in vitro methods aiming to get more insights into the effect of dapsone to inflammatory effector cells, cytokines, and/or mediators, such as cellular toxic oxygen metabolism, myoloperoxidase-/halogenid system, adhesion molecules, chemotaxis, membrane-associated phospholipids, prostaglandins, leukotrienes, interleukin-8, tumor necrosis factor α, lymphocyte functions, and tumor growth. Moreover, attention has been paid to mechanisms by which dapsone mediates effects in more complex settings like impact of lifespan, stroke, glioblastoma, or as anticonvulsive agent. Additionally, there are some dermatological investigations in human being using dapsone and its metabolites (e.g., leukotriene B₄-induced chemotaxis, ultraviolet-induced erythema). It could be established that dapsone metabolites by their own have anti-inflammatory properties. Pharmacology and mechanisms of action are determining factors for clinical use of dapsone chiefly in neutrophilic and/or eosinophilic dermatoses and in chronic disorders outside the field of dermatology. The steroid-sparing effect of dapsone is useful for numerous clinical entities. Future avenues of investigations will provide more information on this fascinating and essential agent.     

Peripheral ulcerative keratitis associated with erythema elevatum diutinum and a positive rheumatoid factor: a report of three cases

Peripheral ulcerative keratitis (PUK) is a complication of collagen-vascular diseases such as rheumatoid arthritis (RA) and other systemic vasculitides. We report three cases of erythema elevatum diutinum with PUK. These patients presented with nodules and plaques consistent with erythema elevatum diutinum on the extremities and crusted or ulcerated purpuric lesions on the soles. Histopathological examination of these lesions revealed a dense neutrophilic infiltrate with nuclear dust and fibrin around blood vessels. All the patients developed PUK concomitant with the development of the skin lesions. The rheumatoid factor was positive at high titre in all three patients; this was associated with probable RA in one. Cutaneous lesions were dramatically improved by administration of dapsone in all cases. Dapsone was also effective in treating the ocular lesions in two patients.     

Dapsone and sulfones in dermatology: overview and update

In their 60-year history, dapsone and the sulfones have been used as both antibacterial and anti-inflammatory agents. Dapsone has been used successfully to treat a range of dermatologic disorders, most successfully those characterized by abnormal neutrophil and eosinophil accumulation. This article reviews and updates the chemistry, pharmacokinetics, clinical application, mechanism of action, adverse effects, and drug interactions of dapsone and the sulfones in dermatology.     

Adjuvant drugs in autoimmune bullous diseases,efficacy versus safety: Facts and controversies

During the last decades, the conventional therapy for autoimmune blistering diseases has been high-dose, long-term systemic corticosteroid and immunosuppressive agents or adjuvant drugs. Long-term, high-dose steroid therapy can result in serious adverse effects. The rationale for using adjuvant drugs is that concerns reducing the need for corticosteroids, and hence, their side effects, or it may result in better control of the disease, or both. Immunosuppressive agents are not free of adverse effects, however. Prolonged immune suppression may account for high rates of morbidity, disability, and possible death. There is no consensus about the first-choice adjuvant drug for the management of blistering autoimmune diseases. This contribution evaluates six adjuvant drugs—cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, intravenous immunoglobulin, and rituximab—and discusses the choice of a “winning drug” that is effective and safe.     

Use of cyclophosphamide in azathioprine failures in pemphigus

Four patients with pemphigus vulgaris are presented in which diagnosis was confirmed histologically and immunopathologically. Although these patients responded to high-dose prednisone therapy during the initial stages of acute disease, the addition of azathioprine failed to allow lower steroid doses and did not result in prolonged, complete remission. Indeed, the disease was exacerbated during azathioprine therapy, and significant side effects from prolonged high-dose steroid therapy were observed. Both clinical and serologic remission resulted from the addition of cyclophosphamide and dapsone to prednisone therapy. Thus, when azathioprine fails to produce remission or a steroid-sparing effect, cyclophosphamide may be an effective alternative. During a prolonged follow-up period, no recurrences of pemphigus have been observed, and no significant side effects of cyclophosphamide (Cytoxan) have been encountered. The addition of dapsone produced enhanced anti-inflammatory effects without increasing the existing or potential side effects of steroid therapy. Dapsone was easily withdrawn at the onset of remission. Thus the anti-inflammatory effect of dapsone may prove valuable in patients for whom steroids are contraindicated, who develop significant side effects during long-term steroid therapy, or for whom increases of dose threaten to enhance the possibility of catastrophic side effects.     

Short term combination therapy for paucibacillary leprosy--histological evaluation & follow-up study

68 patients with paucibacillary disease were started on various regimes of multi drug therapy, consisting of ethionamide, rifampicin or clofazimine administered with dapsone. Serial skin biopsies were taken from 32 patients at one, two and three years and even later after the initial pre treatment biopsy. Actual material was available for study from 9 patients. All regimens were tolerated well except the one with ethionamide. However the therapeutic response was equal in all combination therapies as supported by histopathology. Compared to that with dapsone monotherapy the response was quicker with combination. Dapsone plus rifampicin combination was best tolerated and it worked out to be economical as well. No relapse was noted in any group during two or more years follow up.