FormalPara Key Points

Dapsone’s multifaceted antimicrobial and antiinflammatory properties make it an effective treatment for various dermatologic conditions, including leprosy and dermatitis herpetiformis, as well as off-label uses for autoimmune and bullous diseases.

Despite potential adverse effects, such as gastrointestinal issues and hematologic reactions, dapsone remains a relatively safe and affordable option for long-term treatment of chronic skin diseases with elevated neutrophils and/or eosinophils.

Special considerations are necessary for its use in pregnant or breastfeeding individuals and children, and regular laboratory monitoring is recommended to manage side effects and ensure patient safety.

1 Introduction

The use of dapsone, initially synthesized in 1908 by Wittman and Fromm with the aim of developing a sulfonamide-based textile dye, took a turn in the 1930s when its antibacterial effects were discovered during chemotherapeutic experiments [1,2,3,4]. Despite initial concerns over the safety of sulfones, exacerbated by high dosing in animal models, research persisted throughout the twentieth century [2]. Alongside its antibacterial properties, dapsone has antiinflammatory activity, though the underlying mechanism for that activity remained unclear [1]. This dual action paved the way for dapsone’s utilization in various disease processes, with its efficacy established for leprosy and dermatitis herpetiformis in the mid-twentieth century [2, 5, 6].

While dapsone holds US Food and Drug Administration (FDA) indications solely for leprosy and dermatitis herpetiformis, numerous case reports support use for a spectrum of other conditions, including autoimmune and bullous diseases, as well as noninfectious inflammation [2]. Offering a relatively safe, affordable, and effective option, dapsone may be valuable for patients unable to access or afford more specialized medications [7]. This review aims to describe dapsone and its diverse applications in dermatology practice.

2 Methods of Literature Review

A PubMed search was conducted using the terms “dapsone” and “use” and “dermatology” and the filters “review” “systematic review” “humans” and “English” were applied, which yielded 74 results. These articles were reviewed, and a representative list of diseases treated with dapsone as a monotherapy or adjunctive therapy was recorded. References from the initial search were reviewed as additional sources, and a secondary search for the “disease of interest” and “dapsone” was conducted for each dermatologic condition. Data extraction involved recording details such as dosing regimens, treatment outcomes, and other notable findings from each selected study.

3 Overview of Dapsone

3.1 Pharmacokinetics and Pharmacodynamics

Dapsone has a bioavailability exceeding 86% with oral administration, achieving peak plasma concentrations within 2–8 h (Wolf). A standard dose of 100 mg per day results in steady-state plasma concentrations ranging from 2 to 6 µmol [2]. Dapsone undergoes hepatic acetylation by N-acetyltransferase to yield monoacetyl-dapsone (MADDS), which is subsequently hydroxylated by cytochrome P-450 enzymes to generate dapsone hydroxylamine (DDS-NOH) [1]. DDS-NOH is crucial for both the therapeutic efficacy of dapsone and the onset of adverse effects such as methemoglobinemia and hemolysis [1]. Neutrophils also metabolize dapsone, activating the pathway to convert dapsone to DDS-NOH within skin lesions characteristic of inflammatory dermatoses [1]. Human keratinocytes, under the influence of cytokines such as TNF-alpha, IL-1beta, and interferon-gamma, also produce DDS-NOH, contributing to the complexity of dapsone metabolism in various physiological contexts [7].

Dapsone has multifaceted antimicrobial and antiinflammatory properties. Functioning as an antimicrobial agent, dapsone exhibits bacteriostatic activity by impeding the synthesis of dihydrofolic acid, thereby hampering microbial proliferation [1]. Its antiinflammatory effects stem from its ability to modulate neutrophil activity, restraining their inflammatory response [1]. Dapsone’s antiinflammatory action may be due to a dose-dependent inhibition of neutrophil reactivity to immunoglobulin A (IgA) and IgG in patients with bullous pemphigoid [8]. Efficacy for neutrophilic dermatoses, such as Sweet syndrome and pyoderma gangrenosum, may be explained by dapsone’s inhibition of neutrophil respiratory burst occurring in the myeloperoxidase-peroxide halide-mediated cytotoxic system [9]. Additionally, dapsone can exert a dose-dependent suppression of mRNA synthesis in vitro, leading to the inhibition of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine implicated in various autoimmune disorders [10].

3.2 Indications and Dosage

Dapsone has off-label uses for a wide array of conditions owing to its safety profile suitable for long-term treatment [1]. Chronic skin diseases with elevated levels of neutrophils and/or eosinophils can benefit from dapsone therapy due to its action on these cells [1]. While the US Food and Drug Administration (FDA) has approved dapsone for the treatment of leprosy and dermatitis herpetiformis, its off-label use is extensive, encompassing both monotherapy and adjunctive therapy approaches [9], (Tables 1, 2). Use of dapsone for recluse spider bites (loxoscelism) in the USA is no longer recommended [11, 12]. Support for off-label applications varies, drawing from a spectrum of evidence including randomized controlled trials, case reports, and retrospective chart reviews (Tables 1, 2).

Table 1 Uses of dapsone in various dermatologic conditions as a first-line agent (both on- and off-label) with recommended dosing and notable findings from the source. Level of evidence for the use of dapsone is described by the type of study/source listed.
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Table 2 Uses of dapsone in various dermatologic conditions as an adjunctive agent with recommended dosing and notable findings from the source. Level of evidence for the use of dapsone is described by the type of study/source listed.
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In adults, initial dosages typically range from 50 mg to 100 mg per day, but if treatment objectives are not met within 4–6 weeks, dose escalation to 150–300 mg per day may be considered. Upon achieving therapeutic goals, dosage adjustments should be made to maintain the minimum effective dose [1].

3.3 Safety and Adverse Reactions

While dapsone is widely used with a relatively favorable safety profile, the adverse events associated with dapsone warrant consideration. The most common adverse reactions, which are reported by approximately 55% of patients, are symptoms of gastrointestinal upset such as abdominal pain, anorexia, and vomiting [1, 13]. Other, less common adverse events include pulmonary eosinophilia, hepatitis, nephrotic syndrome, renal papillary necrosis, peripheral neuropathy, and muscle weakness [9, 14].

In addition to these adverse effects, dapsone is often associated with hematologic effects. After dapsone undergoes hepatic N-hydroxylation to DDS-NOH, transport of DDS-NOH into the red blood cells can cause methemoglobinemia, hemolysis, and agranulocytosis [1, 15]. Vitamins C and E may be offered concurrently to reduce the hematologic adverse effects [15]. If methemoglobinemia develops, a “saturation gap” between arterial blood gas and pulse oximetry readings is often used without serum methemoglobin levels [16]. Treatment includes cessation of dapsone and supportive care unless signs of hypoxia or methemoglobin levels exceed 30%, which warrants administration of methylene blue at 1–2 mg/kg (Burke). Activated charcoal may be used to improve methemoglobin clearance in accidental or intentional dapsone overdose [17]. In patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), there is a twofold increase in hemolysis of RBCs, warranting pre-treatment evaluation of G6PD levels of patients prior to dapsone administration [1].

Dapsone use is also associated with exfoliative dermatitis, erythema multiforme, urticaria, erythema nodosum, toxic epidermal necrolysis, and drug-induced lupus erythematosus [1, 9]. A rare, potentially fatal adverse event is dapsone hypersensitivity syndrome (DHS), which has an incidence ranging from 0.5 to 3% [9, 18]. DHS is a systemic syndrome characterized by fever, rash, eosinophilia, and hepatic and pulmonary manifestations that can lead to irreversible organ damage or death without management, with a mortality rate ranging from 12 to 23% [18]. Manifestation of DHS can develop weeks to up to 6 months after dapsone initiation [16]. Treatment for DHS includes discontinuing dapsone and starting systemic steroids with other supportive care [18]. Since the half-life of dapsone is up to 35 days, steroids should be tapered over a period longer than a month [18].

3.4 Special Considerations in Pregnancy and Pediatrics

Special considerations for the use of dapsone in specific populations include pregnant or breastfeeding individuals and children [1]. Dapsone can cross the placental barrier and is detectable in breast milk, posing potential risks to the developing fetus or neonate [1]. Case reports include neonatal hemolysis and cyanosis associated with dapsone use during pregnancy, leading to its classification as a category C drug for use in pregnancy [1, 9]. Dapsone is safe for use in children under the age of 10 years, with recommended dosing at 2 mg per kg of body weight [1, 9].

3.5 Monitoring and Management of Side Effects

Regular laboratory monitoring is recommended for dapsone, with varying frequencies based on institutional protocols and practice standards. Prior to initiating dapsone treatment, it is commonly advised to assess G6PD levels to identify individuals at risk for hemolytic anemia [1, 9]. Baseline complete blood count (CBC) with differential is often recommended with repeat labs every 1–2 weeks for the first month. Following this initial period, CBC may be monitored monthly for 6 months then semiannually [19]. However, specific recommendations may vary by institution or provider. Monitoring of hepatic function tests is recommended at baseline and then periodically [1, 9, 19], with adjustments to dapsone therapy warranted in the presence of elevated bilirubin or liver enzyme levels [1].

3.6 Contraindications

The use of dapsone is contraindicated in individuals with an allergy to dapsone, while caution is advised in those with allergies to other sulfonamide medications [1, 9]. Prior hypersensitivity with agranulocytosis, DHS, or severe anemia are also contraindications [1, 9]. Relative contraindications include conditions such as G6PD deficiency, methemoglobin reductase deficiency, severe hepatopathy, cardiac insufficiency, heart failure, pulmonary disease, and renal impairment [9]. Though G6PD deficiency is considered a relative contraindication, many providers select an alternative if baseline G6PD testing is decreased. Concurrent use of medications that induce methemoglobinemia, such as certain anesthetics such as benzocaine or lidocaine, is also a relative contraindication. It is recommended to discontinue dapsone prior to surgical procedures due to the risk of methemoglobinemia with anesthetics [1]. Patients should also receive counseling regarding the risk of methemoglobinemia associated with the use of spray and cream formulations of local anesthetics when taking dapsone [1].

4 Conclusions

4.1 Clinical Utility and Versatility

Dapsone is indicated to treat leprosy and dermatitis herpetiformis [9], but its synergistic antiinflammatory and antibiotic qualities provide clinical versatility beyond these indications [1]. With effectiveness of dapsone in the treatment of rare, “off-label” indications, such as EED, SPD, and cicatricial pemphigoid, often more than 80%, dapsone is reliable alternative for many rare, difficult to manage diseases. Dapsone was initially thought to be effective in the treatment of neutrophilic dermatoses. However, many eosinophilic dermatoses such as EPF, EAE, and eosinophilic fasciitis and cellulitis have also been successfully managed with dapsone, leading to an expansion of its utility in clinical practice.

Dapsone’s favorable, long-term safety profile [5, 9] and status as an older medication makes it an efficacious and cost-effective treatment alternative for patients who are unable to afford or lack access to newer, specialized medications. Adverse effects such as hemolytic anemia and methemoglobinemia occur infrequently, particularly when prescribed at appropriate doses and with proper monitoring [1]. Though dapsone has an FDA indication for only two diseases, it is often used in the treatment of diseases that lack a standard medication regimen to manage symptoms.

4.2 Ongoing Clinical Trials and Future Use

While dapsone is currently only indicated for two conditions, trials looking into its efficacy in other conditions are ongoing. There are currently two clinical trials investigating the use of dapsone in various dermatologic conditions. One study, with an expected completion date in December 2023, is comparing the efficacy of colchicine, dapsone, and azathioprine in the treatment of skin vasculitides, including primary cutaneous vasculitis, cutaneous polyarteritis nodosa, IgA vasculitis, and Henoch–Schönlein purpura (NCT02939573). This trial aims to evaluate the effectiveness of these medications in managing these conditions over a 6-month period.

Another ongoing study (NCT05984381) is investigating the efficacy and safety of dapsone compared to methotrexate as a steroid-sparing adjunctive therapy for the treatment of bullous pemphigoid. This trial seeks to provide insights into the potential role of dapsone in managing bullous pemphigoid while minimizing the need for systemic corticosteroids. These studies hold promise for expanding our understanding of dapsone’s therapeutic potential and optimizing its use in dermatologic practice.

Continued investigation and trials of dapsone in diseases with pathophysiology similar to those named in the review can further promote dapsone’s future use in dermatology. Dapsone is a versatile option, characterized by its safety, effectiveness, and affordability across various conditions. In many of the conditions discussed with topical corticosteroids therapies as a first line, the addition of dapsone as an adjunctive in recalcitrant diseases or use as a steroid-sparing agent may be beneficial. Dapsone’s status as an older medication with increased availability compared with more specialized medications may provide an option to those in developing regions seeking dermatologic care. This review describes its broad applications, encompassing both FDA-approved indications and off-label uses with efficacy in clinical practice.