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Questions
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Q20.1 What is the role of hydroxylamine metabolites in dapsone toxicities, and how does cimetidine alter these effects? (Pg. 224)
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Q20.2 What is the overall function of the myeloperoxidase system in neutrophils? (Pg. 225)
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Q20.3 Concerning the myeloperoxidase system, (1) what are several additional cells that use this enzyme, and (2) which dapsone-responsive dermatoses involve these cell types? (Pg. 226)
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Q20.4 What is a typical timing of initial dapsone response in dapsone-responsive dermatoses? (Pg. 226)
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Q20.5 Concerning bullous dermatoses responsive to dapsone, (1) what are several that are immunoglobulin A (IgA) mediated, and (2) what are several other dapsone responsive immunobullous dermatoses? (Pg. 227)
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Q20.6 What are several ‘neutrophilic dermatoses’ which typically respond to dapsone? (Pg. 227)
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Q20.7 Why is hemoglobin (Hgb) A1c often falsely low in patients on dapsone therapy? (Pg. 229)
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Q20.8 What are several ethnic groups which are more likely to be glucose-6-phosphate dehydrogenase (G6PD) deficient and how does this impact ordering baseline determination of G6PD in all groups? (Pg. 229)
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Q20.9 What are some of the factors that increase methemoglobinemia: (1) an enzyme deficiency, (2) dapsone dose, (3) the metabolite responsible, and (4) relevant comorbidities? (Pg. 229)
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Q20.10 What is the role of these measures in patients with significant hemolysis and/or methemoglobinemia: (1) methylene blue, (2) cimetidine, (3) vitamin C, and (4) vitamin E? (Pg. 229)
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Q20.11 Concerning dapsone agranulocytosis, what is (1) the incidence, (2) typical timing, (3) clinical presentation, and (4) resolution after dapsone discontinuation? (Pg. 229)
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Q20.12 Concerning dapsone neuropathy, what is (1) the clinical presentation, (2) the role of dapsone dose, and (3) resolution after dapsone discontinuation? (Pg. 230)
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Q20.13 What is the typical timing and presentation of dapsone hypersensitivity syndrome (subset of drug reaction with eosinophilia and systemic symptoms [DRESS])? (Pg. 230)
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Q20.14 Concerning screening tests in patients before starting dapsone therapy, (1) what screening test should be considered in Asian populations, and (2) what is this population at risk for if treated with dapsone? (Pg. 231)
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Q20.15 What are the key issues to consider regarding sulfonamide and dapsone cross-reactivity? (Pg. 231)
Abbreviations used in this chapter
AE
Adverse effect/event
AIDS
Acquired immunodeficiency syndrome
CBC
Complete blood count
CS
Corticosteroid
DH
Dermatitis herpetiformis
DDS
Diaminodiphenylsulfone (dapsone)
DRESS
Drug reaction with eosinophilia and systemic symptoms
FDA
US Food and Drug Administration
G6PD
Glucose-6-phosphate dehydroxygenase
G-CSF
Granulocyte-colony stimulating factor
HETE
Hydroxyeicosatetraenoic acid
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
LFT
Liver function test
MADDS
Mono-acetyl diaminodiphenylsulfone
NOH
Hydroxylamine
RBC
Red blood cell
SLE
Systemic lupus erythematosus
UVB
Ultraviolet B
WBC
White blood cell
Introduction
Fromm and Wittman first formulated dapsone (4,4’-diaminodiphenylsulfone, DDS) in 1908 as a chemical to be used in the dye industry. The first use of dapsone in humans, however, occurred over 20 years later after prontosil, a commercially available sulfonamide antibiotic, was created, leading to a Nobel Prize for its creator in 1932. This sparked an unprecedented interest in sulfones, including dapsone, in the 1930s and 1940s, as the scientific community began to look for antibacterial functions. Dapsone was used to treat tuberculosis, and soon thereafter leprosy, after Feldman and colleagues showed its potent antimycobacterial activity in animals in the 1940s. It has remained a principle drug in multi-drug regimens for leprosy since this discovery was made. Thereafter, dapsone’s usefulness in treating malaria and Pneumocystis carinii (also known as P. jirovecii ) pneumonia in acquired immune deficiency syndrome (AIDS) patients was established. Other uses in infectious diseases have been noted; however, this chapter will focus primarily on treatment of inflammatory skin diseases.
In 1947, Costello reported on the successful use of sulfapyridine in the treatment of dermatitis herpetiformis (DH). This observation resulted in the investigation of a number of different sulfonamide-type drugs for the treatment of DH ( Table 20.1 ). Subsequent studies by Kruizinga and Hamminga documented the efficacy of dapsone in the treatment of DH. Although dapsone has many associated pharmacologic and idiosyncratic adverse events (AE), a complete understanding of the drug’s pharmacology, as well as proposed mechanisms of action and potential AE, will allow clinicians to use the drug in a manner that maximizes the therapeutic benefit and minimizes the likelihood of significant AE.
Table 20.1
Dapsone and Related Drugs
| Generic Name | Trade Name | Generic Available | Manufacturer | Tablet/Capsule Sizes | Special Formulations | Standard Dosage Range |
|---|---|---|---|---|---|---|
| Dapsone | Dapsone | Yes | Jacobus | 25, 100 mg | None | 50–200 mg/day |
| Sulfapyridine | Currently unavailable | N/A | Jacobus | 500 mg (in studies) | N/a | 1–2 g/day |
| Sulfasalazine | Azulfidine Azulfidine EN |
Yes | Pfizer, various others | 500 mg | None | 1–2 g/day |
Pharmacology
Table 20.2 contains key pharmacologic concepts for dapsone and related drugs. Fig. 20.1 demonstrates the structure of dapsone.
Table 20.2
Pharmacology Key Concepts—Dapsone and Related Drugs
| Drug Name | Drug Category | Absorption and bioavailability | Elimination | ||||
|---|---|---|---|---|---|---|---|
| Peak Levels (h) | Percentage Bioavailable (%) | Protein Binding (%) | Half-Life (h) | Metabolism | Excretion | ||
| Dapsone | Sulfone | 2-6 | 70–80 absorbed | 70–90 | 10–50; mean 28 | N -acetylation, N -hydroxylation | Hepatic and renal |
| Sulfapyridine | Sulfonamide | 1.5–4 | >80 | 50–70 | 5–14 | N -acetylation, N -hydroxylation | Hepatic and renal |
| Sulfasalazine | Sulfonamide | 10–30 | 15 | 99 | 6–15 | Mostly acetylation; in bowel converted to SP and 5-ASA | Hepatic and renal |
5-ASA, 5-Acetylsalicylic acid; SP, sulfapyridine.
Absorption and Bioavailability
Dapsone is a lipid-soluble, water-insoluble compound that penetrates well into cells and various tissues. Dapsone is well absorbed from the gut with approximately 70% to 80% of a single oral dose absorbed, with an absorption half-life of approximately 1 hour. Peak concentrations of dapsone in plasma are reached within 2 to 8 hours after administration, with approximately 70% of the drug bound to plasma protein. In a steady state condition, 100 mg of dapsone results in a mean level at 24 hours of 1.95 mg/L, with a peak dapsone level of approximately 3 mg/L occurring at 2 to 6 hours after an oral dose. The elimination half-life of dapsone has been shown to average between 24 and 36 hours (with significant individual variability ranging from 10–50 hours). This long elimination half-life results in dapsone remaining in the circulation for as long as 30 days after a single oral dose and may be a result of a significant enterohepatic recirculation and of the strong protein binding of both dapsone and its major metabolite mono-acetyl diaminodiphenylsulfone (MADDS). The observed increased effectiveness of dapsone compared with other sulfones and sulfonamides (sulfapyridine) is probably related to the superior absorption of dapsone from the gut and its effective penetration into various cells. It is notable, however, that studies in leprosy patients and drug concentration algorithms indicate that the elderly and obese have lower drug plasma concentrations after standard dosing of dapsone.
Dapsone is able to cross the placenta and is excreted into breast milk . Hemolysis has been demonstrated to occur in nursing infants of mothers taking dapsone. No harmful effects of dapsone have been demonstrated on development in utero in case reports and small series, but lack of definitive proof of the safety of dapsone in pregnancy has resulted in its categorization as a (original US Food and Drug Administration [FDA] category) class C drug for use in pregnancy.
Metabolism ( Fig. 20.2 )
Dapsone is primarily metabolized by two methods: N -acetylation and N -hydroxylation. Dapsone is acetylated in the liver by N -acetyltransferase to MADDS, and subsequently deacetylated back to DDS by arylacetamide deacetylase. There is significant variability in individual rates of acetylation; however, this variability is not relevant clinically. Despite the fact that some individuals are relatively quick acetylators, deacetylation is invariably rapid, and a state of equilibrium soon develops between acetylation and deacetylation. Additionally, initial acetylation of dapsone is a reversible process, further reducing the importance of acetylator status. Initial laboratory evaluation before starting dapsone therapy need not include acetylator phenotype. During the early phases of absorption, however, an increased ratio of MADDS/DDS is likely observed because of the stronger protein binding of MADDS than that of DDS.
The second major pathway of metabolism of dapsone is hydroxylation. N -hydroxylation of dapsone occurs in the liver via various cytochrome P-450 enzymes, including CYP2C9, CYP2C19, CYP2E1, CYP2D6, and CYP3A4. Q20.1 This hydroxylamine metabolite (DDS-NOH) is thought to be responsible for the hematologic AE associated with dapsone including methemoglobinemia and the development of a hemolytic anemia. N -hydroxylation of dapsone can be inhibited in vivo by the use of cimetidine, which mainly inhibits CYP2C19 with minor inhibition of CYP3A4 and others, and has been demonstrated to decrease methemoglobinemia in patients without decreasing plasma levels of dapsone.
Excretion
Dapsone and its metabolites are also conjugated in the liver as dapsone glucuronide, which is more water soluble and rapidly excreted via the kidneys. These conjugates represent the major metabolites of dapsone found in the urine and are not easily detectable in the circulation, suggesting that they are rapidly cleared. Dapsone has been suggested to have a significant enterohepatic recirculation, in part because of the observation that treatment with activated charcoal increases the rate of elimination of dapsone up to five times. Dapsone is excreted via the kidneys with the parent drug, and N- hydroxydapsone is the main product detected, most often conjugated with glucuronide. Additionally, the observation that treatment with probenecid decreases renal clearance implies renal tubular transport. The role of liver failure in the clinical use of dapsone has been evaluated in patients with cirrhosis, and although minor changes in the metabolism of dapsone have been documented, no dosage adjustment appears to be needed. The impact of varying degrees of renal failure on the clinical use of dapsone has not been thoroughly investigated. No clinically significant difference in the absorption of dapsone has been observed in patients with DH despite the presence of a gluten-sensitive enteropathy in these patients.
In summary, dapsone is well absorbed from the gut and metabolized by N -acetylation and N -hydroxylation. The N -hydroxylated forms of dapsone are important, as it is these forms that play a critical role in the hematologic AE noted with dapsone. Dapsone is excreted via the kidneys with a significant enterohepatic circulation, resulting in an effective half-life of approximately 24 to 36 hours and allowing for once daily dosing.
Table 20.3
Dapsone Mechanisms of Action
| Postulated Mechanisms | Potential Clinical Effects |
|---|---|
| Inhibition of neutrophil myeloperoxidase | Inhibition of neutrophil respiratory burst mechanisms with inhibition of neutrophil tissue damage |
| Inhibition of eosinophil myeloperoxidase (enzyme present in monocytes also) | Potential mechanism by which dapsone may affect some eosinophil mediated dermatoses such as eosinophilic cellulitis |
| Inhibition of neutrophil adhesion to vascular endothelium integrins | Impaired neutrophil chemotaxis |
| Inhibition of chemotaxis in part by inhibition of f-met-leu-phe mediated chemotaxis | Impaired neutrophil chemotaxis |
| Inhibition of LTB 4 binding | Impaired neutrophil chemotaxis |
| Inhibition of generation of 5-lipogenase products in neutrophils and macrophages | Inhibition of chemotaxis and inflammatory damage to tissue |
| Inhibition of dihydropteroate synthetase (enzyme in reduction of folic acid) | Probable mechanism for clinical effect in leprosy patients (and selected other infectious diseases) |
LTB, leukotriene B 4 .
Mechanisms of Action ( Table 20.3 )
Although the mechanism of action of dapsone in the treatment of leprosy has been shown to be a result of inhibition of the folic acid pathway, the mechanism of action of dapsone in inflammatory diseases is not well understood. Clinically, it appears that dapsone is most useful in treating diseases with neutrophilic infiltrates in the skin. This has led to suggestions that dapsone may directly affect neutrophil function. Following are several potential mechanisms by which dapsone may alter neutrophilic function.
Neutrophil Respiratory Burst ( Fig. 20.3 )
Initial observations suggested that dapsone might inhibit complement function. Dapsone has not, however, been demonstrated to affect either the presence of complement deposits in the skin of patients with DH or the activation of complement in experimental systems. The frequent presence of neutrophils in the inflammatory infiltrate of many ‘dapsone responsive’ skin diseases also led to the suggestion that dapsone may inhibit lysosomal enzymes. This effect, however, has been demonstrated only at concentrations of dapsone up to 20 times that seen in serum after a 300 mg dose. If dapsone does exert an effect on lysosomal enzymes, it must be highly concentrated in the lysosome, which to date has not been demonstrated. Q20.2 Stendahl and coworkers investigated the effect of dapsone on neutrophils and found no evidence of an effect on random movement, chemotaxis, release of lysosomal enzymes, or oxidative metabolism at concentrations of 1 to 30 g/mL. They did demonstrate that dapsone was able to inhibit the myeloperoxidase-peroxide-halide-mediated cytotoxic system (component of neutrophil respiratory burst), which likely plays a role in controlling the degree of neutrophil-induced destruction in lesions. Functioning as one of the strongest scavengers of reactive oxygen species known, dapsone decreases hydrogen peroxide and reduces hydroxyl radical levels. As tissue damage in certain skin diseases such as DH, linear immunoglobulin A (IgA) bullous dermatosis, and lupus erythematosus may be in part a direct consequence of polymorphonuclear neutrophils (PMN)-generated reactive oxygen intermediates, the beneficial effects of dapsone in hastening the resolution of these skin lesions may be a result of its free oxygen radical quenching effects. These findings, however, do not address the ability of dapsone to prevent the formation of new lesions and the finding that neutrophils do not accumulate in the skin of patients treated with dapsone.
Neutrophil Chemotaxis
The lack of neutrophils in the skin of patients being treated with dapsone suggests that dapsone may affect the chemotaxis of neutrophils. Initial investigation showed no consistent inhibition of chemotaxis by dapsone. Harvath and coworkers demonstrated a selective inhibition of neutrophil chemotaxis in vitro by dapsone, showing that although neutrophil chemotaxis to either C5a or leukocyte-derived chemotactic factor was not affected by dapsone, chemotaxis to the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (F-met-leu-phe) was inhibited in human neutrophils by dapsone. Thuong-Nguyen and associates showed that dapsone was able to inhibit the migration and binding of neutrophils to IgA deposits in skin in an in vitro neutrophil adherence assay. Nelson and coauthors have investigated the possible role of dapsone in the inhibition of integrin mediated neutrophil adherence. Their results demonstrated that dapsone can inhibit the CD11b/CD18-mediated binding of neutrophils in vitro, and that this is associated with an inhibition of chemoattractant-induced signal transduction in neutrophils. Investigators have also demonstrated that some sulfones can inhibit synthesis of chemotactic lipids and interfere with leukotriene B 4 (LTB 4 )-mediated chemotaxis in neutrophils.
These studies suggest that although the actual mechanism of dapsone is not clearly known, the drug does have a specific effect on human neutrophils, perhaps both by moderating the level of damage by neutrophils at the site of lesions and by decreasing neutrophil migration to lesions.
Effect on Eosinophils and Monocytes
Q20.3 It should be briefly noted that the enzyme inhibited by dapsone, myeloperoxidase, is also present in significant amounts in eosinophils and monocytes. It stands to reason that dapsone might also be effective in dermatoses in which these cell types have a central role in the pathogenesis. Anecdotal evidence and series of case studies support the use of dapsone in disorders such as granuloma annulare (monocytes) as well as eosinophilic cellulitis and eosinophilic annular erythema (eosinophils).
Effects of Dapsone Metabolites
The two major metabolites of dapsone, MADDS and DDS-NOH, may possess intrinsic antiinflammatory properties of their own. Analysis of 5-lipoxygenase products from neutrophils showed that DDS-NOH is significantly more effective than DDS (parent compound) and MADDS in suppression of leukotriene B 4 and 5-hydroxyeicosatetraenoic acid (HETE) generation. Additionally, chemiluminescence studies of neutrophils and whole blood showed that DDS-NOH causes significant and dose-dependent inhibition of oxidative burst. Although the anti-inflammatory effects of MADDS in these studies were found to be statistically insignificant, skin treated with topical formulations of each of the three compounds (DDS, MADDS, and DDS-NOH) showed significant reduction in ultraviolet B (UVB)-induced erythema.
Clinical Use
Box 20.1 lists indications for dapsone.
Box 20.1
Dapsone Indications
| US Food and Drug Administration-Approved Indications | |
|
|
| Off-Label Dermatogic Indications ( Consistent Efficacy ) | |
|
|
| Other Dermatologic Uses ( Variable Efficacy ) | |
Autoimmune Bullous Dermatoses
Vasculitis
Neutrophilic Dermatoses
|
Other Dermatoses
|
Dermatologic Indications – Consistent Efficacy
Dapsone has been approved by the FDA for the treatment of patients with DH, leprosy, and acne vulgaris (topical), and has been recognized as an effective therapy for a variety of skin diseases. Dapsone-responsive dermatoses can be divided into two general categories: those in which a response has been clearly documented, and those in which the response has been noted only anecdotally or in a minority of patients treated (see Box 20.1 ). A common element in many of the inflammatory conditions that have found to be most responsive to dapsone is the predominance of a neutrophilic infiltrate in the skin. Because of the relative toxicity of dapsone and the erratic nature of many inflammatory skin diseases, it is important that clear criteria be established for dapsone responsiveness in diseases in which the efficacy has not been firmly established. Most often, if dapsone is going to be effective in the treatment of an inflammatory dermatosis, the patient will experience a relatively rapid response (within 24–48 h) to dapsone therapy, with a similar relatively rapid recurrence of the disease after withdrawal of the medication.
Dermatitis Herpetiformis
Dapsone is the drug of choice for the treatment of DH. A recent study by Gorog and coworkers found that dapsone corrects a fibrinolytic defect found in the plasma of DH patients, suggesting plasma-derived factors may be implicated in the skin lesions of DH and elucidating the role of dapsone in alleviating these symptoms. Patients may also be treated with a gluten-free diet with good results; however, the difficulty of consistently following that diet often makes treatment with dapsone the best option for many patients (in conjunction with at least a ‘gluten-reduced’ diet). In addition, the clinical response to a gluten-free diet in patients with DH may be delayed often for weeks or months. Q20.4 Most patients will respond within 24 to 36 hours of initiating dapsone with marked decrease in both itching and new blister formation. Similarly, withdrawal of dapsone results in a rapid (within 24–48 hours) initial recurrence of the signs and symptoms of DH. This is a reproducible finding and should be the measure against which all therapy with dapsone is judged.
The great majority of patients with DH can be maintained on 100 to 200 mg of dapsone daily, although considerable variability exists in this response, with dosage ranges from 25 to 400 mg daily reported. If no significant risk factors such as severe cardiac, pulmonary, or hematologic disease exist for the pharmacologic AE of dapsone (hemolytic anemia and methemoglobinemia), therapy can be begun with 100 mg daily. This results in rapid control of the disease in most patients. Adjustment of the dosage can then be undertaken to achieve the lowest possible dose needed to control the disease process. Because toxicity from the pharmacologic AE is directly related to the dose of the drug, patients must be warned against self-medication and self-adjustment of the dosage of dapsone in response to small changes in disease activity. The severity of DH also may vary with time for reasons that are not clear, including some patients experiencing remission. A retrospective study from the National Institute of Health of patients with DH who experienced remission recommended patients be challenged with decreasing dosage or monitoring of lesions during a period of skipped dosages, per patient report. This may allow the dapsone dose to be reduced, decreasing toxic AE with no change in clinical symptoms. Of note, there is limited evidence for topical dapsone usage in DH patients, with only one case study in the literature reporting any benefit.
It is critical that patients be evaluated before the institution of dapsone therapy for any factors that may place them at high risk for pharmacologic AE and that they be followed up closely during therapy (see Monitoring Guidelines).
Linear Immunoglobulin A Bullous Dermatosis and Chronic Bullous Dermatosis of Childhood
Q20.5 Patients with linear IgA disease (either of the two entities above) generally present with clinical and histologic features very similar to those seen in patients with DH. These patients for the most part also respond to treatment with dapsone in a manner similar to that of patients with DH, with most patients controlled on 100 to 200 mg of dapsone daily. Occasionally, patients with linear IgA bullous dermatosis cannot be controlled on dapsone alone and may require adjunctive therapy, often with low-dose systemic corticosteroids (CS). This seems to be the case more often in children with linear IgA bullous disease (chronic bullous dermatosis of childhood). This response is difficult to predict, and decisions about the addition of systemic CS should be made on an individual patient basis.
Bullous Eruption of Systemic Lupus Erythematosus
Patients with the bullous eruption of systemic lupus erythematosus (SLE) have an urticarial, bullous or vesicular eruption with a histologic picture similar to that seen in patients with DH. These patients often have a dramatic response to dapsone therapy in doses as low as 50 mg daily. The presence of neutrophils in a vesicular eruption in a patient with SLE suggests that dapsone will be effective, commonly reducing the need for systemic CS. Patients with SLE may have significant anemia secondary to the inherent disease process that could increase the clinical severity of the pharmacologic effects of dapsone. Therefore, special care should be taken in both pretreatment and posttreatment monitoring in SLE patients (see Monitoring Guidelines).
Leprosy
The treatment of leprosy is constantly being reviewed and a discussion of this use of dapsone is beyond the scope of this chapter. The World Health Organization issues frequent guidelines, which should be referred when treating patients with leprosy. It is important to emphasize that monotherapy with dapsone is contraindicated in essentially all cases of leprosy.
Erythema Elevatum Diutinum
Patients with erythema elevatum diutinum, a distinct type of leukocytoclastic vasculitis, often respond dramatically to dapsone therapy. The dosages used are similar to those for DH and other blistering diseases.
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