Dapsone in dermatology: a comprehensive review 1

Review Article Dapsone in dermatology: a comprehensive review J K K Seneviratne1 Sri Lanka Journal of Dermatology, 2019/2020, 21: 1-9

Introduction antiparasitic agent (pneumocystic jeroveci and malaria as well). Not many drugs have withstood the test of time. Some were found to be less efficacious, whereas others have Sulphapyridine, a sulphonamide, was success- fizzled out due to intolerable or serious side effects. fully used in 1947 to treat dermatitis herpeteformis However, certain drugs are still being used since (DH). Subsequently, dapsone became the drug of discovery. A few examples are metformin, and choice for the treatment of DH. relevant to dermatology, methotrixate and dapsone. The main groups of systemic drugs used in Since dapsone is widely used by dermatologists dermatology include antibacterials and a variety of in Sri Lanka, a better understanding of its pharma- anti-inflammatory agents and an impressive group cology, mechanism of action and mechanisms by of immunosuppressives. Since dapsone exhibits all which it causes damage to human tissue should result of the above properties, it is still being used widely in in its proper use and will allow us to maximize the dermatology worldwide. therapeutic benefits. It will also prevent/minimize the significant adverse effects and relieve the phobia Though dapsone was first synthesised in 1908, some have about this valuable drug. researchers only became interested in the drug after the discovery of the sulphonamide, prontosil, the first Pharmacology sulphonamide antibiotic to be discovered. The award of the Nobel Prize for Medicine for this discovery Dapsone is highly lipophilic and is therefore readily resulted in widespread interest in other related absorbed from the intestines and easily penetrates into human tissues. It penetrates well into all the cells compounds. 4-diaminodiphenylsulfone is the of the human body. Peak concentration is reached chemical name of dapsone. To date, it remains the within 2-8 hours. The elimination half-life is fairly prototypic drug of sulfones. long (1-1.5 days). This allows daily dosing. The metabolites of the drug remain in circulation as long Though structurally related, the two groups are as 30 days after the last dose. The latter is important metabolized differently by the human body, hence in managing dapsone hypersensitivity syndrome. their side effects differ. Other sulphur-containing compounds are sulphonylureas and thiazide diu- Dapsone’s incomparable effectiveness com- retics. Dapsone was first used to treat streptococcal pared to other members of the sulfones and sulpho- infections using a very high dose (1-2 g daily). The namides is due to its superior absorption and easy discovery of its antimycobacterial property in penetration into most cells, including activated animals led to its widespread use in treating leprosy, neutrophils and mononuclear cells. Hence its indis- a disease with a worldwide prevalence. In fact, putable efficacy in many granulomatous infectious dapsone was used for decades as monotherapy for disorders like leprosy. Dapsone is excreted in breast leprosy. Though bacteriostatic, dapsone remains a milk and crosses the blood-brain barrier. However, principal drug in multi-drug regimens for leprosy to its widespread use in leprosy in developing countries date. Since then, it has also been used as an has proven its safety in pregnancy and lactation.

1Consultant Dermatologist, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka.

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Metabolism

Dapsone

N-acetyl transferase N-hydroxylase

Dapsone hydroxylamine (DDS – NOH) Monoacetyl dapsone

Glucuronidation G6PD Strong oxidant

damages RBC membrane Renal excretion Reduced metabolites

Metabolism lation, hydroxylation also takes place, a part from the liver, in keratinocytes and also by polymorphonuclear In order to excrete a lipophilic drug like dapsone, leukocytes and mononuclear cells. DDS-NOH is the it needs to be converted to a hydrophilic compound. most effective metabolite of dapsone therapeutically This process (biotransformation) also results in it is a potent anti-inflammatory and antibacterial generation of reactive intermediate metabolites (bio- compound. Unfortunately, the same compound is activation). responsible for dapsone’s adverse effects.

As shown above, dapsone is reversibly Dapsone undergoes significant enterohepatic acetylated in the liver by N-acetyl-transferase to circulation. Dapsone can be safely used in both liver N-acetyl-dapsone (MADDS) and deacytelated back and renal failure with minor dose adjustments. to diaminodiphenylsulfone (DDS). As a result, a Dapsone is well-absorbed in dermatitis herpetifomis state of equilibrium develops between these two (DH) despite the presence of gluten-sensitive compounds. enteropathy.

The second metabolic pathway of dapsone is hydroxylation. This is a phase I drug metabolic Excretion pathway mediated by cytochrome P-450 enzymes Dapsone and its metabolites are conjugated in the (CYP-450). This process of hydroxylation generates liver and rapidly excreted as dapsone glucuronide dapsone hydroxylamine (DDS-NOH). Unlike acety- by the kidneys.

Sri Lanka Journal of Dermatology Dapsone in dermatology: a comprehensive review 3

Mechanism of action Oxygen

(Activated PMN) NADPH oxidase

Superoxide radical

Superoxide dismutase

Hydrogen peroxide

Chloride Myeloperoxidase Dapsone X

Hypochlorite Other strong oxidants

Mechanism of action disease, bullous SLE, DH and Sweet’s syn- drome. Dapsone’s therapeutic benefit in these Dapsone has both antimicrobial and inflam- conditions has been proven beyond a doubt matory properties, the latter by several mechanisms. worldwide. Similarly, corticosteroids too may have anti-neutrophilic effects and can be used As can be seen, myeloperoxidase plays an to contribute for a better therapeutic effect. Both important role in quenching the harmful effects of can be used concomittantly for an additive O -free radicals generated by neutrophils, eosinophils 2 effect. and monocytes. The latter cells play a key role in granulomatous dermatitis. 2. Neutrophil chemotaxis Dapsone binds to intergrins on the neutro- The main antibacterial effect of dapsone is by phils and inhibits adherence to endothelial inhibition of dihydropteroate synthetase, a key initial cells, thereby preventing chemotaxis. It is also enzyme in folic acid utilization. believed to inhibit LT4-mediated neutrophil chemotaxis. Since dapsone, therapeutic benefit is well-esta- 3. Neuroprotection blished in neutrophilic dermatoses. It is reasonable Recent research indicates that dapsone can to argue it affects a number of key inflammatory influence functions of the central nervous pathways of neutrophils. These include: system. Its neuroprotective function is well- 1. Myeloperoxidase – halide mediated cyto- seen in stroke patients, and is believed to be toxicity (part of neutrophil respiratory burst). mediated by its antioxidative and anti-

As a major scavenger of reactive O2 species, convulsive properties. Of special interest is its

dapsone reduces both H2O2 and free hydroxyl benefit in neuro-Sweet’s syndrome. Addi- radicals. It is well-known that neutrophil- tionally, it is also known to inhibit the growth mediated skin damage occurs in linear IgA of glioblastomas.

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Over the years, dapsone has been established as a B) In combination with other antimicrobial/ very useful drug for dermatologists of the entire antiprotozoal agents world. Currently, no other drug used in dermatology 1. Leprosy exhibits such a wide array of benefits. Among these 2. Pneumocystis jeroveci infection in AIDS are: 3. Malaria 1. A combination of anti-inflammatory, anti- microbial and anti-protozoal effects. Dosage of dapsone in dermatology 2. Its proven safety in children, adults, the elderly Fixed dose regimens of WHO blister packs makes its and in pregnancy. use easier in leprosy. The newer uniform multi-drug therapy further simplifies its use. However, in other 3. Safety of long-term treatment (once used as inflammatory skin diseases, its dosage should be one life-long monotherapy of leprosy patients). of a minimum required to control the disease activity. 4. Unique, powerful disease-specific effects on Initial dosage in adults ranges from 50 to 100 mg dermatitis herpeteformis. daily. A higher dose upto 300 mg per day can be tried 5. Fast relief of loxoscelism associated with after 4 to 6 weeks of low dosage therapy. However, brown recluse spider bites. this will depend on the tolerability and monitoring laboratory results. Once control of the disease is 6. Its safety in combination with other drugs, e.g. achieved, the dose can be reduced to one of multi-drug therapy for leprosy, steroids. maintenance. 7. Its free availability and very low cost. For children, tablets can be crushed and dis- solved in a sweet syrup. The general recommended Clinical uses of dapsone dose is 2 mg/kg/day, doubled if necessary after four Indications weeks. Dapsone is currently used worldwide in the treatment Adverse effects of neutrophilic/eusinophilic/monocytic (granulo- matous) mediated skin diseases and in the treatment Adverse effects to dapsone are of two types – of leprosy, the latter as the World Health Organi- pharmacological and idiosyncratic. The first is dose- zation’s multi-drug therapy regimens (MDT). It can dependent, and the latter dose-independent, therefore be used as monotherapy or as part of combination the latter cannot be predicted. therapy. Its main indications are: Pharmacological adverse effects 1. As monotherapy, benefits proven beyond doubt The two most commonly encountered types are A) Dermatitis herpetiformis haemolysis and methaemoglobinaemia. As said B) Linear IgA disease earlier, these are often encountered side effects and C) Infantile acropustulosis can be severe at a higher dosage exceeding 100 mg daily. Dapsone per se is not harmful to red blood D) Erythema elevatum diutinum cells. However, its red cell toxicity comes from its N- E) IgA pemphegus hydroxy metabolites (N-hydroxy-dapsone-hydroxy- lamine and N-hydroxy-monoacetyl-dapsone-hydroxy- F) Subcorneal pustular dermatosis lamine). These are potent oxidants, produced in the 2. liver by the cytochrome P-450 (CYP) system. As red A) As combination therapy, along with other blood cells have lost their nuclei, they do not immunosuppressives, especially oral steroids synthesise new molecules. Their survival depends 1. Sweet’s syndrome on cell membrane integrity carried out by the anti- 2. Bullous pemphigoid oxidant system glutathione, the hexose mono- 3. Bullous SLE phosphate pathway and glycolysis providing energy to glutathione in a reduced state. 4. Eosinophilic folliculitis 5. Leucocytoklastic vasculitis Haemolysis 6. Pyoderma gangrinosum For the aforementioned reasons, older red blood cells 7. Pemphegous vulgaris are especially vulnerable to oxidative stress and 8. Relapsing polychondritis undergo destruction. This is seen in all patients

Sri Lanka Journal of Dermatology Dapsone in dermatology: a comprehensive review 5 receiving dapsone within the first few days. The associated with a distant motor neuropathy. Rarely, resultant drop in haemoglobin stimulates the bone they may also have sensory symptoms. Clinically, marrow to release young red blood cells both short exposure of high dosage (1.2 g for 7 days) (reticulocytes) into circulation. This may lead to a or low-dose prolonged exposure (150 mg for 5 years) falsely low HbA1C in poorly-controlled diabetic are known to cause this. Fortunately, most patients patients. As N-hydroxy-metabolites are potent recover on withdrawal of the drug, but symptoms oxidants, they pose a persistent oxidative on the may last upto two years. Though the exact mechanism RBCs. The resulting depletion of reduced glutathione is unknown, it is believed to be caused by axonal leads to the formation of glutathione disulphides, degeneration. Other neurological manifestations altering the red cell membrane pliability, Heinz body include optic atrophy (overdosage) and acute formation and subsequent splenic destruction. psychosis. Lipid peroxidation is another mechanism of RBC membrane alteration leading to early destruction. The Gastrointestinal adverse effects above mechanisms significantly differ in individual These are often mild and well-tolerated, allowing patients. This is specifically dependent on the amount continuation of treatment. They are often encountered of glucose 6-phosphate dehydrogenase enzyme levels. A significant variability of G6PD levels is in the early phases of treatment. These adverse effects found in all races. People who are severely lacking include nausea, anorexia and vomiting. Rarely, the above enzyme will develop acute severe intra- dapsone is known to cause pancreatitis and gall vascular haemolysis. Cimetidine in high dosage is bladder perforation. known to reduce the risk of this side effect. Dapsone hypersensitivity syndrome (sulfone/ Methaemoglobinimia dapsone syndrome) The second major haematological side effect is Typically, patients present with fever, a generalized methaemoglobinimia. This too is caused by the N- erythematous maculopapular rash and jaundice seen hydroxy-metabolites. This too is dose-dependent. In between the third and twelfth weeks of treatment. The patients taking small doses of dapsone, the amount jaundice is mainly due to the liver damage and partly of methaemoglobin produced is insignificant. due to haemolysis. Rarely, more severe cutaneous Methaemoglobin reductase in RBCs reconverts reactions are seen, including Stevens-Johnson methaemoglobin to haemoglobin. Patients taking syndrome or toxic epidermal necrolysis. The liver higher doses of dapsone produce significant amounts injury is a variable mixture of hepatocyte damage and of methaemoglobin. As methaemoglobin has less cholestasis. A peripheral blood eosinophilia is often capacity to carry oxygen, higher levels of methae- seen. Rarely, auto-antibodies (ANA) may become moglobin can result in a state of hypoxia. This is positive. All patients suffering from this syndrome especially severe in patients who are anaemic or have compromised cardiopulmonary functions. require immediate withdrawal of all drugs, hospital admission, exclusion of other forms of liver disease and a prolonged course of oral steroids to cover the Idiosyncratic adverse effects effects of dapsone metabolites in circulation, which Agranulocytosis is the most lethal idiosyncratic may last upto 6 weeks from the last dose. Patients adverse effect of dapsone. Though the exact may also require supportive therapy in the event mechanism is unclear, it is believed to be caused by hepatic synthetic functions are compromised. N-hydroxylamine metabolites destroying the neutro- Examples include albumin transfusions and adminis- phil precursors in the bone marrow. Fortunately, this tration of vitamin K. As these patients often have severe 6 is rare, with an incidence of 65 cases per 10 patient vomiting, they may require intravenous fluids as well years. It is commonly encountered in patients treated as intravenous steroids, especially during the first with dermatitis herpeteformis and very rarely week of treatment. In paucibacillary leprosy, they may encountered in leprosy patients. There is no clear explanation for this difference. Agranulocytosis is not require further treatment with anti-leprosy drugs. encountered between the third and twelfth weeks of This is because the N-hydroxy-metabolites of treatment. Early leukopenia, if seen, necessitates early dapsone, the cause of hypersensitivity, are also lethal stoppage of treatment. to the few organisms in paucibacillary leprosy. Many a dermatologist has observed the disappearance of Peripheral neuropathy skin lesions of paucibacillary leprosy patients once they recover from dapsone hypersensitivity Rarely, prolonged treatment with dapsone is syndrome.

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Photosensitivity Some patients on long-standing dapsone therapy may develop mild photosensitivity. However, this usually settles with photoprotection and the use of a mild topical steroid.

Drug interactions Drug interactions are relatively uncommon. The most important ones are outlined below.

Dapsone monitoring guidelines

Baseline History and examination Complete history and physical with emphasis on cardiopulmonary, gastrointestinal, neurological, hepatic and renal systems Laboratory Full blood count with differential WBC count Liver function tests (particularly AST/ALT) Renal function tests Urine full report (UFR) Glucose-6-phosphate dehydrogenase level (G6PD) Follow-up History and examination Each visit reassess peripheral motor neurologic examination Each visit assess for signs and symptoms of methemoglobinemia Question for any other significant adverse effects Laboratory FBC with differential WBC count every week for 4 weeks, then every 2 weeks until week 12, then every 3-4 months Reticulocyte count as needed to assess degree of response to dapsone hemolysis Liver function tests every 3-4 months (particularly AST/ALT) Renal function tests and urinalysis every 3-4 months Methemoglobin levels as clinically indicated

By proper pre-treatment evaluation and subse- the compensatory bone marrow response to dapsone- quent careful and proper follow-up, toxicity can be induced haemolysis will be significantly reduced, minimized and treatment outcomes can be optimized. resulting in severe anaemia. Similarly, a poor As suggested, G6PD levels should be obtained reticulocytic response may indicate an underlying whenever possible in all patients. It is important to deficiency state rather than poor compliance. realize that G6PD levels may be falsely normal in patients who have an elevated reticulocyte count or Summary have a genetic variant that is less capable of handling Dapsone is an important drug for dermatologists oxidative stresses on the RBC. The genetic hetero- worldwide. One should be fully conversant with its geniety of G6PD deficiency means that patients of clinical uses. It should not be avoided out of fear of its different G6PD levels may respond differently to the side effects. Instead, one should use it carefully. Since same dose of dapsone. However, in remote areas, dap- both pre-treatment evaluation and subsequent follow- sone can be given in the absence of G6PD screening. up require simple clinical skills and simple haema- tological testing, the drug can be used even in remote Measurement of haemoglobin is of critical areas. To facilitate this, a dapsone card can be issued importance in all patients receiving dapsone during to each and every patient receiving dapsone. The one early periods of treatment. As leprosy is prevalent that is used in Lady Ridgeway Hospital is shown in among poorer communities, who also suffer from the diagram. This summarizes all aspects relevant to mixed-deficieny anaemia, it is important to correct its use and outlines urgent measures that have to be the deficiency before commencing dapsone, otherwise taken in the event of an adverse effect.

Sri Lanka Journal of Dermatology Dapsone in dermatology: a comprehensive review 7

Dapsone Card

Name: Address:

Age: DR’s contact cell phone no's

Indication for therapy: Combined therapy

Monotherapy: Specify

Date of commencement of treatment:

Fixed Non Fixed

Dosage:

Pre treatment assessment

Cardio pulmonary status: Consanguinity:

Past history of allergies: Drug induced haemolysis:

Base line parameters:

• G6PD level (Screening / quantitative):

• Haemoglobin / Retic count:

• WBC/DC:

• Platelets:

• Methaemoglobin reductase levels:

• AST:

• ALT:

• Serum albumin

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Follow up assessment

Hb/Retic WBC PLT AST ALT Meth Hb Count levels 1st Week

1st Month

Sri Lanka Journal of Dermatology Dapsone in dermatology: a comprehensive review 9

Use with caution the following drugs: Atropine, Bupivocaine, Lidocaine, Mepivacaine, Prilocaine, Xylocaine, Ciprofloxacin, Pyrimathamine, Sulfadoxine, Trimethoprim, SMX-TMP, Sulfonamide

Advice

• Treatment should be stopped immediately if patient develops fever, rash, yellow eyes (dapsone hypersensitivity syndrome) or patient becomes acutely breathless (Methaemogloblinemia) Refer guideline

• Drugs to be avoided Methotrexate Co trimoxazole Hydroxychloroquine (Worsens the hematological side effects)

• The drug to be taken after dinner

• Pregnancy, lactation, immunization not contraindicated

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