Dermatology Online Journal - praxis-schuster.ch · Prontosil in 1935. [18,19] This represented the...

Dermatology Online JournalUC Davis

DapsoneRonni Wolf1, Hagit Matz1, Edith Orion1, Binnur Tuzun2, Yalcin Tuzun3

Dermatololgy Online Journal 8(1): 2

1. The Dermatology Unit, Kaplan Medical Center, Rechovot, Israel, 2. The Department of Dermatology, Trakya University, Medical Faculty, Edrine, Turkey, 3.The University of Istanbul, Cerrahpasa Medical Faculty, Istanbul, Turkey.

Abstract

Dapsone (4,4'-diaminodiphenylsulfone, DDS) was synthesized a century ago and continues to be a powerful therapeutic tool in many skin diseases. We havetried to retrieve and present the available knowledge and relevant information on this old but still very useful drug with the hope of encouraging and guidingpracticing dermatologists to adapt it for various indications. Our objective is to familiarize the clinician with how this agent works, in what disease states it iseffective, how to administer it, what adverse effects may occur, and how to monitor the patient receiving this drug.

Adapted from R. Wolf et al. "Dapsone: unapproved uses or indications" Clinics in Dermatology Vol. 18, January/February 2000, pp. 37-53.

Introduction

"Because the newer methods of treatment are good, it does not follow that the old ones were bad: for if our honorable and worshipful ancestors had notrecovered from their ailments, you and I would not be here today." [Confucius]

The unprecedented advances in immunology, molecular biology, and genetics over the last decade have created exciting opportunities and brought about theintroduction of promising new drugs to ameliorate and even therapeutically cure many challenging skin diseases. Many of the new and innovative therapeuticdevices and drugs are, however, produced by companies motivated largely by commercial interests. The physician of the third millennium is thus underconstant pressure from both the pharmaceutical industry, and his/her patients to use and prescribe new (and usually expensive) drugs, while some older, nolonger patented ones remain neglected "orphans" simply because they are no longer profitable or cost-effective for the pharmaceutical industry.

Dapsone has been the principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy since it becameavailable in the 1940s. [1,2,3,4] As an anti-infective agent, it is also used for treating malaria [5,6] and, recently, for Pneumocystic carinii pneumonia in AIDSpatients. [7,8,9] Though dapsone's usefulness in these diseases is unquestioned, this chapter will mainly be devoted to the use of dapsone in non-infectiousdiseases.

Since the early 1950s, dapsone was recognized as being uniquely effective against a number of non-infectious inflammatory diseases, of which dermatitisherpetiformis is the best known. [10,11,12,13] The response of this disease to the drug is so dramatic (the pruritus is relieved within 48-72h) that it has evenbeen considered as being a diagnostic indicator. [14,15,16] A considerable number of other inflammatory as well as bullous diseases have been shown torespond in varying degrees to dapsone, although the drug is not approved for them all. Today, dermatologists are much more aware of and interested in theanti-inflammatory immunosuppressive effects of the drug than in the antibacterial and antibiotic properties.

Historical perspective

Dapsone was synthesized in 1908 by Fromm and Wittmann. [17] The discovery was not based on the search for a solution of a therapeutic problem butrepresented an achievement in the field of chemistry aimed at identifying a molecule for producing azo dyes.

Unrelated to Fromm and Wittmann's discovery, intensive efforts were being made at that time to combat bacterial infections by means of chemotherapy andmany sulfonamide compounds were tested. In 1933, the first effective sulfonamide compound was submitted to clinical trials and it was put on the market asProntosil in 1935. [18,19] This represented the great achievement of Gerhard Domagk who discovered that certain sulfonamides that had been developed bythe chemists with whom he collaborated, Drs. Klarer and Mietzsch, showed antibacterial potential. In 1939, Domagk received the Nobel Prize for medicineand physiology for the "Discovery of the antibacterial effect of Prontosil", but was not permitted to accept it by the National Socialists of prewar Germany. InDecember 1949, he was awarded the diploma and the medal: "Professor Domagk. It has become clear during the eight years that have passed since it wasdecided to award you the Nobel Prize that the sulphonamides have introduced a new era in the treatment of infectious disease." An extensive search forchemically similar substances and for their anti-infective effects on various diseases soon followed.

Although dapsone was synthesized at the turn of the century, long before the synthesis of the sulfonamides, its anti-bacterial effects were not investigateduntil the late 30s. Two research groups, Buttle et al. [20] in England and Fourneau et al. [21] in France were the first to return to experimenting with the drugand investigating its chemotherapeutic effects. Since 1937, sulfones had been found to suppress the growth of various pathogenic bacteria, such asStreptococci, Staphylococci, Gonococci, Pneumococci, Mycobacteria leprae and tuberculosis, and others. [1,22,23] However, the observed beneficial effectsof killing bacteria in experimentally induced infections of mice seemed to be associated with unacceptably toxic side effects. The sulfones were soonconsidered too toxic for humans and of no value in the treatment of human infections. [1,24] There is now no doubt that the negative side effects of dapsonehad resulted from the excessive dosage which was administered at that time, compared to the amounts being used today. In any event, experimental studieson dapsone and related sulfones were not abandoned, and in the early 1940s these drugs gained worldwide recognition for treating leprosy and otherinfectious diseases. [25,26,27,28]

In 1950, a great discovery that prepared the way for sulfones in dermatology was made serendipitously, because of an incorrect assumption. Tworesearchers from Portugal assumed that dermatitis herpetiformis of Duhring was an infectious disease. When they examined the effects of various sulfoneson this disease they found excellent results.[29] Other investigators soon confirmed the efficacy of the compound for this disease. [30] The introduction ofpenicillin as well as of many other efficient antibiotics has considerably altered the uses of dapsone in medicine, and its main applications are now in thetreatment of non-infectious inflammatory, autoimmune, and bullous diseases.

Pharmacology of dapsone

Dapsone is absorbed rapidly and nearly completely from the gastrointestinal tract. Peak concentrations of dapsone in plasma are reached within 2 to 8 hoursafter administration. The mean half-life of elimination is about 20 to 30 hours. Twenty-four hours after oral ingestion of 100 mg, plasma concentrations rangefrom 0.4 to 1.2 µg/ml, and a dose of 100 mg per day produces steady-state plasma concentrations of free dapsone of 2 to 6 µmol/L. [31,32] About 70% of thedrug is bound to plasma protein.

Dapsone [eScholarship] http://escholarship.org/uc/item/30m4b5kr

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Dapsone is distributed throughout total body water and is present in all tissues. However, it tends to be retained in skin and muscle and especially in the liverand kidney: traces of the drug are present in these organs up to 3 weeks after therapy cessation.

After absorption from the gastrointestinal tract, dapsone is transported through the portal circulation to the liver, where it is metabolized by two distinct routes,N-acetylation and N-hydroxylation. (Figure 1) Dapsone toxicity, in particular methemoglobin formation, is putatively initiated by N-oxidation, resulting in theformation of a hydroxylamine metabolite by cytochrome P450. [33] A recent study showed that the P450 accounting for the majority of dapsonehydroxylamine formation in vivo is the CYP2E1.[34] To a lesser extent, CYP2C also metabolizes dapsone. A single dose of disulfiram, a slowly reversinginhibitor of CYP2E1 in vivo, inhibited dapsone hydroxylamine formation clearance by 73%, and inhibited methemoglobin formation by 78% in a group ofhealthy volunteers. Dapsone-induced methemoglobin formation in healthy volunteers was also diminished by 61% following the administration of cimetidine, arelatively non-selective P450 inhibitor. The authors speculated that the treatment-limiting toxicities of dapsone might be diminished by co-administration of asuitable inhibitor of hydroxylamine formation, as evidenced in their study.

Previous studies found the forms CYP3A4 [35], CYP 2C6/2C11 and 3A1 [36] and CYP 1A2 [37] to play the greatest role in the N-oxidation of dapsone.

The fate of the toxic metabolite of dapsone, dapsone hydroxylamine, has been studied in the human red cell. The parent amine was produced from dapsonehydroxylamine during methemoglobin formation in the red cells, and there was a linear relationship between hydroxylamine-dependent methemoglobinformation and conversion of hydroxylamine to dapsone. The authors suggested that a cycle exists between the hepatic oxidation of dapsone to itshydroxylamine form and reduction to amine within the red cell, a process, which might lead to re-oxidation by the hepatic cytochrome P450. They speculatedthat this process might contribute to the persistence of the drug in vivo. [38]

Clinical uses in various cutaneous diseases (in alphabetical order)

Acne

The usefulness of dapsone has long been recognized in the treatment of severe, nodulocystic, inflammatory acne. Although it is mentioned in most of thetextbooks and review articles as one of the many therapeutic options for treating acne, the evidence to support this has been inadequate and largelyanecdotal or based on single case reports. Four studies have attempted to evaluate its efficacy.

In a double-blind trial comparing dapsone and placebo, a significant number of cases, which responded favorably, were observed only at the 5% level. Theauthor concluded that the results achieved with dapsone were inferior to those normally seen with broad-spectrum antibiotic therapy.[39]

In an uncontrolled study of 484 cases of acne of varying severity treated with dapsone 300 mg weekly, a dramatic response was found in patients with GradeIV disease: there was a remission of 80% of the lesions at the end of a 3-month treatment period. [40] The response of patients with mild and moderate formsof acne was minimal, not reaching that of oral tetracycline. Similar results were obtained in another study on eleven acne patients: nine of them improvedwithin 8 weeks of commencing dapsone 300 mg weekly. [41] Unfortunately, both studies were uncontrolled and the authors did not indicate how their clinicalassessments had been made, thus their results are difficult to evaluate.

In a comparison of daily doses of 100 mg dapsone with 40 mg 13-cis retinoic acid in forty male patients with nodular/cystic acne, only a marginal clinicalbenefit was observed with dapsone, which also produced no significant effect either on the sebum excretion rate or on skin surface microflora. Dapsone wasobviously inferior to retinoic acid. [42]

Interestingly, the apparent aim of many of the reports that mention dapsone in conjunction with acne is to describe unusual side effects of the drug.[43,44,45,46,47,48]

The introduction of isotretinoin in the treatment of acne in the early 1980s has brought a significant change in our approach to the treatment of this disease.[49] Because of its extraordinary efficacy, it became the drug of choice for severe cases of acne, replacing all other therapies, including dapsone.

There is one exception, however. The role of isotretinoin in the treatment of acne fulminans or acne with musculoskeletal symptoms is still uncertain. Thereare at least 15 reported cases of acne fulminans induced or precipitated by isotretinoin. [50,51,52,53,54,55] The few contrasting reports on the successfultreatment of acne fulminans with retinoids are not sufficient to support the use of retinoids in acne fulminans and do not justify a change in our therapeuticapproach to this disease.[56,57,58] Thus, until more data are available, systemic steroids [59,60] and dapsone [55,61] still remain the two recommended andsafest drugs for this disease.

Behcet's disease

According to a recent review, dapsone is an effective oral therapy for persistent aphthae and cutaneous manifestations of moderate cases of Behcet'sdisease.[62] It was not recommended for severe mucocutaneous or ocular and systemic manifestations. Dapsone is mentioned as a therapeutic option forBehcet's disease in many other review articles and textbooks as well.

It is quite surprising that the scientific basis for this therapeutic option consists of, in fact, only very few reported studies and case reports. All seven affectedmale patients who had been treated with dapsone 100 mg daily showed a noticeable symptomatic improvement in one study. The uro-genital ulcers,erythema nodosum, and boil-like lesions cleared up within a few weeks. The condition of two patients flared up upon stopping dapsone and treatment wassatisfactorily resumed. All the patients had suppression of their pathergic reaction to a deep needle-prick. [63] One patient had a similar improvement: theflare-up of his lesions, which followed discontinuation of the drug, resolved when dapsone was readministered. [64] In a report of five cases in South Africa,four of them responded well to the administration of dapsone. [65] In a report from the United States of twenty-five patients who had prominentmucocutaneous involvement, all four who were treated with dapsone demonstrated a 50% decrease in the size, frequency, and duration of theirmucocutaneous lesions. [66]

The value of dapsone for the treatment of Behcet's disease needs to be further confirmed by carefully controlled trials before it can become an establisheddrug for treating this disease.

Bullous pemphigoid

Bullous pemphigoid is not generally considered to be a sulfa-responsive dermatosis. In his two monographs on pemphigus and bullous pemphigoid. [67,68]Lever stated that the sulfones are of little or no value for treating these conditions. Indeed, a bullous dermatosis responsive to sulfas and sulfones was onceconsidered by some to be diagnostic of dermatitis herpetiformis. [69,70,71] However, in 1953, when sulfapyridine was used to treat 17 of 38 patients withbullous pemphigoid, the condition was controlled in four, it improved in seven and it was unchanged or aggravated in six. [72] Too little has been writtenregarding the use of sulfones for the treatment of bullous pemphigoid to reach any firm conclusions.

In 1972, Honeyman et al. described five patients with clinical histopathologic and immunofluorescent criteria for both dermatitis herpetiformis and bullouspemphigoid who had a good response to dapsone. [73]

A report in 1976 on 3 patients with classical bullous pemphigoid noted that they responded dramatically to dapsone and showed control of the disease within2 weeks [74]. The same group, one year later reported three additional proven cases of bullous pemphigoid in childhood, which responded to dapsone. [75]These studies supported previous case reports by others who also found dapsone effective in the treatment of bullous pemphigoid.[76,77,78]

Of 84 patients with bullous pemphigoid treated in the Mayo Clinic between 1968 and 1975, 41 were given a trial of sulfapyridine or dapsone. Only six showeda significant response of whom five were controlled completely. [79,80]


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Other authors were more enthusiastic about the benefits of dapsone in bullous pemphigoid. In one open study, 18 patients with proven bullouspemphigoid were treated with a trial of the drug. Eight patients (44%) had a complete response and six (33%) had a partial one. [81] The authorsconcluded that a trial of a sulphone drug is warranted in bullous pemphigoid either as an initial treatment or in the treatment of relapse, particularly whenthere is a contraindication to the use of corticosteroids.

Another study evaluated the efficacy of dapsone as adjuvant therapy. [82] Thirteen patients with recurrent, severe, widespread, recalcitrant bullouspemphigoid who had initially responded to prednisone and azathioprine continued to have flare-ups of the disease while still on high doses of the drugs.The addition of dapsone as an adjuvant to the treatment helped to produce a complete clinical remission in 12 patients (92%), and enabled the tapering ofprednisone. The authors concluded that the addition of dapsone to the existing regime of corticosteroid immunosuppressive drugs might be beneficial.

These and other reports [83,84,85] bring us to the same conclusion that Lever expressed more than thirty years ago, namely, that sulfones might be ofvalue to some patients with bullous pemphigoid, but the mainstay of therapy for this disease are the corticosteroids. Dapsone can be used in patients inwhom systemic steroids are ineffective, or are contraindicated, or have to be discontinued because of side effects.

This is also the conclusion of a retrospective study of 36 patients with bullous pemphigoid who were treated with dapsone alone (n=15), dapsone withtopical corticosteroids (n=19) or dapsone and systemic steroids (n=2). [86] In this study the efficacy of dapsone appeared to be limited (a response rate of44%, mainly in patients also treated with topical steroids), not far from that recorded by other investigators in patients receiving potent topical steroidsalone. [87]

Cicatricial pemphigoid

Cicatricial pemphigoid, previously termed benign mucosal pemphigoid, is actually not so "benign" but a rather chronic progressive disease that seldomgoes into complete remission spontaneously, and one that scars mucous membranes and might cause severe complications. Therapy of cicatricialpemphigoid depends on the extent of the disease, its severity and the organs involved. In limited cases, topical and intralesional treatment will suffice,however, systemic therapy is mandatory in patients with extensive oral or ocular involvement. Dapsone is certainly one of the drugs to be considered inthe treatment of this disease, which is not highly responsive to steroids. There are several published studies that have shown the therapeutic efficacy ofdapsone.

Twenty-four patients with cicatricial pemphigoid were treated with dapsone. Twenty (83.3%) had partial or complete control of the inflammatory activity.The use of dapsone was discontinued in two patients because it failed to control their disease and in four patients because of drug-related side effects.The authors concluded that cicatricial pemphigoid might be added to the list of dapsone-responsive dermatoses. [88]

The records of 105 patients treated with three different chemotherapeutic agents for ocular cicatricial pemphigoid were reviewed to compare long-termefficacies and side effects of different drug regimens. [89] As the initial agent, dapsone failed to control the disease in 2% of patients, compared with an8% failure in patients taking cyclophosphamide and 9% in those on azathioprine.

Oral dapsone was used to treat five patients who presented in the acute inflammatory phase of ocular pemphigoid. In all cases, it was the inflammatoryrather than the cicatricial features which responded to treatment. The clinical response was obtained after 1-4 weeks and could be maintained on a doseof between 50 mg on alternate days and 100 mg/day. All cases required continuation of the therapy in order for it to remain effective. [90]

In a study of long-term outcome and follow-up (average 4 years) of 104 patients with ocular cicatricial pemphigoid, dapsone was used as the first-lineagent with azathioprine or cyclophosphamide being added in cases of unsatisfactory response. [91] Slightly more than one-third of the patients respondedto therapy and remained free of inflammation following cessation of therapy. Another one-third was free of disease activity but needed continuation oftherapy. Nearly one-third of the patients responded only partially to treatment.

The response to sulphapyridine 500 mg twice daily was evaluated in a prospective, single-armed, unmasked clinical trial of 20 consecutive patients withocular cicatricial pemphigoid. Sulphapyridine was clinically effective in 50% of patients with moderately marked inflammation. The authors suggested thatit might be a good alternative to dapsone. [92]

A recent study characterized a subset of cicatricial pemphigoid in which the disease was limited to only the oral cavity ("oral pemphigoid").[93]Twenty-nine random patients with this form of the disease were studied. The patients with limited or minimal disease received only local therapy. In the 14patients (48%) with extensive or severe disease, systemic therapy was added, while dapsone was the only treatment used in seven patients. Patients withsevere disease who were treated with dapsone followed a clinical course similar to that of patients with minimal disease, which indicated that dapsonewas beneficial and that it did cause an alteration in their clinical course.

In conclusion, there is general agreement among experts that dapsone is an effective treatment for cicatricial pemphigoid in the majority of patients andthat it should be used as the first-line drug in those patients for whom local therapy is unsuitable. [94,95,96,97,98,99,100] For severe, rapidly progressiveforms of the disease with involvement of the eye, esophagus, or larynx, aggressive systemic therapy with immunosuppressive agents, such ascyclophosphamide, is warranted.

Epidermolysis bullosa acquisita (EBA)

The rarity of this condition has precluded proper therapeutic trials. The disease is characterized by resistance to usual treatment modalities, such as highdoses of systemic steroids, azathioprine, methotrexate and cyclophosphamide, especially in its classical, mechanobullous form. The bullous pemphigoidvariant of the disease is somewhat more responsive to treatment with the above-mentioned agents.

Dapsone alone or in combination with steroids is considered one of the standard treatments for this disease. Moreover, this combination appears to be themost effective one for pediatric EBA. Remission is achieved within a few days to a few weeks, and the use of prednisone can generally be stopped withinone year. Treatment with dapsone alone is sometimes continued for a few months or years. The prognosis in children seems generally better than inadults. [101,102,103,104,105,106,107,108,109,110,111,112] Indeed, treatment of EBA in adults is inconsistent and less promising. There are manyreports on failures following a combination treatment of dapsone and prednisone. [113,114,115,116] It should be noted, however, that the literature reflectsan abnormally and disproportionately high incidence of treatment failures because of the tendency to report unusual and innovative treatments, ascompared to the prednisone/dapsone combination, which is a conventional and standard therapy for EBA. It follows that many reports on new treatments,such as extracorporal photochemotherapy, cyclosporin A, plasma exchange, intravenous immunoglobulins, colchicine, and others, were started in patientswho were refractory to dapsone/prednisone therapy and thus the high number of reports on resistance to dapsone.

Erythema elevatum diutinum

Erythema elevatum diutinum is a rare, chronic form of cutaneous vasculitis. The disease is so rare that one large tertiary referral center with specialexpertise in cutaneous vasculitis has seen only 13 cases over a period 60 years. [117] Probably because of the tendency to publish rare conditions, thereare more reports on the effectiveness of dapsone in this disease than there are on other forms of leukocytoclastic (necrotizing) vasculitis. Many casereports [118,119,120,121,122,123,124,125,126,127] and series of patients [128,129,130,131] have indicated the regularity with which a dramatic responseis obtained when patients with erythema elevatum diutinum are treated with dapsone. The prompt recurrence of skin lesions and systemic symptoms aftersulfone withdrawal is evidence of the suppressive but not curative effect of sulfones in this disease. It should be noted that the disease as well as theindividual lesions are chronic and persistent ("diutinum" means persistent) and usually show no tendency for spontaneous remissions. [130] Therefore,the dramatic clearing of lesions in treated patients could be attributed with confidence to therapeutic efficacy.

All early and most late lesions of erythema elevatum diutinum show a leukocytoclastic angiitis associated with a dense, dermal infliltrate composedprimarily of neutrophils and occasionally of monocytes. Some late lesions show fibrohistiocytic proliferation with areas of granulation tissue and fibrotic


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replacement of normal dermal structure. [128] These late fibrotic nodules are not responsive to dapsone. [132]

Kaposi's sarcoma

Regression of Kaposi's sarcoma in a 38-year-old homosexual man with AIDS after treatment with dapsone was reported in 1984. [133] The patientwas treated exclusively with dapsone 100 mg daily, and two Kaposi plaques had regressed and turned into brownish atrophic scars after 6 weeks oftherapy. The whole area was then excised and no histological features of Kaposi's sarcoma were found.

This observation encouraged the same group to study the effect of dapsone in six patients with Kaposi's sarcoma of the skin. [134] The patients, fourmales and two females, with biopsy-proven plaque and/or nodular Kaposi's sarcoma of the skin for 3-10 years without clinical signs of systemicspreading, were given 100 mg dapsone daily for a period of four months. The treatment resulted in clinical improvement in four of the six patients.These four patients had presented with plaques of Kaposi's sarcoma, and during the treatment, all the plaques gradually regressed into brownishpigmented atrophic scars in three, while the plaque became less infiltrated in the fourth patient. No clinical improvement was found in the other twopatients, of whom one had only nodules and the other both nodules and plaques. Three of the patients had complete histological regression of thetumor.

One year later, another group of authors tried to confirm these observations in a pilot study of twelve homosexual male volunteers with biopsy-provenKaposi's sarcoma skin lesions. [135] These patients, who were receiving no other medications, were put on dapsone 100 mg daily. Therapy wasdiscontinued early in three patients because of side effects. All of the nine men who completed at least a 6-week course of dapsone continued to havenew lesions develop throughout the treatment period. The original lesions did not change or increase, and no lesion resolved or decreased in size. Theobvious conclusion of the authors was that, in disagreement with previous studies, dapsone is totally ineffective in AIDS patients with Kaposi'ssarcoma.

In another study, the authors described the clinical and histological changes in well-established classic Kaposi's sarcoma lesions during 2 years oftherapy with dapsone. Both patients showed a vast improvement in their symptoms although the clinical examination showed no significantmodifications of the lesions. Histology did show a striking reduction in the spindle-cell component and an increase in the number of mature vessels.

A more recent study described two patients with classical, non-HIV-related Kaposi's sarcoma who were successfully treated with dapsone, furtherconfirming the contention that dapsone might favorably modify the lesions of Kaposi's sarcoma. [136]

This form of therapy clearly requires additional randomized trials with uniform staging and evaluation criteria before its use in Kaposi's sarcoma can berecommended. In view of the current data and our own disappointing experience (unpublished observations), it seems overly optimistic to assume thatdapsone will be the panacea for Kaposi's sarcoma.

Linear IgA bullous dermatosis

Linear IgA bullous disease is an acquired, autoimmune subepidermal blistering disorder characterized by linear deposition of IgA at the basementmembrane zone. It has a clinical presentation and a histopathologic appearance similar to that of both dermatitis herpetiformis and bullouspemphigoid. Until 1979 when it was first described and defined as a disease entity by Chorzelski et al. [137], some authors considered it as a variantof dermatitis herperiformis, some as bullous pemphigoid [73,138,139,140,141,142] and others as an intermediate form between the two diseases.[143]

The most important difference between dermatitis herpetiformis with granular IgA deposits and linear IgA bullous disease is the absence in the latter ofnontropical sprue [144,145]. A gluten-free diet, which is helpful in dermatitis herpetiformis if strictly observed, is of no benefit in cases of linear IgAbullous dermatosis. [146,147,148]

Considering the similarities between dermatitis herpetiformis and linear IgA bullous dermatosis, it is not surprising that both diseases respond to thesame therapy, dapsone. Indeed, it is generally accepted that dapsone is the drug of choice in linear IgA bullous dermatosis. Most patients will respondto 100-150 mg dapsone with clearing of the skin lesions. The dosage is then gradually lowered to a maintenance level of 50 mg every second day.Some patients (the minority) who improve only with very high doses of dapsone can be controlled with a combination of dapsone and small doses ofcorticosteroids. [137,149,150,151]

Finally, it should be noted that there are two reports on sulfonamide-induced linear IgA bullous dermatosis. [152,153]

Linear IgA bullous disease of childhood (chronic bullous disease of childhood)

Most authors currently consider chronic bullous dermatosis of childhood and linear IgA bullous dermatosis of adults as being the same disease; hencethe proposed name, linear bullous disease of adults and childhood. [148,154,155,156,157] The majority of patients with linear IgA bullous dermatosisof childhood will go into remission usually within 2 to 4 years, and almost always before puberty. [148,158]

As in the adult variant of the disease, treatment with sulfapyridine or dapsone usually results in excellent control of the disease.[158,159,160,161,162,163] The response is rapid, usually within 72 hours. In patients who do not respond adequately, prednisone in small doses maybe added as adjunctive therapy. [150,159]

Lupus erythematosus (LE)

Patients with cutaneous discoid lupus erythematosus (DLE) or subacute cutaneous LE (SCLE) generally have a favorable prognosis and can bemanaged with safe, yet effective, therapy. Sun protection and sunscreens (with both UVA and UVB protection) are the most important measures.Topical steroids, with or without occlusion, and intralesional steroid injections are effective local therapies. Systemic therapy with antimalarials isusually effective for patients who do not respond to topical regimens. Dapsone is not considered a first-line therapy. However, under certaincircumstances (e.g., when "standard" therapy fails, is contraindicated, or when dealing with special forms of cutaneous lesions) it may be effective andis worth trying.

Urticarial lesions with underlying vasculitis seem to be quite common in systemic lupus erythematosus (SLE). [164] In 1978, a dramatic improvementof such lesions in a female patient with SLE was reported [165], a therapeutic effect of dapsone that could be reproduced in several other cases.[166,167]

Vesiculobullous lesions of SLE have been reported to respond dramatically to treatment with dapsone and are recommended as the first-line ofsystemic therapy in these patients. [168,169,170]

Mucosal ulcerations [171] and annular lesions of SCLE [167,172,173] also respond favorably to dapsone.

Thrombocytopenia is a serious problem in patients with SLE. It is sometimes refractory to steroid therapy and splenectomy, which is the alternativerecommended treatment. There are at least two reported cases in which dapsone corrected the thrombocytopenia in these patients. [174,175]

Although dapsone use has led to an improvement in some patients with DLE, the level of benefit was too small to suggest routine use of this therapy.Nearly one-fourth of 37 patients with DLE had an excellent resopnse to dapsone; another fourth showed some effect; while no response was seen in52% of the patients. [176] Of the patients who had earlier been treated with hydroxychloroquine, 76% had an excellent response to the treatment. Sixpatients (18%) stopped dapsone treatment because of side effects. The authors concluded that hydroxychloroquine and not dapsone remains the drug


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of choice when systemic therapy is needed. These results are in agreement with previous studies by the same group and by others. [177,178]

Mycetoma

Mycetoma is a localized, chronic infection by various species of fungi or actinomyces (which occur as saprophytes in soil or on vegetable matter).These infections frequently result in severe damage to skin, subcutaneous tissues and bones of the feet, hands and other parts of the body.

The disease (a clinical and not an etiological entity) occurs most commonly in tropical and subtropical climates, usually among laborers who workbarefoot and observe poor hygiene.

The course of the disease is prolonged, and treatment has been notoriously unsatisfactory. The combination of dapsone with other antibiotic andantifungal drugs has been reported to give favorable results. [179,180,181,182,183,184,185,186,187]

Panniculitis

In 1972, a new form of panniculitis was described, namely, lobular panniculitis associated with alpha-1-antitrypsin deficiency. [188] It is inherited asthe ZZ phenotype, and occurs in about one in 2500 individuals This form of panniculitis probably accounts for about 14% of all cases ofpanniculitis, although only a few have been reported thus far, probably because of lack of awareness and underdiagnosis. [189]

The most direct approach to therapy of alpha-1-antitrypsin deficiency-associated panniculitis may be alpha-1-proteinase inhibitor replacement, andindeed, there are several reports on good responses to this form of therapy. [190] There are, however, many more reports of good responses todapsone. [190,191,192,193,194,195,196] Dapsone is considered by most, if not all, of the authors as the first drug of choice for this distinctive andunique form of panniculitis.

Pemphigus

Oral steroids are the cornerstone and primary agent for treatment of pemphigus. Before the introduction of adequate treatment with steroids theprognosis of pemphigus was very poor, with a mortality rate of up to 90%. With the introduction of systemic steroids in the 1950s the picture haschanged dramatically and the mortality rate has dropped sharply. However, steroid therapy has created other problems, including rates of mortalityof about 25%. [197]

Although there are some reports of the effectiveness of dapsone in the treatment of pemphigus vulgaris [198,199,200], mostly in conjunction withsteroids [201,202,203], and in pemphigus foliaceous [204,205,206,207], pemphigus is not generally considered to be a dapsone-responsivedermatosis and we do not recommend its use in this disease.

Interestingly, in two in vitro experiments dapsone did not inhibit acantholysis of human epidermal cells cultured with pemphigus antibody [208], nordid it reduce the production of plasminogen activator in contrast to steroids.[209]

Pemphigus herpetiformis

Pemphigus herpetiformis is recognized as a distinct variant of pemphigus. This disease was originally named and the diagnostic criteria weredescribed by Jablonska et al. in 1975.[210] However, patients with similar clinical phenotypes were described as early as 1955 by Floden andGentale under the heading "dermatitis herpetiformis with acantholysis".[211] Since then more than 40 additional cases have been presented in theliterature. [212,213,214,215]

Pemphigus herpetiformis combines the clinical features of dermatitis herpetiformis with the immunologic and histologic features of pemphigus.

Dapsone is the drug of first choice for the treatment of pemphigus herpetiformis with doses ranging from 100 to 300 mg daily.[150,212,213,216,217] The response to dapsone is as dramatic in some (but not all) patients as in dermatitis herpetiformis. Cases with low ornegative antibody titers or those demonstrating eosinophilic spongiosis are the best candidates for this therapy. Dapsone may be given asmonotherapy or in combination with systemic corticosteroids and immunosuppressants. [218]

IgA pemphigus

IgA pemphigus is a newly characterized group of autoimmune, intraepidermal blistering diseases presenting with a vesiculopustular eruption,neutrophil infiltration, acantholysis, and in vivo bound and cirdulating IgA autoantibodies that target cell surface components of the epidermis.[219,220,221] There are two distinct types of IgA pemphigus: the subcorneal pustular dermatosis (SPD) type and the intraepidermal neutrophilic(IEN) type. [222,223] Patients with both types of IgA pemphigus clinically present with flaccid vesicles or pustules or both on erythematous ornormal skin. Pruritus is a significant symptom that may interfere with the patient's daily activities.

Dapsone has proved to be the drug of choice in the treatment of IgA pemphigus. [219,220,221,224,225] Therapeutic alternatives in cases in whichdapsone is not well tolerated, or its effects are insufficient or transient, include systemic or topical steroids, PUVA, retinoids and variouscombinations of these. Though all of these are second-line treatments, while dapsone remains the drug of choice.

Pyoderma gangrenosum

Although the belief that pyoderma gangrenosum was an infectious condition has fallen into disfavor, certain antimicrobial agents have been triedand even found to be successful in treating the disease.[226] Their mode of action is clearly not related to their antibacterial effect, but rather to ananti-inflammatory, immunomodulating effect.

Sulfa drugs have been one of the most commonly used agents in the treatment of pyoderma gangrenosum. Sulfasalazine, a sulfonamide whosemain use is for treating inflammatory bowel disease, was the first sulfa drug to be tried for alleviating pyoderma gangrenosum. It was initiallyreported in 1957 to be beneficial in the treatment of nine of twelve patients with pyoderma gangrenosum and proved to be effective even in patientswithout underlying inflammatory bowel disease. [227]

Because sulfasalazine is metabolized in the gut to sulfapyridine and 5 aminosalicylate, several researchers tried sulfapyridine alone and reportedsuccess in several cases of pyoderma gangrenosum. [227,228,229,230] In some of them, the response to sulfapyridine was seen after failure withsulfasalazine, possibly because of the higher blood levels that can be achieved with the former.

The first report of the successful treatment of pyoderma gangrenosum with a derivative of dapsone appeared in 1962 with a report of four patientsthat responded favorably to this therapy.[229]

Subsequently, several other authors reported on the successful treatment of pyoderma gangrenosum with dapsone alone [231,232] and incombination with oral [233,234], intravenous [235], or intralesional steroids. [236]

All told, there are only a very few reports on the efficacy of dapsone in the treatment of pyoderma gangrenosum, and all of them describe singlecases or limited case series (i.e., a maximum of 4 patients). This may be due to the rarity of the disease, estimated at 3 cases per 1 millionpopulations per year. However, we suspect that the real reason is probably the unconvincing outcomes of this therapy combined with the tendency


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of investigators to report mostly positive results. Although currently available treatment for pyoderma gangrenosum is far from satisfactory, wecannot recommend the use of dapsone until more data on this therapy are available.

Malignant pyoderma, which was described as a new disease entity in 1968 is now considered a subtype of pyoderma gangrenosum [237,238].Generally, malignant pyoderma responds well to corticosteroid therapy, but relapses occur when the dose is gradually lowered. Dapsone can begiven in combination with steroids and in some rare cases, it was reported to be effective even when steroids failed. [236,239]

Relapsing polychondritis

First described in 1923, relapsing polychondritis is an uncommon disease of possible autoimmune etiology manifested by recurrent episodes ofprogressive inflammation and destruction of cartilages.[240] This multisystem disease can have severe consequences: it can cause facialdeformities as a result of destruction of the nose and ear cartilages; it can lead to blindness; and it was shown to have a fatal outcome in asmany as one-fourth of affected patients. [241] Until 1976, the recommended treatment was systemic steroids. Two articles, both appearing in1976 and in the same issue of the Archives of Dermatology, described the effectiveness of dapsone in treating relapsing polychondritis.[242,243] Since then, several other reports confirmed the beneficial effects of dapsone in controlling the disease,[244,245,246,247,248,249,250,251,252] although the experience of other authors with dapsone alone or in combination with steroids wasdisappointing. [249,253,254,255,256,257]

The rarity of relapsing polychondritis, the diversity of its presentation, and the unpredictable recurrence rate are all factors that precluderandomized controlled therapeutic clinical trials, critical evaluation of the efficacy of dapsone and the establishment of a standardizedtherapeutic protocol. Although the ideal treatment for relapsing polychondritis has not yet been found, the available evidence indicates thatdapsone and/or systemic corticosteroids are the most effective therapies, with neither showing significant advantage over the other.

Spider bites

Bites from spiders range in severity from a minor and negligible reaction to full-thickness skin necrosis and/or to severe systemic symptomsleading to death. Although most bites are not serious and resolve without any interventions, severe reactions require hospitalization andmedication. The treatment of spider bites is varied and very controversial. The first documented case of cutaneous loxoscelism in NorthAmerica was reported in 1929. It had been ineffectively treated with sedation, starch, and sodium bicarbonate. Current therapies for spiderbites, such as corticosteroids (systemic or intralesional), antibiotics, antihistamines, surgical treatments, heparin, NSAIDs, and hyperbaricoxygen appear not to be much more effective in preventing necrosis and ulcers.

The fact that dapsone is an inhibitor of polymorphonuclear (PMN) leukocyte function, which had been proven effective in 'neutrophilicdermatoses', and that PMN leukocytes play a dominant role in spider bite-induced necrosis, led some investigators to attempt treating thiscondition with the drug. [258] In 1983, the first case was reported on the successful use of dapsone in the treatment of a documented bite fromthe brown recluse spider. [259] A 27-year-old man killed the spider immediately after it had bitten him on the leg. Forty-eight hours after theevent, the lesion was tender, erythematous and indurated and there was evidence of early blister formation and incipient cutaneous necrosis.The patient was treated in the hospital with leg elevation, ice packs and dapsone 100 mg orally twice daily. By the second hospital day, thebitten area was pain free and there was a marked reduction in the erythema and induration. The lesion completely resolved during 14 days ofdapsone therapy. This clinical trial was done after the authors had confirmed the effectiveness of dapsone in a guinea pig model of cutaneousloxoscelism. [259] Thirty guinea pigs pre-treated with oral dapsone (1.73 mg/g body weight) had a marked reduction in skin lesion size at 24hours, compared with control guinea pigs, after having been injected intradermally with a partially purified brown recluse spider venom fraction.

Following this report, the effectiveness of dapsone on local and systemic symptoms of spider bites was evaluated in clinical and experimentalstudies.

The effect of three treatment methods, hyperbaric oxygen, dapsone and cyproheptadine, on the severity of skin lesions resulting fromexperimental Loxosceles envenomation in New Zealand white rabbits was determined in a randomized, blinded, controlled study. The threegroups of animals did not differ significantly with respect to lesion size, ulcer size, or histopathologic ranking. The authors concluded, "Given thenegative result in this study with adequate power to detect meaningful treatment benefits, we cannot recommend hyperbaric oxygen, dapsone,or cyproheptadine in the treatment of Loxosceles envenomation.." [260] Although their study involved the use of venom from Loxoscelesdeserta (not venom from the true brown recluse spider, L. reclusa) and new Zealand white rabbits (not humans), the results should raisesecond thoughts about such enthusiasm for using dapsone to treat spider bites.

Another animal study examined the effectiveness of dapsone or electric shock therapy vs. placebo on the size of lesions induced by intradermalinjections of spider venom in guinea pigs. The dapsone therapy group demonstrated significantly less induration and necrosis (p<0.05) thanthat shown by the other groups at 72 hours after envenomation. The authors concluded that dapsone therapy was more effective than eitherelectric shock or no therapy for brown recluse spider envenomation in their guinea pig model. [261]

The management of eyelid spider bites is particularly difficult. [262] Several treatment regimens of eyelid envenomation have been studied in arabbit model. [263] The combination of dapsone and antivenom treatment comprised the optimal animal regimen, although it was notcompletely effective in eliminating microscopic necrosis. The authors also reported dramatic clinical improvement in the human inflammatoryresponse with dapsone therapy and recommended immediate dapsone therapy combined with specific antivenom, if available, in humans.

Early surgical excision versus dapsone and delayed surgical excision were compared in a prospective study of 31 patients with brown reclusespider bites. Patients were matched for age, gender and lesion size. In 14 patients treated with immediate surgical excision, delayed woundhealing (N=5) and unacceptable scarring (N=6) were common complications. Pre-treatment with dapsone reduced the incidence of woundcomplications, objectional scarring, and the need for surgical excision in one case of each (p<0.05). This study clearly demonstrated thebenefits of the treatment with dapsone in terms of reducing surgical complications and improving significantly patients' outcomes. [264]

The same group of authors reported on their experience with 31 patients who had brown recluse spider bites of an upper extremity. [265] Theirconclusions were similar to those of the previous study, namely, that there would be a high incidence of functional complications unlessconservative wound management, dapsone, and antibiotics were administered.

The experience of the same group with 95 patients who were bitten by brown recluse spiders between 1983 and 1986 was described in anotherpaper. [266] The patients were randomized into three treatment groups: dapsone, brown recluse spider antivenom, or combination therapy. Inaddition, all the patients were treated with erythromycin. Excluding two patients with very severe lesions, the wounds of patients in all thegroups healed in an average of 20 days. No clear conclusions about the superiority of one form of therapy could be drawn from this study, norfrom the comparison of the results with similar reported cases.

Clinical presentation and outcome were evaluated in 111 patients with suspected brown recluse spider bites and who were treated during a30-month period. [267] Most wounds (59%) involved the leg. At the time of presentation, 81% had central discoloration and 37% had necrosis.Sixteen patients (14%) were systemically ill, and six (5%) were admitted to the hospital. Most (86%) were treated with antibiotics, and only 9%of the patients had received dapsone before presentation to the clinic. In this series, the long-term outcome after brown recluse spider bite wasgood compared to other reported series. Serious complications were rare, as was the need for skin grafting (only 3 patients). The authors'conclusion was that since the vast majority of bites heal with supportive care alone, aggressive medical therapy is not warranted.

In conclusion, several experimental studies and large clinical trials have shown the beneficial effect of dapsone in reducing the severity of localand systemic reactions to spider bites, decreasing complications and improving patients' outcome. Most of the cases of spider bites are mildand free of severe complications, and symptomatic therapy with rest, ice, compression and elevation is usually sufficient. If necrosis or systemic


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reactions occur, then most [268,269,270,271,272,273,274,275,276], although not all [277] authors recommend early treatment with oraldapsone.

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease)

This disorder was originally described in 1956 by Sneddon and Wilkinson, who differentiated it from other pustular and vesicular eruptions.[278] A sufficient number of patients (over 130 from 1965 when the first review appeared to the present) has been reported to establish thecondition as a morphological entity separate and distinctive from other pustular and vesicular conditions.[279]

Dapsone 50-100 mg daily is the treatment of choice for Sneddon-Wilkinson disease and, although the response is slower than that seen indermatitis herpetiformis, the majority of patients obtain partial, if not complete, relief. Unlike dermatitis herpetiformis, treatment can often bestopped without relapse. [280,281,282]

A review of 29 patients with intraepidermal IgA deposits and with clinical and histological features of Sneddon-Wilkinson disease appearedin 1992. [221] Dapsone was the first line of therapy in 23 patients, and was judged as being effective, resulting in a dramatic and long-lastingimprovement in 16 of these patients.

A condition that can very closely resemble subcorneal pustular dermatosis is pustular psoriasis. Most [283], although not all [284], authorsagree that the failure of pustular psoriasis to respond to sulfones as opposed to subcorneal pustular dermatosis is one of the most reliablecriterion to differentiate between these two diseases.

Urticarial vasculitis syndrome

Urticarial vasculitis syndrome is a distinct clinico-pathological entity characterized by purpuric, urticarial weals and histologically showing allthe criteria of leukocytoclastic vasculitis. It represents a systemic disease that involves a number of organs, particularly the joints, lung andkidneys. In most of the cases, it is associated with or is a result of an underlying disease, such as a drug reaction, connective tissuedisorder, infection or malignancy. In these cases, the primary therapeutic principle is to remove the stimulus, i.e., to treat the associateddisease. [285,286,287] The treatment of idiopathic cases, classified as primary urticarial vasculitis syndrome, is difficult and challenging.

Dapsone alone or in combination with other drugs has been one of the various treatment modalities tried in this disease. It has beensuccessful in most [167,288,289,290,291,292,293,294,295], but not all [296,297] of the reported cases.

We think that it is worth a trial in recalcitrant and refractory cases.

Vasculitis leukocytoclastic

Although the usefulness of dapsone has long been recognized in leukocytoclastic vasculitis and is mentioned in this capacity in most of therelevant textbooks and review articles there are very few studies on its effectiveness in this disease and most of them are single casereports. [298,299,300,301,302,303,304,305,306,307] Since the unpredictable waxing and waning course of the disease in its usual formmakes the effects of any therapeutic agent difficult to assess, we need more extensive, carefully controlled randomized studies than hadbeen performed until now in order to objectively evaluate the effectiveness of dapsone. On the other hand, even on the basis of our currentknowledge, this form of therapy should not be rejected out of hand since it might be of use in a selected group of patients.

Table 1: Clinical use of dapsone in various cutaneous diseases

DiseaseDrugofchoice

Goodalternative

Wortha trial

Notrecommended

Acne vulgaris V

Acne fulminans V

Behcet’sdisease V

Bullouspemphigoid V

Cicatricialpemphigoid V

Dermatitisherpetiformis V

Epidermolysisbullosa aquisita V

Erythemaelevatumdiutinum

V

Kaposi’ssarcome V

Lepra V

Linear IgAbullousdermatosis

V

Linear IgAbullous diseaseof childhood

V

Lupuserythematosus :

DLE V


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SCLE V

SLE-vesiculobullousvariant

V

SLE- urticarialvasculitis V

Mycetoma V

Panniculitis(alpha-1-antitrypsindeficiency

V

Pemphigusvulgaris V

Pemphigusherpetiformis V

IgA pemphigus V

Pyodermagangrenosum V

Relapsingpolychondritis V

Spider bites V

Subcornealpustulardermatosis(Sneddon-Wilkinsondisease

V

Pustularpsoriasis V

Urticarialvasculitis V

Leukocytoclasticvasculitis V

Mechanisms of action of dapsone in dermatological diseases

Dapsone acts against bacteria and protozoa in the same way as sulphonamides,that is by inhibiting the synthesis of dihydrofolic acidthrough competition with para-amino-benzoate for the active site of dihydropteroate synthetase. The anti-inflammatory action of the drugis unrelated to its antibacterial action and is still not fully understood. An inflammatory disease which responds to dapsone is almostinvariably associated with the infiltration of large numbers of polymorphonuclear leukocytes into the affected tissue. [11]

Various mechanisms affecting the function of neutrophils have been proposed. Perhaps the best-studied action of dapsone is itsinterference with the myeloperoxidase-hydrogen peroxide-halide mediated cytotoxic system in neutrophils.

Neutrophils that are recruited at sites of inflammation generate superoxide anion (O2-), which rapidly dismutates to hydrogen peroxide(H2O2). H2O2 is then transformed into hypochlorous acid (HOCl) by neutrophil myeloperoxidase (MPO). As a consequence of itsextremely high reactivity, HOCl represents the most toxic and potent oxidant generated by neutrophils, with a potential to causeconsiderable tissue damage in many inflammatory diseases. This process, the 'respiratory burst', uses large quantities of oxygen, and asingle neutrophil may produce enough acid in one second to destroy 150 bacteria. [308] In the absence of chloride ions or when there isexcess hydrogen peroxide, the myeloperoxidase is converted to its inactive form. There are numerous studies which indicate thatdapsone reversibly inhibits myeloperoxidase activity by promoting the formation of an inactive intermediate of the enzyme, thuspreventing the conversion of hydrogen peroxide to hypochlorous acid, an extremely potent neutrophil oxidant.[309,310,311,312,313,314,315]

Dapsone inhibits neutrophil lysosomal enzymes. In 1974, an experimental model that may allow identification of the effect of sulfoneswas described. [316] It is a standard model of hypervitaminosis A causing collapse of the cartilage in rabbit ears. The hypervitaminosis Ain rabbits results in the activation of lysosomal enzymes, with the loss of chondroitin sulfate from cartilage. Dapsone prevented this fromhappening, and this was attributed to inhibition of lysosomal enzyme activity.

Dapsone stabilizes neutrophil lysosomes. [317] It is also an antioxidant, capable of scavenging reactive oxygen intermediates generatedby neutrophils. [318,319]

Although it has been proven that dapsone interferes with various leukocytes' functions, several authors raised doubts concerning the roleof this mechanism in the anti-inflammatory action of the drug. [320] They argued that the clinical response to dapsone is characterizedby the inhibition of accumulation of neutrophils in the skin, rather than the accumulation in the tissue of neutrophils that do not functioncorrectly. Several studies showed that dapsone may impair neutrophil chemotaxis. [321,322,323,324] It was found to inhibit theadherence of neutrophils to the basement membrane zone antibody in a dose-dependent manner. A similar inhibition was also producedwhen dapsone was added directly to the antibody, which showed that the effect was related directly to the antibody. [320] Dapsonesupressed integrin-mediated neutrophil adherence function. [324] It also inhibited chemoattractant-induced signal transduction and thussuppressed neutrophil recruitment and local production of toxic products in the affected skin of neutrophilic dermatoses. [325]

From the above, we can conclude that although the modes of action of dapsone in reducing inflammation are not entirely known, itappears that neutrophils and neutrophil products are the major targets for this drug. While it would be convenient and tidy to ascribe allthe effects of dapsone to a single site of action, this does not seem to be the case: the drug might react with neutrophils at more thanone location and impair more than one neutrophlic function.


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Adverse effects

Dapsone therapy may cause a variety of adverse effects, which may be categorized as pharmacologic, dose-dependent, and allergic,or idiosyncratic reactions.

The most frequent and well-documented pharmacologic reactions are the hematological side-effects, such as methemoglobinemia,hemolysis and anemia. [326,327,328,329,330]

Effective clinical use of dapsone is limited because of dose-dependent adverse hematological reactions, even at the low dailydosages of 100 mg used in the chemotherapy of leprosy and dermatological conditions. Patients with a genetic deficiency of certainenzymes (i.e., glucose-6-phosphate dehydrogenase or glutathione reductase) are more susceptible to the hematological effects.

Long-term administration of dapsone at standard doses (100 mg/d) in normal patients usually results in methemogloginemia of 15%,which is not clinically significant. [331] The hemotoxicity of dapsone is not caused by the drug itself, but by its hydroxylaminemetabolites. The formation of hydroxylamine is catalyzed either by hepatic enzymes such as cytochrome P450, flavinmonooxygenase and others, or by myeloperoxidase found in peripheral polymorphonuclear leukocytes.(Figure 1) [332,333,334]Dapsone hydroxylamine reacts with oxyhemoglobin (Fe2+) to form methemoglobin (Fe3+) and nitrosoarene, which, in turn, isreduced to hydroxylamine by either NADPH methemoglobin reductase or glutathione. The hydroxylamine then reacts with anothermolecule of oxyhemoglobin, thus continuing the redox cycle. Each hydroxylamine molecule is capable of oxidizing up to fiveoxyhemoglobin molecules, and the cycle only ceases when the erythrocyte is almost totally depleted of glutathione. [335]Methemoglobinemia occurs to some extent in all patients receiving dapsone and becomes less pronounced as treatment is continueddue to an adaptive increase in the activity of NADH-dependent reductase in the erythrocytes. Methemoglobin levels of under 20% arenot usually associated with symptoms. Dyspnea, nausea and tachycardia usually occur at levels of 30% or above, while lethargy,stupor and deteriorating consciousness occur as methemoglobin levels approach 55%. Levels of 70% are usually fatal. [328]

Agranulocytosis is another hematologic adverse effect of dapsone. Unlike methemoglobinemia, this severe adverse effect is due toan unpredictable idiosyncratic reaction. For unknown reasons, the risk of agranulocytosis in patients with dermatitis herpetiformis ismore than 25-fold compared with other patients. [336] Agranulocytosis was estimated to develop in 1 of 240 - 425 patients withdermatitis herpetiformis receiving dapsone therapy, whereas this side effect in patients with leprosy is almost unknown.[337] Factorssuch as drug dosage, immune status, degree of malnutrition, and ethnic origin are probably important determinants of the risk ofdeveloping agranulocytosis.

Another serious idiosyncratic adverse effect is the dapsone hypersensitivity syndrome. Drug hypersensitivity syndrome is a severeidiosyncratic reaction to a drug defined by the clinical triad of fever, rash, and internal organ involvement (most commonly the liverand the hematologic system). It occurs in a relatively small proportion of patients but is associated with considerable morbidity andmortality. The unpredictability and potential severity of this reaction make it a major concern in clinical practice and drugdevelopment.

Although this reaction to dapsone is rare considering the widespread use of the drug (particularly in patients receiving multidrugtherapy for leprosy), it ranks high among drugs that cause this syndrome. Dapsone-induced hypersensitivity syndrome usuallyappears four or more weeks after initiation of therapy. Symptoms include a mononucleosis-like rash with fever and lymphadenopathy.Involvement of other organs varies and includes the liver (hepatomegaly, icterus, hepatitis and hepatic encephalopathy),lymphadenopathy, eosinophilia, and others. [46,338,339,340] The course of the disease is also variable, but it may last four weeks ormore and fatalities have been reported. [341,342,343,344,345] Exanthematous skin eruptions usually resolve within two weeks ofstopping dapsone, although patients in whom Stevens-Johnson syndrome or toxic epidermal necrolysis develops have increasedmorbidity and mortality.

There is a low and insignificant risk of congenital malformations in patients receiving dapsone during prengnancy.[361,362,363,364,365,366] In lactating mothers, since dapsone diffuses into breast milk [367] and there are reports of hemolyticanemia induced by this drug transmitted through breast milk [368], we recommend that if dapsone is required, breast feeding shouldbe discontinued.As for treatment of pregnant patients, it is now generally considered that the benefits of dapsone in the treatment ofleprosy and other infectious and non-infectious diseases outweigh any potential risk.

Table 2. Miscellaneous side effects of dapsone

Adverse effect Reference

Pharmacologic/toxic

Methemoglobinemia, hemolysis,anemia

Nausea, vomiting, fatigue, anorexia,headache, dizziness

Allergic/idiosyncratic

Dapsone hypersensitivity syndrome

Agranulocytosis

Exanthematous eruption, Stevens-Johnson syndrome, toxic epidermalnecrolysis

[346, 347,348]

Photosensitivity [349]

Peripheral neuropathy[331, 350,351, 352,353, 354]

Hepatitis, cholestatic, cytolytic andmixed

[47, 343,349, 355]

Nephritis and renal failure [355]

Hypoalbuminemia [356]

Psychosis [357, 358,359]


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Hypothyroidism [360]

Monitoring guidelines

Dapsone is used by millions of patients without serious problems. There are, however, several potentially harmful adverse effectsthat necessitate careful monitoring of patients under this treatment.

Dapsone is considered unsafe and should not be used in the following conditions: severe anemia, porphyria, deficiency ofglucose-6-phosphate dehydrogenase, glutathione reductase or methemoglobin reductase, allergy to sulfonamides, or significantliver disease. It should not be paired with other hemolytics or dideoxyinosine. Before starting therapy, a complete blood count,reticulocyte count, glucose-6-phosphate dehydrogenase level, liver function studies, urinanalysis and renal function tests shouldbe performed. During therapy, complete blood count, reticulocyte count, platelet count and leukocyte count with differential shouldbe obtained weekly for the first month, then twice per month during the next two months and every three months thereafter. Liverand renal function should be tested every three months. Methemoglobin levels should be obtained in patients who becomesymptomatic for methemoglobinemia.

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