Am J Clin Dermatoi 2009:10(6): 383-396n75 )561/09/0006.O383/S49.95/0

® 2009 Adis Data intormation BV. Aii rights reserved.

Efficacy of Dapsone in the Treatment of Pemphigusand PemphigoidAnalysis of Current Data

Hakan M. Gürcan and A. Razzaque Ahmed

Center for Blistering Diseases, New England Baptist Hospital, Boston, Massachusetts, USA

Contents

Abstract 3831. Materials and Methods 3842. Results 384

2.1 Pemphigus Vulgaris 3842.2 Pemphigus Foliaceus 3872.3 Mucous Membrane Pemphigoid 3872.4 Bulious Pemphigoid 387

3. Discussion 3873.1 Adverse Effects 389

4. Conclusions 395

Abstract Dapsone is a chemotherapeutic agent primarily used in treating leprosy, Pneumocystisjiroveci (previouslycarinii) pneumonia, and malaria. It is also used as an adjuvant in the treatment of pemphigus and pem-phigoid. To assess the role of dapsone in the treatment of pemphigus and pemphigoid, a retrospective reviewof reports in the English-language literature was conducted. Information on the number of patients treated,their average age, prior therapies, indications for use, protocol (dose and interval) used, concomitanttherapies, reported adverse effects, and clinical outcomes were analyzed.

There were 35 case reports/series published describing the use of dapsone in a total of 427 patients. Dataon 55 pemphigus patients were obtained from several case reports and some case series and one randomizedcontrolled trial. Of these, 32 patients with pemphigus vulgaris and 14 patients with pemphigus foliaceusresponded to dapsone. Data from 13 case series, each including at least five patients, accounted for372 patients with pemphigoid. The overall response rates to dapsone, when given either alone or in com-bination with corticosteroids or immunosuppressive agents, were 84% in mucous membrane pemphigoid,and 81 % in builous pemphigoid. Hemolysis was the most common adverse effect observed.

Dapsone is a promising and useful agent in patients with autoimmune mucocutaneous blistering diseases,especially in mucous membrane pemphigoid. It can be used as a corticosteroid-sparing agent. Therefore, itscombined use with oral corticosteroids may be useful in pemphigus vulgaris and bulious pemphigoid.Adverse effects of dapsone are dose dependent and usually reversible. Hemolysis and concomitant anemiasecondary to hemolysis are expected in most patients. In the opinion of the authors, dapsone is underutilizedin the treatment of autoimmune mucocutaneous blistering diseases.

Dapsone is a chemotherapeutic agent primarily used in effects, it is used as an anti-inflammatory agent in the treatmenttreating leprosy, Pmumocystis jiroveci (previously carinii) of several other conditions. It is the drug of choice in dermatitispneumonia, and malaria.t'^ In addition to its antimicrobial herpetiformis, with a response rate of 95-97%. It has been used

384 Gürcan & Ahmed

in many other dermatologie diseases, including pemphigus andpemphigoid.' l

Pemphigus and pemphigoid are rare autoimmune diseasesthat have certain common features and are considered poten-tially fatal. They involve the skin and frequently one or moremucous membranes. The immunopathology of these diseases iswell characterized and the target antigens to which the auto-antibodies are directed have been studied. Pemphigus is causedby autoantibodies directed against (iesmogleins. Pemphigoid iscaused by autoantibodies directed against several epidermalbasement membrane zone proteins. The clinical presentation ishighly variable, as is the course and prognosis. The majority ofpatients respond to conventional therapy, which consists ofhigh-dose systemic corticosteroids and immunosuppressiveagents. Patients who are not responsive to conventional im-munosuppressive therapy, or in whom it is contraindicated, aretreated with intravenous immunoglobulin.' 1 Rituximab is an-other biologic agent that has been recently used.t"*' There isevidence in the literature suggesting that patients who haveprolonged immunosuppression secondary to corticosteroids,immunosuppressants, and rituximab can die from opportu-nistic infections.f ' ' Therefore, thenj is a clear and distinct needto produce less immunosuppression when treating patients withpemphigus and pemphigoid, by the discovery of new drugs andbiologic agents, or the use of currently available drugs.

This review is a retrospective analysis of the available lit-erature with the purposes of evaluating (i) the efficacy of dap-sone, and (ii) its possible role in druj; management strategies forpatients with pemphigus and pemphigoid.

1. Materials and Methods

A retrospective review of the English-language literature wasconducted for reports on the use of dapsone in the treatment ofpemphigus and pemphigoid. PubMed was searched using thefollowing keywords: 'dapsone' and 'pemphigus' or 'pemphi-goid.' The search was conducted in January 2008. Thirty-fivereports published between October 1969 and August 2008describing its use in 427 patients were analyzed.

There were 23 case reports/series identified for pemphigus.The studies on pemphigus included in this analysis werebased on the following inclusion criteria: (i) English language;(ii) diagnosis based on histology and immunopathology; and(iii) data for efficacy provided. There were 13 case seriesavailable for pemphigoid. The clinical studies/reports on pem-phigoid included in this analysis were based on the followinginclusion criteria: (i) English language; (ii) diagnosis based on

histology and immunopathology; (iii) minimum of five patientsin each series; and (iii) data for efficacy provided. Since therewere fewer patients with pemphigus, case studies were included.However, in pemphigoid, the abundance of patients treatedrequired our limiting the data to series with five patients ormore.

The data provided in these 35 reports were critically ana-lyzed to determine what conclusions, if any, could be made. Thedata from each of these reports is presented under the followingcategories: numbers of patients treated, average age, priorsystemic therapies, indications for use, protocol (dose and in-terval) used, concomitant systemic therapies, reported adverseeffects, and clinical outcomes. Control of disease was defined ashaving no new lesions and achieving healing of existing lesions.

2. Results

2.1 Pemphigus Vuigaris

The data for patients with pemphigus vuigaris are pre-sented in table I. There were 37 patients in 13 reports who weretreated with dapsone.I^''^' Dapsone was used as monotherapyin six (16%) patients.!^''"''^! All six patients had a clinical re-sponse that resulted in clinical remission with a dosage of100-200 mg/day. Nonetheless, all six were receiving main-tenance therapy at the time of reporting.

In 16 (43%) patients, dapsone in dosages of 50-200 mg/daywas added to prednisone.t*'^'"'''*"'^''^! In three patients, pred-nisone was discontinued; in seven patients, the dose of pred-nisone prior to initiation of dapsone was reduced. It was notpossible to reduce prednisone dose in three patients. In a furtherthree patients, addition of dapsone improved symptoms buthad to be discontinued or replaced with immunosuppre-ssants because of adverse effects.

In 15 (41%) patients, dapsone was used in combination withprednisone and immunosuppressants.I'^''^''^' Of these, 11 pa-tients had a clinical response. In one patient, dapsone had tobe discontinued because of adverse effects. Three of these11 patients did not meet the criteria for response to dapsonespecified in the randomized controlled trial.t' ^

Overall, 32 of 37 (86%) patients responded to dapsone atdosages varying between 50 and 200 mg/day when used eitheralone or in combination with prednisone and/or immunosup-pressants. Five (14%) patients did not respond. A total of nine(24%) patients developed adverse effects. However, dapsonewas discontinued in only four (11%) of these t^^'

© 2009 Adis Data information BV. Aii rigtits reserved. Am J Ciin Dermotoi 2009:10 (6)

Dapsone for Pemphigus and Pemphigoid 385

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Dapsone for Pemphigus and Pemphigoid 387

2.2 Pemphigus Foliaceus

The data for patients with pemphigus foliaceus are presentedin table II. There were 18 patients with pemphigus foliaceus re-ported to be treated with dapsone.t ' "' ' Dapsone was used asmonotherapy in 14 (78%) patients.' - " ' ! Of these, nine patientshad a clinical response that resulted in clinical remission with adosage of 100-300 mg/day. Two of these patients continued toremain in remission after the discontinuation of dapsone, whileseven required maintenance therapy at the time of reporting.One patient initially responded, but dapsone was discontinuedbecause of adverse effects. Four of 14 patients did not respond.

Dapsone was given with prednisone in the remaining four(22%) patients, resulting in clinical remission with a dosageof 25-75 mg/day.[ "' ' ' ' 1 Two patients had remission afterdiscontinuation of dapsone, and two required maintenancetherapy. In three patients, use of dapsone resulted in discon-tinuation of prednisone. In one patient, use of dapsone allowedthe tapering of prednisone; however, dapsone had to be dis-continued because of adverse effects.

Overall, 14 of 18 (78%) patients responded to dapsone whengiven at dosages between 25 and 300 mg/day, alone or in com-bination with prednisone. Four (22%) patients did not respond.A total of six (33%) patients developed adverse effects, and intwo (11%) patients, dapsone had to be dis

11 MMP patients who had not responded to initial use ofcyclophosphamide/azathioprine had their disease controlledwhen dapsone was

2.3 Mucous Membrane Pemphigoid

The data for patients with mucous membrane pemphigoid(MMP) are presented in table III. There are at least 202 MMPpatients in seven reports who were treated with dapsone.t ^"^ 'Dapsone was used as monotherapy in 91 patients and in com-bination with corticosteroids and/or immunosuppressants in111 patients. Dapsone alone or in combination with cortico-steroids and/or immunosuppressants was the initial treatmentchoice in 187 of 202 patients. Overall, 170 (84%) of 202 patientsshowed clinical improvement with dapsone when given at do-sages between 25 and 200 mg/day. Thirty-two patients did notrespond, providing a failure rate of 16%. A total of 76 (37%)patients developed adverse effects, but discontinuation waswarranted in only 20 (10%) patients.' '"^^!

In the largest series, dapsone as initial therapy controlleddisease and inhibited progression in 31 of 69 patients.t^^l Theaddition or substitution of cyclophosphamide or addition ofazathioprine provided control of disease in an additional29 patients. Thus, 60 of 69 patients had their disease controlledwith dapsone alone or in combination with cyclophosphamideor azathioprine. In the same study, it was reported that 10 of

2.4 Buiious Pemphigoid

The data for patients with bullous pemphigoid are presentedin table IV. There are at least 170 bullous pemphigoid patientswho were treated with dapsone reported in six studies.I^*" ''Dapsone was used in combination with corticosteroids and/orimmunosuppressants in 88 patients and as monotherapy in82 patients. Dapsone alone or in combination with cortico-steroids and/or immunosuppressants was the initial treatmentchoice in 142 of 170 patients. Overall, 139 of 170 (81%) patientsshowed clinical improvement when dapsone was given at varyingdosages of 50-300 mg/day. 31 (18%) patients did not respond todapsone. A total of 63 (37%) patients developed adverse effects,but dapsone was discontinued in only nine (5%) patients.f^^''

In the largest series with 62 patients, dapsone was given at adosage of 1-1.5 mg/kg/day in combination with methylpredni-solone and topical corticosteroids. At 6 months, 100% of pa-tients demonstrated clearing of all skin lesions. At 3 months,20% of the patients had discontinued systemic therapy; at6 months, 30%; and at 12 months, 53% of the 62 patients haddiscontinued systemic therapy. Unfortunately, follow-up ofpatients receiving systemic therapy beyond 12 months was notprovided.!'"' Since the patients received combination therapy,the contribution of each of the two drugs to the induction andsustained clinical remission cannot be determined.

3. Discussion

The lack of randomized controlled trials to evaluate the ef-ficacy of dapsone in the treatment of pemphigus or pemphigoidis a limitation of the available data. The rarity and the potentialfatality of these diseases may be some of the many reasons whystudies that provide definitive objective and comparative dataare largely unavailable. Analysis of the data in this reviewwould indicate that, among several drugs used to treat patientswith pemphigus and pemphigoid, dapsone is a useful agent incertain patients and under certain circumstances.

In MMP, the overall response rate to dapsone when usedeither alone or in combination with corticosteroids or im-munosuppressants was 84%. The clinical response was seen asearly as 2 weeks in many patients. Ocular lesions require longerto demonstrate maximal benefit, while gingival lesions respondmore rapidly.P'' Patients with localized mucosal disease activity

© 2009 Adis Data Information BV. Aii rights resen/ed. Am J Ciin Dermatoi 2009:10 (6)

388 Gürcan & Ahmed

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Dapsone for Pemphigus and Pemphigoid 389

are more responsive to dapsone.t^"' Dapsone is the most effec-tive agent for modestly active ocular cicatricial pemphigoid(OCP) when compared with cyclophosphamide and azathio-prine.t l Dapsone is recommended as the initial drug of choicefor patients with MMP who have mild to moderate disease thatis not rapidly progressive.[^°' '' ' ''l Serious adverse effectsusually occurred when the dosage exceeded 100 mg/day.' '' '*' ^1In one study, when dapsone was given at 25-75 mg/day for3 months, no anemia was reported.t ^^ Dr Rogers''* ' has re-ported on his experience of treating 129 patients with MMP atthe Mayo Clinic (Rochester, MN, USA). His observations in-dicate that dapsone is valuable in mild or localized MMP as thedrug of first choice. In patients with extensive or rapidly pro-gressive disease, it can be a valuable adjuvant to corticosteroids,with or without immunosuppressants.'** '

In patients with bullous pemphigoid, the overall responserate to dapsone was 81% when given either alone or in com-bination with corticosteroids or immunosuppressants. Dap-sone was less effective as monotherapy than when combinedwith topical corticosteroids.t^'l It is recommended that inwidespread, recurrent, recalcitrant bullous pemphigoid, whenadequate control is not achieved with prednisone and aza-thioprine, before increasing the prednisone dose, a brief courseof dapsone be included in the overall treatment strategy.' ' Theeffectiveness of dapsone when combined with oral prednisonealone or with azathioprine was 92% in one study.' ' In a morerecent study of 62 patients, the combination of dapsone andoral methylprednisolone achieved control of disease in 100% ofpatients.''"' Patients who respond to a sulfone will also respondto sulfonamides. A trial of dapsone therapy prior to resorting tocorticosteroids is recommended, especially if there is a pre-existing contraindication to corticosteroids. ^^1 All of the non-responders and partial responders in the study by Venninget al.t 'l were subsequently controlled relatively easily with pred-nisone alone or in combination with dapsone or azathioprine.Among patients <60 years of age, those who were middle agedand had pure vesicular, vesiculobullous or mixed bullous dis-ease responded well to dapsone.'^^' However, in two otherstudies, this was not confirmed.' '''-' ! Adverse effects were re-versible when dapsone was stopped.!" '

The analysis of the data demonstrated that 32 of 37 (86%)patients with pemphigus vulgaris' "' ' and 14 of 18 (78%) pa-tients with pemphigus foliaceust ' "" *' responded to dapsone.In most of these reports, dapsone was used as an adjuvantbecause of inadequate responses or contraindications to cortico-steroids and immunosuppressants.' ' '""' ' ^"-^^] It has beendemonstrated that the addition of dapsone decreases the doseof corticosteroid required to control the

Similarly, use of dapsone allows a safer taper of prednisone,reducing the possibility of recurrence. Recently, a randomizedcontrolled trial was conducted by Werth et al.t'^' The 19 pa-tients in this study were in the maintenance phase of theirtreatment and therefore did not have acute disease. All thepatients continued to receive immunosuppressive therapiesduring the entire trial. The purpose of the trial was to determineif the use of dapsone facilitated the reduction of oral pred-nisone, compared with placebo. Not surprisingly, patients inthe placebo group improved, because they were still beingtreated with immunosuppressive agents. The statistical analysisdid not demonstrate a clear superiority of dapsone over pla-cebo, but there was a definite trend to efficacy of dapsone asa corticosteroid-sparing agent in the maintenance phase ofpemphigus vulgaris.t"'

Dapsone acts against microorganisms by inhibiting thesynthesis of dihydrofolic acid through competition with para-aminobenzoate for the active site of dihydropteroate synthe-tase.i'' ' Dapsone has an outstanding therapeutic efficacyagainst many skin diseases characterized by neutrophil-richinfiltrates. Inflammatory diseases that respond to dapsone arealmost invariably associated with the infiltration of largenumbers of polymorphonuclear leukocytes into the affectedtissues.''! Dapsone has been shown to suppress human neu-trophil migration.'"*^" '! A more recent study has shown that theanti-inflammatory action of dapsone is via inhibition of cal-cium-dependent functions of neutrophils, including release oftissue-damaging oxidants and proteases in the affected skin.' 'Dapsone also reduces the release of prostaglandins andleukotrienes, and blocks their inflammatory effects.t " ' Inantibody-mediated diseases such as pemphigus vuigaris, pem-phigus foliaceus, MMP and bullous pemphigoid, very little isknown about the mechanism of action of dapsone. In onestudy, it has been shown that dapsone inhibits neutrophil ad-herence to pathogenic IgG in bullous pemphigoid and to IgA inpatients with IgA dermatoses in a dose-response manner.'^^' Italso inhibits the bullous pemphigoid IgG-induced interleukin-8release from cultured normal human epidermal keratinocytesby mechanisms that act at the post-transcriptional level.' ' 1

3.1 Adverse Effects

Adverse effects were observed in 24-37% of the patients inthis analysis. However, in only 5-11% of patients, were theirconsequences serious enough to require discontinuation of thedrug. The overall incidence of adverse effects appears to be un-usually high. However, the adverse effects associated with pro-longed administration of the high doses of corticosteroids that

© 2009 Adis Data Information BV. Ali rigtits reserved. Am J Ciin Dermatoi 2009: 10 (6)

390 Gürcan & Ahmed

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Dapsone for Pemphigus and Pemphigoid 393

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are often needed to achieve control of the diseases are signi-ficant, catastrophic, and potentially fatal.' 1 There are manypossible explanations for the high incidence of adverse effectsobserved in these patients treated with dapsone. First, themajority of patients were older. Such patients often have mul-tiple medical problems and are frequently receiving multiplemedications that compound and complicate drug metabolism.Second, in order to be effective, dapsone causes an unavoidablehemolytic anemia. Third, glucose 6-phosphate dehydrogenase(G6PD) levels are critical for metabolism of the drug. If G6PDscreening is not carried out, the rate of adverse effects may behigher. It is critical to highlight that, compared with cortico-steroids, the adverse-effect profile of dapsone is far less seriousand in most instances the adverse effects are reversible.'^'

Adverse effects associated with dapsone at daily doses belowlOOmg are mostly not serious. They can be categorized aspharmacologic/toxic and allergic/idiosyncratic (table V).''-^'!The most common pharmacologic/toxic adverse effects aremainly hématologie and include methemoglobinemia, hemo-lysis, and anemia.''- ''* ' '' Absorption of dapsone is virtuallycomplete within 3 hours of administration, and a high propor-tion of the drug is converted to hydroxylamine, which is themetabolite that causes these hématologie adverse effects.Methemoglobinemia occurs to a variable extent in all patients.It becomes less pronounced as treatment is continued becauseof adaptive mechanisms. It may increase dramatically in pa-tients with methemoglobin reductase enzyme deficiency.''* !Long-term administration of dapsone at dosages of 100 mg/dayin relatively healthy patients usually results in methemoglobi-nemia that is not clinically significant. At methemoglobinemialevels of 30% or higher, dyspnea, nausea, and tachycardiaoccur. Lethargy, stupor, and deteriorating consciousness occurat methemoglobinemia levels of around 55%, and a level of 70%is usually fatal.t'l

Hemolysis induced by dapsone occurs in healthy individualsin a dose-dependent manner, and a reduction in hemoglobinwill be detectable at dapsone dosages >50 mg/day.f'* ! In onestudy of 100 leprosy patients receiving an average dosage ofdapsone 100 mg/day, an average fall in hemoglobin levels of2g/dL was seen.I l Patients with G6PD deficiency are moresusceptible to developing hemolysis. To minimize hemolysis,the daily dapsone dose should not exceed 1.5 mg/kg body weightor lOOmg in healthy people with normal G6PD levels, and50 mg in G6PD-deficient people.'^'

Agranulocytosis is reported mostly in patients with derma-titis herpetiformis, and its cause is not known.t^ ' Most casesof agranulocytosis due to dapsone develop within the first8-12 weeks of therapy .[" l

© 2009 Adis Data Intormation BV. Ali rights reserved. Am J Clin Dermatol 2009: 10 (6)

394 Gürcan & Ahmed

Table V. Adverse effects of dapsone

Pharmacologic/toxic

Methemoglobinemia

Hemolysis

Anemia

Nausea

Vomiting

Fatigue

Anorexia

Headache

Dizziness

Allergic/idiosyncratic

Dapsone hypersensitivity syndrome

Agranulocytosis

Exanthematous eruption

Stevens-Johnson syndrome/toxic epidermal necrolysis

Photosensitivity

Peripheral neuropathy

Hepatitis

Nephritis and renal failure

Hypoalbuminemia

Psychosis

Hypothyroidism

Drug-induced lupus erythematosus

A rare but serious adverse effect is dapsone hypersensitivitysyndrome. The syndrome consists of fever, rash, lymphade-nopathy, and different degrees of organ involvement. This en-tity is also termed drug reaction with eosinophilia and systemicsymptoms (DRESS). Dapsone hypersensitivity syndrome maybe considered a manifestation of DRESS syndrome.f^' Only afew cases have been reported in ])atients taking dosages of<100 mg/day. The incidence is less than 0.5% and it occurs, onaverage, 27 days after the initiation of therapy.' ^ It is generallyself-limiting and most patients recover following cessation ofdapsone therapy. However, deaths have been reported.'^'

Peripheral neuropathy is less commonly reported in auto-immune mucocutaneous blistering diseases, but is more com-mon in leprosy patients and is also reported in patients withdapsone hypersensitivity syndrome. It frequently only involvesthe motor neurons, or mixed sensorimotor neurons, and mayaffect upper, lower, or both extremities. It occurs with dosagesover 100 mg/day with a variable onset, which can be withinweeks to years of beginning therapy. It is reversible and usuallyresolves within 1 year after discontinuation of dapsone, butmay persist l I ^ ^ l

Other less commonly reported adverse effects include ex-anthematous eruption, fever, Stevens-Johnson syndrome, toxicepidermal necrolysis, photosensitivity, hepatitis, nephritis andrenal failure, hypoalbuminemia, psychosis, hypothyroidism,and minor gastrointestinal complaints.''' '' ' '

Sulfapyridine has been reported to be a good alternativeto dapsone in OCP patients with reduced tolerance to

°' ' ' It has also been used in bullous pemphi-The efficacy has been shown to be similar to dap-

sone in patients with OCP.' ' Sulfasalazine, an oral precursorof sulfapyridine, which is used mainly in the treatment ofrheumatoid arthritis and ulcerative colitis, has also been re-ported to be effective and a good alternative to dapsonein patients with OCP.' ' ' Sulfasalazine has multiple immuno-modulatory properties: (i) it normalizes lymphocyte activityby inhibiting T-lymphocyte proliferation and reducing theproduction of immunoglobulins and several cytokines; (ii) itinhibits the chemotactic response of neutrophils, the release ofenzymes and Superoxide anions, the metabolism of pros-taglandins by leukocytes, and folate-dependent enzyme activ-ity; and (iii) it has antibacterial properties.!^'' Gastrointestinaland CNS symptoms (headache, dizziness) are the most fre-quent adverse effects of sulfasalazine. Other rare adverse effectsinclude hypersensitivity reactions, hepatotoxicity, pulmonarydisease, immtine disorders, and lupus-like syndromes.!^'' In onestudy, allergic reactions presenting as skin rash have been re-ported with an incidence of 15% in OCP patients treated with

Rifampin (rifampicin) lowers dapsone concentrations 7- to10-fold by accelerating plasma clearance. Folie acid antagonistssuch as pyrimethamine may increase the likelihood of hémato-logie reactions. There is a mutual interaction between dapsoneand trimethoprim in which each raises the concentration of theother about 1.5-fold.[™]

Because of several potentially harmful adverse effects, dap-sone therapy needs careful monitoring. Prior to startingdapsone, a complete blood count, reticulocyte count, G6PD,liver function studies, urine analysis, and renal function testsshould be performed. During therapy, blood count, re-ticulocyte count, platelet count, and leukocyte count should beobtained weekly for the first month, then twice per monthduring the next 2 months and every 3 months thereafter. Liverand renal function should be tested every 3 months. Methemo-globin levels should be obtained in patients who becomesymptomatic for methemoglobinemia.'^'' The use of cimeti-dine, a metabolic inhibitor that reduces hepatic oxidation ofdapsone to the hydroxylamine, may reduce the anemia asso-ciated with

© 2009 Adis Data information BV. Aii rights reserved. Am J Ciin Dermatoi 2009:10 (6)

Dapsone for Pemphigus anci Pemphigoid 395

4. Conclusions

Despite the limitations of our analysis, certain importantpreliminary conclusions can be drawn from the existing data.Dapsone is a promising agent in patients with autoimmunemucocutaneous blistering diseases. It appears that dapsone canbe used as an adjuvant when patients are not responsive to cor-ticosteroids, or in younger patients to avoid long-term adverseeffects of corticosteroids. Larger case series or randomizedcontrolled trials need to be conducted to evaluate the efficacy ofdapsone in the treatment of pemphigus. In pemphigoid, despitethe fact that randomized controlled trials are not available, theefficacy of dapsone is better established, and it is often preferredas initial treatment, either alone or in combination with pred-nisone or immunosuppressants. The majority of patients withMMP and bullous pemphigoid are responsive to dapsone.Adverse effects are dose dependent and usually not clinicallysignificant when the dosage is <100 mg/day. In the opinion ofthe authors, dapsone is a valuable and useful agent that is un-derutilized. One of the reasons for this underutilization maysimply be the lack of information available. .The ease of usingrapidly effective systemic corticosteroids may not stimulatephysicians to look for alternative drugs. As the population agesin North America, Europe and Japan, it is likely that drugsother than corticosteroids will gain more favor, simply becausethey are effective, but less toxic.

Acknowledgments

The authors are grateful to Christopher Vaillaincourt, BA, MA, MLISand Olga Lyczmanenko, BA, MA, MLIS for assistance in the preparationof this manuscript. No sources of funding were used to assist in the pre-paration of this review. The authors have no conflicts of interest that aredirectly relevant to the content of this review.

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Correspondence: Dr A. Razzaque Ahmed, Center for Blistering Diseases,New England Baptist Hospital, 70 Parker Hill Avenue, Suite 208, Boston,MA 02120, USA.E-mail: aramanuscript@msn.com

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