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   Historical aspects
   Epidemiology
   Aetiopathogenesis
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   Differential dia...
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CONTINUING MEDICAL EDUCATION
Year : 2000  |  Volume : 66  |  Issue : 3  |  Page : 117-120

Dapsone (sulfone) syndrome (CME)




Correspondence Address:
D M Thappa


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PMID: 20877050

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How to cite this article:
Thappa D M, Sethuraman G. Dapsone (sulfone) syndrome (CME). Indian J Dermatol Venereol Leprol 2000;66:117-20

How to cite this URL:
Thappa D M, Sethuraman G. Dapsone (sulfone) syndrome (CME). Indian J Dermatol Venereol Leprol [serial online] 2000 [cited 2020 May 31];66:117-20. Available from: http://www.ijdvl.com/text.asp?2000/66/3/117/4892


Dapsone (DDS) syndrome is also called the "five week dermatitis", because it suddenly occurs five to six weeks after the administration of dapsone. It usually subsides on cessation of dapsone therapy [1] . This drug-induced hypersensitivity syndrome also known as "sulfone syndrome" consists of exfoliative dermatitis and/or other skin rashes, generalised lym­phadenopathy, hepato-splenomegaly, fever and hepatitis. [2],[3] Apart from the cutaneous lesions which are always found, the other features may not neces­sarily be present in all cases. [4],[5]


  Historical aspects Top


The use of sulphones in leprosy was first reported from Carville USA in 1943. [6] Dapsone/DDS was introduced for the treatment of leprosy patients by Robert Cochrane [7] in 1947 in Chingelput,South India. However, nearly a decade passed before DDS was widely used for its remarkable efficacy in leprosy. [8] Since then, dapsone has been effectively used in various antileprosy regimens and in many other dermatological disorders. While a variety of adverse and toxic effects are associated with dapsone, the "dapsone syndrome" is a distinct hypersensitivity reaction. The earliest report of a hypersensitivity re­action to it was published in 1949. It was thought then that dapsone precipitated glandular fever. The adverse reaction occurred early during the course of treatment and was characterised by fever, lymphad­enitis, splenomegaly, jaundice, abnormal liver function tests, mononucleosis and dermatitis including generalised exfoliation. Diagnosis was confirmed by a negative Paul - Bunell test and mononucleosis. Since this reaction was I nitially as­sociated with high doses of dapsone, the authors suggested a gradual build up of dapsone to 300mg daily to avoid this complication. [9] In 1950 Lowe [10] reported three cases of hypersensitivity to the drug and advised early withdrawl of dapsone and the use of antihistamines followed by desensitization. Allday and Barnes [11] in 1951 gave it the name "dapsone syndrome".


  Epidemiology Top


The dapsone syndrome has been known since the earliest days of sulfone therapy in leprosy. Lowe and Smith [12] reported a high incidence of dapsone syndrome in adult males but the episodes were mild except in few cases with an exfoliative dermatitis. The incidence apparently diminished with the passage of time for unknown reasons. From 1956 until 1980, there were only two reports of this syndrome. [5] In the year 1981 and after, several reports of this syndrome appeared in the literature [4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Three significant facts emerged from these reports. Firstly, that dapsone syndrome can occur even when pa­tient is receiving a daily dose of 50mg [13] and secondly, that leucocytosis is not always mononucleosis. [4],[5],[6],[7],[8],[9],[10],[11],[12],[13] Thirdly, the remergence of dapsone syndrome, the world over is possibly due to the use of relatively high doses of dapsone or the result of multidrug regimens in leprosy [9],[10],[11],[12],[13],[14],[15],[16] .Based on a postal survey, the frequency of dapsone syndrome was found to vary from 0 to 2% among new cases treated. [17] Richardus and Smith [9] reported an incidence of 0.3 to 0.6% during monotherapy and 3.6% after introduction of multidrug therapy(MDT). In India Rege et al [18] recorded an incidence of 1.3% among leprosy pa­ tients treated with MDT as per recommendations of WHO. However, earlier, Sharma et al [16] had observed a low incidence of 0.25% among dapsone users for various dermatological disorders including leprosy. We, in our institute, recorded seventeen cases of dapsone syndrome in five years from January 1992 to January 1997. [19] Apart from leprosy, the dapsone syndrome has been described in cases of acne vulgaris, [14] psoriasis, [14] erythema elevatum diutinum, [20] dermatitis herpetiformis [15] and lichen planus. [19]


  Aetiopathogenesis Top


The pathogenesis of the dapsone syndrome is as yet unknown. However, Allday and Barnes [11] reported that it was probably due to hypersensitivity, because there was an interval of 5 to 6 weeks from the beginning of therapy in every case. Furthermore, Tomecki and Catalano [4] suggested that the hypersensitivity reaction of dapsone was not dose related. In contrast, hepatotoxicity is dose related. Saito et al, [1] on the basis of immunohisto­chemical investigations on skin biopsy material in­terpreted that clinical manifestations such as dermatitis, hepatitis, lymphadenopathy, and mononucleosis may be due to modified graft-versus­host disease type of reaction, probably mediated by activated T cells. There is some evidence to suggest that metabolic differences in the production and detoxification of reactive metabolites of dapsone play an important role in sulfonamide hypersensitivity reactions. [21] Dapsone is metabolized in two pathways, N-acetylation and N-hydroxylation (oxidation). The formation of toxic intermediate metabolites such as nitrosamines and possibly other compounds through N-hydroxylation pathway [22] are thought to be responsible for the haemolytic anemia, methemoglobinemia and dapsone syndrome. [23] However, the production and detoxification of toxic metabolites of dapsone is influenced by a number of genetic and environmental factors. [23] Ageing and pre-existing liver disease (cirrhosis) offer relative protection against adverse affects because of decreased enzyme activity and therefore, decreased production of toxic metabolites [22],[23],[24] But these are not proven protective factors in the occurrence of dapsone syndrome.

A critical analysis of previously described cases with regard to hepatic injury in dapsone syndrome has shown that cholestasis, rather than hepatitis to be commonest pattern of injury. [3]


  Clinical manifestations Top


Unlike other drug reactions, this syndrome can begin after prolonged exposure to the offending drug which can be as long as six months or more or as short as 48 hours. [25],[26] This reaction, termed dapsone syndrome, is characterized by sudden onset of papular or exfoliative rash, accompanied by fever, malaise and weakness, followed by jaundice and tenderness of liver, lymphadenopathy and mononucleosis (lymphocytes and monocytes 70%). [1] However, all symptoms need not necessarily be present. [5] Leucocytosis may not always be mononucleosis. [4],[5],[6],[7],[8],[9],[10],[11],[12],[13] In addition, hemolytic anemia , methemoglobinemia, eosinophilia, raised ESR,increased level of serum bilirubin and raised liver enzymes may be corroborative findings. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] The raised ESR and increased levels of liver enzymes were invariable findings in our study. [19] All age groups without any sex predilection are affected. [19]

The dermatitis component of dapsone syndrome is always present, though others may be absent. [11] The cutaneous manifestations of this syndrome show wide variations including erythroderma,papular erythematous eruptions, ery­thema multiforme, toxic epidermal necrolysis and  Stevens-Johnson syndrome More Details. [9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] Erythematous macu­lopapular rash and exofoliative dermatitis are present in the majority of cases. [9],[10],[11],[12],[13],[14],[15],[16],[17], [18,], [19],[20] [21],[22],[23],[24],[,25],[26],[27],[28]


  Diagnosis Top


The diagnosis of dapsone syndrome is based mainly on history, clinical and laboratory examination encompassing those above set of findings discussed under clinincal manifestations. Patch testing with dapsone tablet or injection form and the delayed type intradermal skin test with 0.05% dapsone in saline may be undertaken. 'These tests are, however, unreliable. [19] lf facilities are available, lymphocyte stimulation test with dapsone may be done. [1] Oral challenge test with dapsone may be dangerous in previously sensitized person, [3] hence may be carried out under supervision. [19]


  Differential diagnoses Top


Rifampicin hypersensitivity, infectious mononucleosis and other viral exanthemata are im­portant differential diagnoses for dapsone syndrome. Infection with hepatitis B virus share some common clinical features like fever, icterus and lymphadenopathy. However, cutaneous manifesta­tions in hepatitis B virus infection are less common. When they occur, they usually do so during prodromal phase. Moreover, an exfoliative rash has not been descibed in hepatitis B virus infection. [18] More importantly, dapsone syndrome has to be distin­guished from the type II lepra reaction (erythema nodosum leprosum) by the presence of a different kind of rash and the onset of jaundice. [29] The course of dapsone syndrome is variable, but it may last for four weeks or more. [19],[20], [21] ,[22], [23] It may end fatally, but that is uncommon. [2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12], [13]


  Treatment Top


The conditions of most patients improve after cessation of dapsone therapy. [5] Although no double blind studies have been performed on the effectiveness of oral glucocorticosteroids in dapsone syndrome, anecdotal experience has resulted in their widespread use. [23] We, in our institute, recommend the use of systemic corticosteroids only in severe cases of dapsone syndrome. [19] The prednisolone in the range of 30 to 60mg per day may be given. Once instituted, prednisolone should be slowly tapered off while functions of the affected organs are closely monitored to minimize recurrence. Since dapsone persists upto 35 days in the organs because of protein binding and enterohepatic circulation, tapering of prednisolone over a period of more than one month is required. [23] Dapsone should be avoided when the antileprosy regimen is reintroduced [19] . With the availability of alternative and effective antileprosy drugs, it is not necessary to desensitize these pa­tients. This practice may in fact, lead to dapsone resistance. [27]


  Conclusion Top


The dapsone syndrome is not a rare adverse drug reaction as previously believed. Early onset and partial forms may be more common than previously thought. It could prove to be fatal unless taken care early. Hence, physicians and leprosy field workers should be familiar with this reaction pattern so that early recognition is possible. Patients who are diagnosed as dapsone syndome should be hospital­ized and systemic steroids instituted wherever nec­essary. Prompt withdrawl of dapsone and minimal use of other drugs are important aspects in the management of the dapsone syndrome.





 
  References Top

1.Satio S, Ikezawa Z, Miyamoto H,et al. A case of the ' dapsone syndrome'. Clin Exp Dermatol 1994; 19:152-156.  Back to cited text no. 1    
2.Jacobson RR. Treatment, In : Leprosy, Edited by Hastings RC, Churchill Livingstone, Edinburgh 1985 ; 198.  Back to cited text no. 2    
3.Puri AS, Gupta R, Ghoshal UC, et al. Hepatic injury in sulfone syndrome: Hepatitis or cholestasis. Ind J Gastroenterol 1995;14:20.  Back to cited text no. 3    
4.Tomecki KJ, Catalan CJ. Dapsone hypersensitivity. Arch Dermatol 1981;117 : 38- 39.  Back to cited text no. 4    
5.Hortaleza Ma AR, Salta-Ramos NG, Barcelona-Tan J, et al. Dapsone syndrome in a Filipino man. Lepr Rev 1995;66:307-313.  Back to cited text no. 5    
6.Jopling WH, Mc Dougall AC. Handbook of Leprosy, Edn 4, Heinemann, Oxford, 1998 : 103-107.  Back to cited text no. 6    
7.Cochrane RG. A comparison of sulphone and hydnocarpus therapy of leprosy. Int J Lepr 1948;16:139-144.  Back to cited text no. 7    
8.Meyers WM. Leprosy research and patient care over the past century(editorial). Int J Lepr 1998;66:43-48.  Back to cited text no. 8    
9.Richardus JJ. Smith TC. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy. Lepr Rev 1989; 60 :267-273.  Back to cited text no. 9    
10.Lowe J. Treatment of leprosy with diamino diphenyl sulphone by mouth. Lancet 1950; i :145-150.  Back to cited text no. 10    
11.Allday EJ, Barnes J. Toxic effects of diamino diphenyl sulphone in leprosy. Lancet 1949;17:181-195.  Back to cited text no. 11    
12.Lower J, Smith M. The chemotherapy of leprosy in Nigeria. Int J Lepr 1949; 17:181-195.  Back to cited text no. 12    
13.Frey HM, Gershon AA, Brokowsky W, et al. Fatal reaction to dapsone during treatment of leprosy. Ann Int Med 1981; 94:777­779.  Back to cited text no. 13    
14.Karomann NP, Vilhelmoen R, Stah D. The dapsone syndrome. Arch Dermatol 1982; 118 : 531-532.  Back to cited text no. 14    
15.Mohammed KN. Hypersensitivity reactions to dapsone becoming more frequent? Lepr Rev 1988; 59:53-58.   Back to cited text no. 15    
16.Sharma VK, Kaur S, Kumar B, et al. Dapsone syndrome in India. Indian J Lepr 1985;57 : 807-812.  Back to cited text no. 16    
17.Smiith WCS. Are hypersensitivity reactions to dapsone becoming more frequent? Lepr Rev 1988;59:53-58.  Back to cited text no. 17    
18.Rege VL, Shukla P, Mascarenhas MF Dapsone syndrome in Goa. Indian J Lepr 1994;66:59-64.  Back to cited text no. 18    
19.Kumar RH, Kumar MV, Thappa DM. Dapsone syndrome - a five year retrospective analysis. Indian J Lepr 1998; 70:271-276.  Back to cited text no. 19    
20.Szymanski PB, Fertzin D. Erythema elevatum diutinum and sulfone hypersensitivity. Arch Dermatol 1967; 95: 436-440.  Back to cited text no. 20    
21.Shear NH, Spielberg SP, Grant DM. Difference in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med, 1986;105:179-184.  Back to cited text no. 21    
22.Grossman SJ, Jollow DJ. Role of dapsone hydroxylamine in dapsone induced hemolytic anaemia. J Phamacol Exp Ther 1998;224: 118-125.  Back to cited text no. 22    
23.Prussik R, Shear NH. Dapsone hypersensitivity syndrome. J Am Acad Dermatol 1996;35:346-349.  Back to cited text no. 23    
24.May DG, Porter J, Wilkinson GR, et al. Frequency distribution of dapsone N-hydroxylase, a putative probe for p4503 A4 activity in a white population. Clin Pharmacol Ther 1994;55 : 492-500.  Back to cited text no. 24    
25.Ramanujan K, Ramu G. Toxic reactions to parent sulphone report of four cases. Lepr India 1968; 40 : 1-7.  Back to cited text no. 25    
26.Singal A, Sharma SC, Baruah MC, et al. Early onset dapsone syndrome. Indian J Lepr 1993;65:443-445.  Back to cited text no. 26    
27.Joseph MS. Hypersensitivity reaction to dapsone. Four case reports. Lepr rev 1985; 56: 315-320.  Back to cited text no. 27    
28.Ghokhale NR, Sule RR, Gharpure MB. Dapsone syndrome. Indian J Dermatol Venereol Leprol 1992; 58:376-378.  Back to cited text no. 28    
29.Boopal Raj JM. Emergencies in leprosy, CME lectures on Emergency Dermatology, seventh South Zone Conference of Indian Association of Dermatologists,Venereologists and Leprologists 1997;107-108.  Back to cited text no. 29    




 

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