Pharmacology and Therapeutics
CURRENT CLINICAL THERAPEUTICS: DERMATITIS HERPETIFORMIS LARRY E. MILLIKAN, M.D. AND RONALD GOLDNER, M.D. Erom the Division of Dermatology, University of Missouri School of Medicine, Columbia, Missouri, and the Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland
ABSTRACT: Dermatitis herpetiformis can be treated by sulfapyridine, sulfones, and glutenfree diet, although patients with this papularvesicular disease respond poorly to steroids. Careful monitoring is a must.
Therapy for dermatitis herpetiformis has been remarkably successful in spite of its empiric basis. It is unusual that approaches to therapy have achieved such a rate of success with the near total lack of knowledge of etiology and pathogenesis of the disease. In reverse scientific order, the mode of action of those drugs successful in dermatitis herpetiformis therapy is now being studied for possible clues to mechanisms through which the disease is mediated. However, in the past 5 years some impressive advances have been made in understanding of the disease process. Foremost among these recent advances has been the elucidation of immunologic factors associated with the disease. These include the discovery of positive immunofluorescence to IgA, in a granular pattern, found at the dermalepidermal junction.' In addition, the role of complement and the alternate Address for reprints: Larry E. Millikan, M.D., Division of Dermatology, University of Missouri Medical Center M752, Columbia, MO 65201.
complement pathway has been valuable recent information.2- ^ The role of the eosinophil in this disease has long been known and its association with iodides, complement, and immunoglobulins is under study."* Through these findings we may approach rational therapy to minimize symptoms. Newer drugs are being sought that may play a role in modifying these immunologic events. The absence of early complement components in the skin of patients with active cases combined with the presence of properdin, C3PA and others suggests an important role for the alternate complement pathway (Fig. 1), which is known to be activated by immunoglobulin-A, tying these factors in as possibly playing an important role in pathogenesis of the clinical symptoms. The bowel disease associated with dermatitis herpetiformis is'reported to occur in about two-thirds of patients but remains a point of controversy.^' '' It has been reported that the group of patients who have dermatitis herpetiformis and bowel disease tend to segregate around the HL-A8 antigen type in histocompatibility testing.^ Patients with dermatitis herpetiformis who lack significant bowel disease do not segregate in the similar manner. In those patients with established presence of bowel disease, there is further disagreement as to the effect of a gluten-free diet.^' '• Initial studies strongly indicated that this was beneficial only for the bowel symptoms. However, now it appears that if a gluten-free diet is pursued as a long-term maintenance diet, it
53S
No. 7
DERMATITIS HERPETIFORMIS
•
Millikan and Coldner
539
THE COMPLEMENT SYSTEM
Bacteria IGA Polysaccharides, yeast
Classical Pathway
Anaphylatoxin
- Vascular Permeability
Cell Lysis Fig. 1.
is useful in diminishing the maintenance dosage of drugs. Upon reintroduction of gluten in the diet in a small series, the disease exacerbated. The controversy over gluten is understandable, for in adult coeliac disease the response to the gluten-free diet is equally erratic and some patients require many months of therapy for relief of symptoms, just as is seen in these cases of dermatitis herpetiformis. Diagnosis
The diagnosis of dermatitis herptiformis rests on the following:
1. Typical clinical picture 2. Atypical clinical picture plus responses to sulfapyridine or sulfone (trial of therapy) 3. Atypical clinical picture plus typical histopathology 4. Additional tests reported to be of value are: A. Potassium iodide skin tests using 50% potassium iodide in petrolatum B. The Rebuck skin window may be of some help in confirmation for with iodides, as the antigen
540
INTERNATIONAL JOURNAL OF DERMATOLOGY
TIIEEULFA/SULFONE DRUGS IN DERMATITIS HERPETI FORM IS THERAPY
September 1976
Vol. IS
primary therapeutic approaches include sulfapyridine, sulfones and gluten-free diet. Sulfapyridine
SULPAPYRIDINE
R= ClIjOSON
Fig. 2. The sulfasulfone drugs in dermatitis herpetiformis therapy.
there appears to be an outpouring of eosinophils into the skin window, as opposed to the normal neutrophil response. Treatment
Progress in the therapy for dermatitis herptiformis has been remarkable because of the poor response that patients with this disease have shown to steroid therapy. It is the exceptional patient who can be expected to respond dramatically to steroids. The mainstay of therapy has been sulfapyridine and the sulfone group of drugs. More recently, additional therapy using a gluten-free diet has been tried and has been met with variable success. With drug sensitivity, additional approaches to therapy have been used, including the use of nicotinic acid, with variable results. The
Sulfapyridine was first used in 1938 for pneumococcal pneumonia. It is related to the parent compound sulfanilamide but is far less soluble and thus poorly and irregularly absorbed. The structural formula is seen in Figure 2.** This drug has been used in the treatment of dermatitis herpetiformis since 1940 and has often been used as a specific test for the diagnosis.^ When metabolized by the body, sulfapyridine is subject to ring hydroxylation followed by conjugation to glucuronic acid and n-acetylation. The ability to hydroxylate and acetylate sulfapyridine is apparently subject to genetic variance.'" An oral dose of 2 gm followed by 1 gm every 4 hours gives blood levels of 4 to 7 mg% after 8 hours." Clinical experience has indicated that the mechanism of action of sulfapyridine is unrelated to its antibacterial effect. Dosages too small to maintain effective antibacterial blood levels often control dermatitis herpetiformis in a striking manner. Antibiotics, on the other hand, in effective antibacterial doses have no effect. The concomitant use of P-aminobenzoic acid with sulfapyridine does not negate its effect on dermatitis herpetiformis as it does the antibacterial effect." Adverse reactions to sulfapyridine have been a problem with the long-term use of the drug. Usually mild problems such as anorexia, headache, malaise, nausea, vomiting and gastrointestinal irritation are reported. More severe reactions such as hemolytic anemia, leukopenia, drug fever, cutaneous eruptions, and crystalluria are less commonly seen. Fatal reactions such
No. 7
DERMATITIS HERPETIFORMIS
as agranulocytosis, bullous eruptions or renal damage are very rare."' '^ A hypothesis on the mechanics of action of sulfapyridine has been proposed by Lorincz and Pearson. They believe that the drug combines or reacts with tissue or bacterial polysaccharides to alter their reactivity and thus inhibit their involvement in pathologic processes." Most treatment regimens for dermatitis herpetiformis recommend sulfapyridine in a dose of 2 to 4 gm per day after an initial test dose of 0.5 gm. The dose is gradually tapered to a maintenance level which keeps the disease suppressed (averaging 1.5 gm per day)."- ^^' " Salicylazosulfapyridine has also been reported to be effective in dermatitis herpetiformis, but in vivo this drug is metabolized to sulfapyridine and aminosalicylic acid.'^ Blood counts and urinalysis should be normal before therapy and should be checked biweekly during the early period of therapy. When a stable maintenance dose is reached, the checkups may be at bimonthly intervals.
Sulfones The sulfones have a record of remarkable effectiveness in the control of dermatitis herpetiformis. These drugs perhaps represent one of the safest medications for treatment of this disorder. It is estimated that about 2,000,000 people are under treatment for leprosy at any given time throughout the world on a dosage averaging 50-100 mg per day, which represents about average therapy for well-controlled dermatitis herpetiformis. It appears that these drugs have a long record of safety and with the minimal recommended follow-up tests can be considered very reliable. The sulfone group of drugs perhaps represents the most widely used single therapy for dermatitis herpetiformis. The
Millikan and Coldner
541
2 principal forms that are available are Diasone (Abbott Laboratories 165 mg tablets) and Avlo sulfone/dapsone/diaminodiphenylsulfone—DDS (Ayerst Laboratories 25 mg and 100 mg tablets) (Fig. 2). DDS represents the most widely used of the sulfones for dermatitis herpetiformis and until recently was the primary drug in worldwide use against leprosy. The popularity of DDS is attributed to its low cost; it represents the prototype drug in that it is the basic core drug for sulfones.'- All other sulfone drugs represent substituted derivatives of dapsone. Diasone, a substituted form, is still available (Fig. 2). It is believed to be broken down to dapsone in the body. Sulfone drugs are slowly metabolized in the body, recirculated by the enterohepatic circulation and have a long halflife. This is exemplified by the characteristic dosage seen in leprosy, where as low as 25 mg of DDS may be given twice a week.^' The reactions to the sulfones of significance (Table 1) have become common knowledge to most practitioners. Reactions can be avoided through careful regulation of dose and a few monitoring laboratory tests. The most serious side reactions, but also one of the rarest associated with dapsone therapy, has been agranulocytosis."^ In our review of drug reactions induced by sulfones, we found 4 cases of agranulocytosis in the leprosy literature.'^ To this was added the Vietnam experience of sulfones used for malaria prophylaxis. In this report, 18 patients were reported to have had agranulocytosis with a 50% fatality rate.'^ The exact mechanism of damage to the marrow cells is still unclear, and is clouded by the dramatic case of a patient who had a severe agranulocytic reaction from sulfones and
542
INTERNATIONAL JOURNAL OF DERMATOLOGY
September 1976
Vol. 15
upon recuperation was inadvertently restarted on sulfone malaria prophylaxis without any ill effects. This suggests that either the sulfones were not the cause of the reaction or the possibility is that the patient might have been taking other antimalarials, which caused an additive effect. The possibility that heat caused degradation of the drug into toxic byproducts has also been considered. This seems unlikely, for there is a long history of use of the sulfones in the tropics for leprosy without any such incidence of severe side reactions. If heat degradation or denaturation were a causative factor in this syndrome, it should have been shown in the leprosy patients. The agranulocytosis seems related to the sulfones by some means for it occurred in Vietnam only in soldiers treated with dapsone and its time of appearance was between 3-12 weeks of therapy. Other reports in the dermatologic literature also suggest that the white cell reaction to the drug occurs early in the course of therapy—between 3-12 weeks of treatment.
affects mostly the older red cells whose enzyme reduction system is diminished. It has been reported that the hemolytic effect of sulfones is caused by acceleration of the aging process rather than a specific selective destruction of older cells.'y This is reasonable, for the oxidative stress from the drug on red cells further decreases the activity of redox enzymes necessary for cell integrity. The effect of sulfones on the C-6P-D deficient cells, which is far more dramatic than in normal cells, can produce clinical symptoms. Therefore, it has been recommended that an initial screen for Heinz bodies may be sufficient to rule out those patients with particularly severe deficiencies.2" While Negroes have been classically identified with the G-6-P-D deficiency, they generally have the milder heterozygous trait. Affected Caucasian patients, however, may be homozygous, with correspondingly much lower levels of the enzymes. In these patients, severe hemolysis can occur and looking for Heinz bodies can be an important predictive test.
Far more common but much less serious are the effects of sulfones on the red cells. The appearance of cyanosis is generally related to methemoglobinemia and is not related to the dose of sulfone. High levels of methemoglobin are seen initially in therapy and then decline on maintenance sulfone therapy. Methemoglobinemia is generally not a problem, unless the patient is exposed to low oxygen tensions in the environment. An unusual exception was a patient reported by Alexander in whom high levels of methemoglobinemia precipitated angina.^8 Hemolysis is common in patients taking sulfones but rarely is a clinical difficulty. The sulfones are strong oxidizers; therefore, they cause an exaggeration of the effect of primiquin on red cells. This
Hepatitis has been described in the past in the leprosy literature and more recently, the cholestatic type of jaundice has been reported with these drugs." There seems to be no reliable prediction of the patients at risk for these disorders. Nor is this unexpected, for other drugs closely related to the sulfones (including chlorothiazide, sulfanilamide and sulfadiazine) cause intrahepatic cholestasis. This cholestasis is a drug sensitivity phenomenon; therefore, it is not dose related as the toxic hepatic reactions are. The reaction usually begins in the first 4 weeks of therapy with a clinical spectrum varying from the asymptomatic patient with the single finding of an elevated alkaline phosphatase to the very ill patient with erythematous rash, fever and jaundice. Severe cholestasis is a contra-
No. 7
DERMATITIS HERPETIFORMIS
indication to further therapy of the sulfones. Other reactions are listed in Table 1. These are diagnosed on clinical findings and therapy is primarily discontinuing of the drug and specific treatment for the drug reaction if indicated. The most recent drug complication that seems on the increase is peripheral motor neuropathy. The present age of polypharmacy has emphasized the problems of drug interactions. These are now being reported even with sulfones. Probenecid competes with the renal excretion of dapsone, among other drugs increasing serum levels.-' Probenecid also has been implicated in hemolytic anemias and in the patients with G-6-P-D deficiencies. Therefore, these 2 drugs should not be used together. Careful evaluation should be made in any patient who is receiving more than one drug to minimize the possibility of serious deleterious drug interactions. For as mentioned previously, the agranulocytosis phenomenon may be accentuated by drug interactions. While the patient is receiving continuous maintenance therapy it is recommended that the following laboratory tests be performed periodically: white cell count, hematocrit and/or hemoglobin and liver function tests (including alkaline phosphatase and transaminase). Periodic checks on methemoglobin levels at about 8-12 week intervals are recommended. If any shortness of breath or cyanosis should occur, recheck of these values should be made at that time also. Traditionally, therapy is begun at fairly high dosage levels, which are tapered as a remission is induced. Usually, doses at the onset of therapy are 200 mg a day. Alexander reported that some patients require as much as 300 mg a day but the majority of the patients, in our experience, will do well on 200 mg daily. On
Millikan and Coldner
543
Table 1. Drug Reaction to Sulfones Hemolysis Methemoglobinemia Hepatitis—infectious mononucleosis Cholestasis Morbilliform eruptions Erythema nodosum Erythema multiforme Exfoliative dermatitis Toxic epidermal necrolysis Agranulocytosis Peripheral motor neuropathy
control of the disease, the dosage is reduced to 100 mg daily for maintenance and if possible even lower dosages, using the 25 mg tablets. From a limited survey of practitioners, it appears that 100 mg daily is the most commonly used dosage level for control of dermatitis herpetiformis and is the dosage that we regularly use. During therapy, laboratory tests mentioned are done on a regular basis.-'-t Table 2. Eoods to be Omitted on a Cluten-Eree Diet* Meat or fish patties or loaf made with bread or bread crumbs, breaded foods, canned meat dishes, cold cuts unless guaranteed pure meat, bread stuffing. Gravies or sauces thickened with wheat flour. Bread, rolls, crackers, cake, cookies, muffins, biscuits made with rye or wheat flour, waffles, pancakes, rusks, zweiback, pretzels. Wheat and rye cereals, wheat germ, barley, oatmeal, buckwheat, kasha, noodles, macaroni, spaghetti, dumplings. Commercial salad dressing, except pure mayonnaise. All canned soups except clear broth, cream soups unless thickened with cream, cornstarch, or potato flour. Cakes, cookies, pastries, commercial ice cream and ice cream cones, prepared mixes, puddings, commercial candy containing cereal products. Postum, malted milk, Ovaltine, instant coffee containing wheat, beer, ale. * The University gluten-free diet is available from the authors upon request.
544
INTERNATIONAL JOURNAL OF DERMATOLOGY
Diasone Diasone was formerly available in 330 mg tablets and daily dosage was 1 or 2 tablets daily. Presently only the 165 mg tablet is available and our maintenance therapy has been 1 to 2 tablets daily. Gluten-Free Diet It is often worthwhile to place the patients on a gluten-free diet to see if this benefits them. Therapy is continued for at least 14 months to adequately evaluate any benefits. Our standard hospital gluten-free diet omits the foods shown in Table 2. In addition, various food companies make lists available of their gluten-free foods. An example of this is the list available from Best Foods, which can be obtained by writing to CPC International Corporation, Best Foods Research Center, Union, NJ 07083. Drug Names diaminodiphenylsulfone (DDS): Avlosulfon P-aminobenzoic acid: PABA salicylazosulfapyridine: Azulfidine sulfoxone sodium: Diasone sodium References 1. Van der Meer, J. B., Granular deposits of immunoglobulins in the skin of patients with dermatitis herpetiformis. An immunofluorescent study. Br. J. Dermatol. 81:493, 1969. 2. Seah, P. P., Fry, L., Mazaheri, M. R., et al.. Alternate pathway complement fixation by IgA in the skin in dermatitis herpetiformis. Lancet 2:175, 1973. 3. Provost, T., and Tomasi, T. B., Dermatitis herpetiformis: Participation of IgA and the alternate complement pathway. Clin. Res. 21:481, 1973. 4. Salo, O. P., Laiho, K., Blomqvist, K., et al.. Papillary deposition of fibrin in iodide reaction in dermatitis herpetiformis. Ann. Clin. Res. 2:19, 1970. 5. Fry, L., McMinn, R. M. H., Cowan, J. D., et al.. Gluten-free diet and reintroduction of gluten in dermatitis herpetiformis. Arch. Dermatol. 100:129, 1969.
September 1976
Vol. 1S
6. Fry, L., Riches, D. J., Seah, P. P., et al.. Clearance of skin lesions in dermatitis herpetiformis after gluten withdrawal. Lancet 1:228, 1973. 7. Gebhard, R. L., Katz, S. I., Marks, j . , et al., HL-A antigen type and small-intestinal disease in dermatitis herpetiformis. Lancet 1:760, 1973. 8. Goodman, L., and Gillman, A, The pharmacological Basis of Therapeutics. 4th edition. New York, MacMillan, 1970. 9. Shelley, W. B.: Consultations in Dermatology II with Walter B. Shelley. Philadelphia, W. B. Saunders, 1974. 10. Schroder, H., and Evans, D. A. P., The polymorphic acetylation of sulphapyridine in man. J. Med. Genet. 9:168, 1972. 11. Lorincz, A., and Pearson, R., Sulfapyridine and sulfone type drugs in dermatology. Arch. Dermatol. 85:2, 1962. 12. Lehr, D.: Clinical toxicity of new sulfamides. Ann. N. Y. Acad. Sci. 69:417, 1957. 13. Alexander, J. O., Treatment of dermatitis herpetiformis. Lancet 1:433, 1973. 14. Millikan, L. E., and Harrell, R., Drug reaction to the sulfones. Arch. Dermatol. 102: 220, 1970. 15. Androzzi, R. H., and Nuss, D. D., Dermatitis herpetiformis: Treatment with azulfidine. Cutis 13:366, 1974. 16. Catalano, P. M., Dapsone agranulocytosis. Arch. Dermatol. 104:675, 1971. 17. Obnibene, A. J., Agranulocytosis due to dapsone. Ann. Intern. Med. 72:521, 1970. 18. Alexander, J. O., An unusual complication associated with dapsone therapy of dermatitis herpetiformis. Scot. Med. J. 3:212, 1958. 19. Mayer, K., and Ley, A. B., Hemolysis of red cells due to sulfone. Ann. Intern. Med. 72: 711, 1970. 20. Hutchison, H. E., Jackson, J. M., and Cassidy, P., Drug induced hemolytic anemia in dermatitis herpetiformis: Importance of Heinz bodies in its recognition. Br. |. Dermatol. 75: 161, 1963. 21. Saqueton, A. C, Lorincz, A.L., Vick, N. A., et al., Dapsone and peripheral motor neuropathy. Arch. Dermatol. 100:214, 1969. 22. Hubler, W. R., and Solomon, H., Neurotoxicity of sulfones. Arch. Dermatol. 106:598, 1972. 23. Goodwin, C. S., and Sparell, G., Inhibition of dapsone excretion by probenecid. Lancet 2:884, 1969. 24. Graham, W. R., Jr., Adverse effects of dapsone. Int. J. Dermatol. 14:494, 1975.
CURRENT CLINICAL THERAPEUTICS: DERMATITIS HERPETIFORMIS LARRY E. MILLIKAN, M.D. AND RONALD GOLDNER, M.D. Erom the Division of Dermatology, University of Missouri School of Medicine, Columbia, Missouri, and the Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland
ABSTRACT: Dermatitis herpetiformis can be treated by sulfapyridine, sulfones, and glutenfree diet, although patients with this papularvesicular disease respond poorly to steroids. Careful monitoring is a must.
Therapy for dermatitis herpetiformis has been remarkably successful in spite of its empiric basis. It is unusual that approaches to therapy have achieved such a rate of success with the near total lack of knowledge of etiology and pathogenesis of the disease. In reverse scientific order, the mode of action of those drugs successful in dermatitis herpetiformis therapy is now being studied for possible clues to mechanisms through which the disease is mediated. However, in the past 5 years some impressive advances have been made in understanding of the disease process. Foremost among these recent advances has been the elucidation of immunologic factors associated with the disease. These include the discovery of positive immunofluorescence to IgA, in a granular pattern, found at the dermalepidermal junction.' In addition, the role of complement and the alternate Address for reprints: Larry E. Millikan, M.D., Division of Dermatology, University of Missouri Medical Center M752, Columbia, MO 65201.
complement pathway has been valuable recent information.2- ^ The role of the eosinophil in this disease has long been known and its association with iodides, complement, and immunoglobulins is under study."* Through these findings we may approach rational therapy to minimize symptoms. Newer drugs are being sought that may play a role in modifying these immunologic events. The absence of early complement components in the skin of patients with active cases combined with the presence of properdin, C3PA and others suggests an important role for the alternate complement pathway (Fig. 1), which is known to be activated by immunoglobulin-A, tying these factors in as possibly playing an important role in pathogenesis of the clinical symptoms. The bowel disease associated with dermatitis herpetiformis is'reported to occur in about two-thirds of patients but remains a point of controversy.^' '' It has been reported that the group of patients who have dermatitis herpetiformis and bowel disease tend to segregate around the HL-A8 antigen type in histocompatibility testing.^ Patients with dermatitis herpetiformis who lack significant bowel disease do not segregate in the similar manner. In those patients with established presence of bowel disease, there is further disagreement as to the effect of a gluten-free diet.^' '• Initial studies strongly indicated that this was beneficial only for the bowel symptoms. However, now it appears that if a gluten-free diet is pursued as a long-term maintenance diet, it
53S
No. 7
DERMATITIS HERPETIFORMIS
•
Millikan and Coldner
539
THE COMPLEMENT SYSTEM
Bacteria IGA Polysaccharides, yeast
Classical Pathway
Anaphylatoxin
- Vascular Permeability
Cell Lysis Fig. 1.
is useful in diminishing the maintenance dosage of drugs. Upon reintroduction of gluten in the diet in a small series, the disease exacerbated. The controversy over gluten is understandable, for in adult coeliac disease the response to the gluten-free diet is equally erratic and some patients require many months of therapy for relief of symptoms, just as is seen in these cases of dermatitis herpetiformis. Diagnosis
The diagnosis of dermatitis herptiformis rests on the following:
1. Typical clinical picture 2. Atypical clinical picture plus responses to sulfapyridine or sulfone (trial of therapy) 3. Atypical clinical picture plus typical histopathology 4. Additional tests reported to be of value are: A. Potassium iodide skin tests using 50% potassium iodide in petrolatum B. The Rebuck skin window may be of some help in confirmation for with iodides, as the antigen
540
INTERNATIONAL JOURNAL OF DERMATOLOGY
TIIEEULFA/SULFONE DRUGS IN DERMATITIS HERPETI FORM IS THERAPY
September 1976
Vol. IS
primary therapeutic approaches include sulfapyridine, sulfones and gluten-free diet. Sulfapyridine
SULPAPYRIDINE
R= ClIjOSON
Fig. 2. The sulfasulfone drugs in dermatitis herpetiformis therapy.
there appears to be an outpouring of eosinophils into the skin window, as opposed to the normal neutrophil response. Treatment
Progress in the therapy for dermatitis herptiformis has been remarkable because of the poor response that patients with this disease have shown to steroid therapy. It is the exceptional patient who can be expected to respond dramatically to steroids. The mainstay of therapy has been sulfapyridine and the sulfone group of drugs. More recently, additional therapy using a gluten-free diet has been tried and has been met with variable success. With drug sensitivity, additional approaches to therapy have been used, including the use of nicotinic acid, with variable results. The
Sulfapyridine was first used in 1938 for pneumococcal pneumonia. It is related to the parent compound sulfanilamide but is far less soluble and thus poorly and irregularly absorbed. The structural formula is seen in Figure 2.** This drug has been used in the treatment of dermatitis herpetiformis since 1940 and has often been used as a specific test for the diagnosis.^ When metabolized by the body, sulfapyridine is subject to ring hydroxylation followed by conjugation to glucuronic acid and n-acetylation. The ability to hydroxylate and acetylate sulfapyridine is apparently subject to genetic variance.'" An oral dose of 2 gm followed by 1 gm every 4 hours gives blood levels of 4 to 7 mg% after 8 hours." Clinical experience has indicated that the mechanism of action of sulfapyridine is unrelated to its antibacterial effect. Dosages too small to maintain effective antibacterial blood levels often control dermatitis herpetiformis in a striking manner. Antibiotics, on the other hand, in effective antibacterial doses have no effect. The concomitant use of P-aminobenzoic acid with sulfapyridine does not negate its effect on dermatitis herpetiformis as it does the antibacterial effect." Adverse reactions to sulfapyridine have been a problem with the long-term use of the drug. Usually mild problems such as anorexia, headache, malaise, nausea, vomiting and gastrointestinal irritation are reported. More severe reactions such as hemolytic anemia, leukopenia, drug fever, cutaneous eruptions, and crystalluria are less commonly seen. Fatal reactions such
No. 7
DERMATITIS HERPETIFORMIS
as agranulocytosis, bullous eruptions or renal damage are very rare."' '^ A hypothesis on the mechanics of action of sulfapyridine has been proposed by Lorincz and Pearson. They believe that the drug combines or reacts with tissue or bacterial polysaccharides to alter their reactivity and thus inhibit their involvement in pathologic processes." Most treatment regimens for dermatitis herpetiformis recommend sulfapyridine in a dose of 2 to 4 gm per day after an initial test dose of 0.5 gm. The dose is gradually tapered to a maintenance level which keeps the disease suppressed (averaging 1.5 gm per day)."- ^^' " Salicylazosulfapyridine has also been reported to be effective in dermatitis herpetiformis, but in vivo this drug is metabolized to sulfapyridine and aminosalicylic acid.'^ Blood counts and urinalysis should be normal before therapy and should be checked biweekly during the early period of therapy. When a stable maintenance dose is reached, the checkups may be at bimonthly intervals.
Sulfones The sulfones have a record of remarkable effectiveness in the control of dermatitis herpetiformis. These drugs perhaps represent one of the safest medications for treatment of this disorder. It is estimated that about 2,000,000 people are under treatment for leprosy at any given time throughout the world on a dosage averaging 50-100 mg per day, which represents about average therapy for well-controlled dermatitis herpetiformis. It appears that these drugs have a long record of safety and with the minimal recommended follow-up tests can be considered very reliable. The sulfone group of drugs perhaps represents the most widely used single therapy for dermatitis herpetiformis. The
Millikan and Coldner
541
2 principal forms that are available are Diasone (Abbott Laboratories 165 mg tablets) and Avlo sulfone/dapsone/diaminodiphenylsulfone—DDS (Ayerst Laboratories 25 mg and 100 mg tablets) (Fig. 2). DDS represents the most widely used of the sulfones for dermatitis herpetiformis and until recently was the primary drug in worldwide use against leprosy. The popularity of DDS is attributed to its low cost; it represents the prototype drug in that it is the basic core drug for sulfones.'- All other sulfone drugs represent substituted derivatives of dapsone. Diasone, a substituted form, is still available (Fig. 2). It is believed to be broken down to dapsone in the body. Sulfone drugs are slowly metabolized in the body, recirculated by the enterohepatic circulation and have a long halflife. This is exemplified by the characteristic dosage seen in leprosy, where as low as 25 mg of DDS may be given twice a week.^' The reactions to the sulfones of significance (Table 1) have become common knowledge to most practitioners. Reactions can be avoided through careful regulation of dose and a few monitoring laboratory tests. The most serious side reactions, but also one of the rarest associated with dapsone therapy, has been agranulocytosis."^ In our review of drug reactions induced by sulfones, we found 4 cases of agranulocytosis in the leprosy literature.'^ To this was added the Vietnam experience of sulfones used for malaria prophylaxis. In this report, 18 patients were reported to have had agranulocytosis with a 50% fatality rate.'^ The exact mechanism of damage to the marrow cells is still unclear, and is clouded by the dramatic case of a patient who had a severe agranulocytic reaction from sulfones and
542
INTERNATIONAL JOURNAL OF DERMATOLOGY
September 1976
Vol. 15
upon recuperation was inadvertently restarted on sulfone malaria prophylaxis without any ill effects. This suggests that either the sulfones were not the cause of the reaction or the possibility is that the patient might have been taking other antimalarials, which caused an additive effect. The possibility that heat caused degradation of the drug into toxic byproducts has also been considered. This seems unlikely, for there is a long history of use of the sulfones in the tropics for leprosy without any such incidence of severe side reactions. If heat degradation or denaturation were a causative factor in this syndrome, it should have been shown in the leprosy patients. The agranulocytosis seems related to the sulfones by some means for it occurred in Vietnam only in soldiers treated with dapsone and its time of appearance was between 3-12 weeks of therapy. Other reports in the dermatologic literature also suggest that the white cell reaction to the drug occurs early in the course of therapy—between 3-12 weeks of treatment.
affects mostly the older red cells whose enzyme reduction system is diminished. It has been reported that the hemolytic effect of sulfones is caused by acceleration of the aging process rather than a specific selective destruction of older cells.'y This is reasonable, for the oxidative stress from the drug on red cells further decreases the activity of redox enzymes necessary for cell integrity. The effect of sulfones on the C-6P-D deficient cells, which is far more dramatic than in normal cells, can produce clinical symptoms. Therefore, it has been recommended that an initial screen for Heinz bodies may be sufficient to rule out those patients with particularly severe deficiencies.2" While Negroes have been classically identified with the G-6-P-D deficiency, they generally have the milder heterozygous trait. Affected Caucasian patients, however, may be homozygous, with correspondingly much lower levels of the enzymes. In these patients, severe hemolysis can occur and looking for Heinz bodies can be an important predictive test.
Far more common but much less serious are the effects of sulfones on the red cells. The appearance of cyanosis is generally related to methemoglobinemia and is not related to the dose of sulfone. High levels of methemoglobin are seen initially in therapy and then decline on maintenance sulfone therapy. Methemoglobinemia is generally not a problem, unless the patient is exposed to low oxygen tensions in the environment. An unusual exception was a patient reported by Alexander in whom high levels of methemoglobinemia precipitated angina.^8 Hemolysis is common in patients taking sulfones but rarely is a clinical difficulty. The sulfones are strong oxidizers; therefore, they cause an exaggeration of the effect of primiquin on red cells. This
Hepatitis has been described in the past in the leprosy literature and more recently, the cholestatic type of jaundice has been reported with these drugs." There seems to be no reliable prediction of the patients at risk for these disorders. Nor is this unexpected, for other drugs closely related to the sulfones (including chlorothiazide, sulfanilamide and sulfadiazine) cause intrahepatic cholestasis. This cholestasis is a drug sensitivity phenomenon; therefore, it is not dose related as the toxic hepatic reactions are. The reaction usually begins in the first 4 weeks of therapy with a clinical spectrum varying from the asymptomatic patient with the single finding of an elevated alkaline phosphatase to the very ill patient with erythematous rash, fever and jaundice. Severe cholestasis is a contra-
No. 7
DERMATITIS HERPETIFORMIS
indication to further therapy of the sulfones. Other reactions are listed in Table 1. These are diagnosed on clinical findings and therapy is primarily discontinuing of the drug and specific treatment for the drug reaction if indicated. The most recent drug complication that seems on the increase is peripheral motor neuropathy. The present age of polypharmacy has emphasized the problems of drug interactions. These are now being reported even with sulfones. Probenecid competes with the renal excretion of dapsone, among other drugs increasing serum levels.-' Probenecid also has been implicated in hemolytic anemias and in the patients with G-6-P-D deficiencies. Therefore, these 2 drugs should not be used together. Careful evaluation should be made in any patient who is receiving more than one drug to minimize the possibility of serious deleterious drug interactions. For as mentioned previously, the agranulocytosis phenomenon may be accentuated by drug interactions. While the patient is receiving continuous maintenance therapy it is recommended that the following laboratory tests be performed periodically: white cell count, hematocrit and/or hemoglobin and liver function tests (including alkaline phosphatase and transaminase). Periodic checks on methemoglobin levels at about 8-12 week intervals are recommended. If any shortness of breath or cyanosis should occur, recheck of these values should be made at that time also. Traditionally, therapy is begun at fairly high dosage levels, which are tapered as a remission is induced. Usually, doses at the onset of therapy are 200 mg a day. Alexander reported that some patients require as much as 300 mg a day but the majority of the patients, in our experience, will do well on 200 mg daily. On
Millikan and Coldner
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Table 1. Drug Reaction to Sulfones Hemolysis Methemoglobinemia Hepatitis—infectious mononucleosis Cholestasis Morbilliform eruptions Erythema nodosum Erythema multiforme Exfoliative dermatitis Toxic epidermal necrolysis Agranulocytosis Peripheral motor neuropathy
control of the disease, the dosage is reduced to 100 mg daily for maintenance and if possible even lower dosages, using the 25 mg tablets. From a limited survey of practitioners, it appears that 100 mg daily is the most commonly used dosage level for control of dermatitis herpetiformis and is the dosage that we regularly use. During therapy, laboratory tests mentioned are done on a regular basis.-'-t Table 2. Eoods to be Omitted on a Cluten-Eree Diet* Meat or fish patties or loaf made with bread or bread crumbs, breaded foods, canned meat dishes, cold cuts unless guaranteed pure meat, bread stuffing. Gravies or sauces thickened with wheat flour. Bread, rolls, crackers, cake, cookies, muffins, biscuits made with rye or wheat flour, waffles, pancakes, rusks, zweiback, pretzels. Wheat and rye cereals, wheat germ, barley, oatmeal, buckwheat, kasha, noodles, macaroni, spaghetti, dumplings. Commercial salad dressing, except pure mayonnaise. All canned soups except clear broth, cream soups unless thickened with cream, cornstarch, or potato flour. Cakes, cookies, pastries, commercial ice cream and ice cream cones, prepared mixes, puddings, commercial candy containing cereal products. Postum, malted milk, Ovaltine, instant coffee containing wheat, beer, ale. * The University gluten-free diet is available from the authors upon request.
544
INTERNATIONAL JOURNAL OF DERMATOLOGY
Diasone Diasone was formerly available in 330 mg tablets and daily dosage was 1 or 2 tablets daily. Presently only the 165 mg tablet is available and our maintenance therapy has been 1 to 2 tablets daily. Gluten-Free Diet It is often worthwhile to place the patients on a gluten-free diet to see if this benefits them. Therapy is continued for at least 14 months to adequately evaluate any benefits. Our standard hospital gluten-free diet omits the foods shown in Table 2. In addition, various food companies make lists available of their gluten-free foods. An example of this is the list available from Best Foods, which can be obtained by writing to CPC International Corporation, Best Foods Research Center, Union, NJ 07083. Drug Names diaminodiphenylsulfone (DDS): Avlosulfon P-aminobenzoic acid: PABA salicylazosulfapyridine: Azulfidine sulfoxone sodium: Diasone sodium References 1. Van der Meer, J. B., Granular deposits of immunoglobulins in the skin of patients with dermatitis herpetiformis. An immunofluorescent study. Br. J. Dermatol. 81:493, 1969. 2. Seah, P. P., Fry, L., Mazaheri, M. R., et al.. Alternate pathway complement fixation by IgA in the skin in dermatitis herpetiformis. Lancet 2:175, 1973. 3. Provost, T., and Tomasi, T. B., Dermatitis herpetiformis: Participation of IgA and the alternate complement pathway. Clin. Res. 21:481, 1973. 4. Salo, O. P., Laiho, K., Blomqvist, K., et al.. Papillary deposition of fibrin in iodide reaction in dermatitis herpetiformis. Ann. Clin. Res. 2:19, 1970. 5. Fry, L., McMinn, R. M. H., Cowan, J. D., et al.. Gluten-free diet and reintroduction of gluten in dermatitis herpetiformis. Arch. Dermatol. 100:129, 1969.
September 1976
Vol. 1S
6. Fry, L., Riches, D. J., Seah, P. P., et al.. Clearance of skin lesions in dermatitis herpetiformis after gluten withdrawal. Lancet 1:228, 1973. 7. Gebhard, R. L., Katz, S. I., Marks, j . , et al., HL-A antigen type and small-intestinal disease in dermatitis herpetiformis. Lancet 1:760, 1973. 8. Goodman, L., and Gillman, A, The pharmacological Basis of Therapeutics. 4th edition. New York, MacMillan, 1970. 9. Shelley, W. B.: Consultations in Dermatology II with Walter B. Shelley. Philadelphia, W. B. Saunders, 1974. 10. Schroder, H., and Evans, D. A. P., The polymorphic acetylation of sulphapyridine in man. J. Med. Genet. 9:168, 1972. 11. Lorincz, A., and Pearson, R., Sulfapyridine and sulfone type drugs in dermatology. Arch. Dermatol. 85:2, 1962. 12. Lehr, D.: Clinical toxicity of new sulfamides. Ann. N. Y. Acad. Sci. 69:417, 1957. 13. Alexander, J. O., Treatment of dermatitis herpetiformis. Lancet 1:433, 1973. 14. Millikan, L. E., and Harrell, R., Drug reaction to the sulfones. Arch. Dermatol. 102: 220, 1970. 15. Androzzi, R. H., and Nuss, D. D., Dermatitis herpetiformis: Treatment with azulfidine. Cutis 13:366, 1974. 16. Catalano, P. M., Dapsone agranulocytosis. Arch. Dermatol. 104:675, 1971. 17. Obnibene, A. J., Agranulocytosis due to dapsone. Ann. Intern. Med. 72:521, 1970. 18. Alexander, J. O., An unusual complication associated with dapsone therapy of dermatitis herpetiformis. Scot. Med. J. 3:212, 1958. 19. Mayer, K., and Ley, A. B., Hemolysis of red cells due to sulfone. Ann. Intern. Med. 72: 711, 1970. 20. Hutchison, H. E., Jackson, J. M., and Cassidy, P., Drug induced hemolytic anemia in dermatitis herpetiformis: Importance of Heinz bodies in its recognition. Br. |. Dermatol. 75: 161, 1963. 21. Saqueton, A. C, Lorincz, A.L., Vick, N. A., et al., Dapsone and peripheral motor neuropathy. Arch. Dermatol. 100:214, 1969. 22. Hubler, W. R., and Solomon, H., Neurotoxicity of sulfones. Arch. Dermatol. 106:598, 1972. 23. Goodwin, C. S., and Sparell, G., Inhibition of dapsone excretion by probenecid. Lancet 2:884, 1969. 24. Graham, W. R., Jr., Adverse effects of dapsone. Int. J. Dermatol. 14:494, 1975.
