Epidermolysis Bullosa

Eisenberg, Stevens and Schofield, Australian Journal of Dermatology (1978),1817 studied the effects of PHT on the collagenolytic system in tissue samples from patients with dystrophic epidermolysis bullosa. The collagenolytic system is known to be excessive in this disorder. PHT was found to inhibit the excessive activity.

As a result of these findings, two children with dystrophic epidermolysis bullosa were given PHT. Marked improvement in skin fragility resulted. The authors concluded that the clinical effects of PHT on both blister formation and collagenase activity are consistent with the protective effect observed in vitro and suggested that PHT is useful in the management of this disease.

1817. Eisenberg, M., Stevens, L. H. and Schofield, P. J., Epidermolysis bullosa-new therapeutic approaches, Aust. J. Derm., 19: 1-8, 1978.

Bauer, Cooper, Tucker and Esterly, The New England Journal of Medicine (1980),1738 citing the work of Eisenberg, Stevens and Schofield,1817 studied the effect of PHT on the collagenolytic system in vitro, and clinically in seventeen patients with recessive dystrophic epidermolysis bullosa. With PHT there was a significant decrease in blistering in all patients. In twelve patients the reduction was from 46% to 90%. The clinical study was controlled in that all patients underwent a period without PHT during which they experienced a notable exacerbation in blistering. The authors state that the correlation of the clinical responsiveness and in vitro inhibition of collagenase indicates that PHT represents a therapeutic option of relatively low risk in a disease for which there has been no rational method of therapy.

1738. Bauer, E. A., Cooper, T. W., Tucker, D. R. and Esterly, N. B., Phenytoin therapy of recessive dystrophic epidermolysis bullosa: clinical trial and proposed mechanism of action on collagenase, New Eng. J. Med., 303(14): 776-81, 1980.
1817. Eisenberg, M., Stevens, L. H. and Schofield, P. J., Epidermolysis bullosa-new therapeutic approaches, Aust. J. Derm., 19: 1-8, 1978.

Bauer and Cooper, Archives of Dermatology (1981),2153 reported an extended study (76 to 99 weeks) of nine patients with moderate or severe recessive dystrophic epidermolysis bullosa. In seven of the nine patients, the decrease in blisters and erosion with PHT was 70%. In the other two patients, blistering decreased 24% to 40%. (See also Refs. 2176, 2188, 2247.)

2153. Bauer, E.A. and Cooper, T.W., Therapeutic considerations in recessive dystrophic epidermolysis bullosa, Arch. Dermatol., 117: 529, 1981.
2176. Eisenberg, M., Williams, J.F., Stevens, L. and Schofield, P.J., Mammalian collagenase and peptidase estimation in normal skin and in the skin of patients suffering from epidermolysis bullosa, IRCS, 2: 1732, 1974.
2188. Epilepsy drug decreases blistering due to a genetic disease, NIH Research Resources Reporter, V(l 2): 1981.
2247. Reinckens, W., New drug treatment reported for rare, blistering skin disease, NIH News & Features, March, 1981.

Bandmann and Perwein, Zeitschrift fur Hautkrankheiten (1982),2306 in a detailed case report, describe a patient with the rare Gedde-Dahl type of epidermolysis bullosa, with severe blistering, erosions, and dysphagia due to esophageal stenosis. With PHT, fewer blisters developed, and blisters and erosions already present healed more quickly. (See also Ref. 2863.)

2306. Bandmann, H. J., Perwein, E., Phenytoin in treatment of epidermolysis bullosa hereditaria dystrophica partim inversa (Gedde-Dahl), Z. Hautkr., 57(21): 1587-98, 1982.
2863. Perwein, E., Diphenylhydantoin therapy of a Gedde-Dahl Inverse (recessive) hereditary dystrophic bullous epidermolysis, Hautarzt., 34(4): 188, 1983.

Wirth, Nesch, Ostapowicz and Anton-Lamprecht, Zeitschrift fur Hautkrankheiten (1983),3075 state that they have used oral PHT in the treatment of eleven patients with recessive dystrophic epidermolysis bullosa (Hallopeau-Siemens and Inversa type) since 1978. The authors detail six of their cases, ages six weeks to sixty-one years. Treatment with PHT, at blood levels of 8-15 mg/ml, resulted in definite reduction in blistering and lessened skin fragility. The authors report that four of their patients had esophageal stenosis, one with complete obstruction. With PHT, improvement was such that esophageal dilation could be performed in all four.

3075. Wirth, H., Nesch, A., Ostapowicz, B., Anton-Lamprecht, I., Phenytoin therapy of recessive dystrophic epidermolysis bullosa hallopeau siemens and epidermolysis bullosa inversa, Z. Hautkr., 58(8): 555-74, 1983.

Cooper and Bauer, Archives of Dermatology (1984), 2406 studied the effects of PHT in twenty-two patients with recessive dystrophic epidermolysis bullosa. Therapeutic response was defined as mean decrease in blistering of more than 40%. The authors stated that, with this strict criterion, fourteen of the twenty-two patients had 46% or more reduction of blistering. PHT, 100-300 mg/day, was adjusted to maintain blood levels if at least 8 mg/ml. To determine if prolonged treatment altered response, nine of the patients were studied for periods longer than seventy-five weeks. Seven of these patients continued to have a mean decrease in blistering of at least 40%. The authors noted that with PHT patients had an enhanced sense of well-being.


See Refs. 2247, 2491, 2532, 2546, 2560, 2602,2617, 2643, 2658, 2793, 2818, 2876, 3009, 3087. Also, regulatory effect of PHT on collagen synthesis and breakdown, Refs. 172, 501, 502, 811, 1867, 1882, 2107, 2571, 2581.

2406. Cooper, T. W., Bauer, E. A., Therapeutic efficacy of phenytoin in recessive dystropic epidermolysis, Arch. Dermatol., 120 (4): 490-5, 1984.
2247. Reinckens, W., New drug treatment reported for rare, blistering skin disease, NIH News & Features, March, 1981.
2491. Feurle, G. E., Weidauer, H., Baldauf, G., Schulte-Braucks, T., Anton-Lamprecht, I., Management of esophageal stenosis in recessive dystrophic epidermolysis bullosa, Gastroenterology, 87: 1376-80, 1984.
2532. Gedde-Dahl, T., Sixteen types of epidermolysis bullosa: on the clinical discrimination, therapy and prenatal diagnosis, Acta Derm. Venerol., 95: 74-87, 1981.
2546. Goerz, G., Merk, H., Progress in dermatology: new biochemical aspects, Fortschr. Med., 100: 1467-71, 1982.
2560. Guill, M. F., Wray, B. B., Rogers, R. B., Yancey, K. B., Allen, B. S., Junctional epidermolysis bullosa: treatment with phenytoin, Am. J. Dis. Child., 137: 992-4, 1983.
2602. Hollander, A., What’s new in American dermatology?, Hautarzt., 130-37, 1982.
2617. Jacobs, A. H., What’s new in pediatric dermatology?, Acta Derm., 95: 91-5, 1981.
2643. Kaluza, C., Kennedy, B. J., Harman, L., Head and neck complications of epidermolysis bullosa, Laryngoscope, 95: 599-600, 1985.
2658. Kero, M., Palotie, A., Peltonen, L., Collagen metabolism in two rare forms of epidermolysis bullosa, Br. J. Dermatol., 110: 177-84, 1984.
2793. Meyer, J., Epidermolysis Bullosa - Phenytoin, Schweiz. Med. Wochensch., 111(4): 1662-3, 1981.
2818. Narr, H., New aspects in the treatment of dermatogenous contractures of the hand in epidermolysis bullosa, Handchir. Mikrochir. Plast. Chir., 16: 48-51, 1984.
2876. Pollack, S. V., Wound healing: a review - systemic medications affecting wound healing, J. Dermatol. Surg. Oncol., 8: 667-72, 1982.
3009. Tesseraud, F., Puissant, A., Epidermolysis bullosa, Rev. Prat., 33(15): 751-8, 1983.
3087. Woscoff, A., Paz, A., Abulafia, J., Jaimovich, L., Grinspan, D., Dystrophic epidermolysis bullosa. Urogenital manifestation and phenytoin treatment, Med. Cutan. lber. Lat. Am., 12(2): 129-35, 1984.
172. Houck, J. C., Jacob, R. A., and Maengwyn-Davies, G. D., The effect of sodium Dilantin administration upon the chemistry of the skin, J. Clin. Invest., 39: 1758-1762, 1960.
501. Houck, J. C., Effect of cortisol and age upon the dermal chemical response to Dilantin, J. Invest. Derm., 40: 125-126, 1963.
502. Houck, J. C. and Jacob, R. A., Connective tissue. VII. Factors inhibiting the dermal chemical response to cortisol. Proc. Soc. Exp. Biol. Med., 113: 692-694, 1963.
811. Bazin, S. and Delaunay, A., Effect of phenytoin on the maturation of collagen in normal skin and granulomatous tissue, C. R. Acad. Sci. Ser. D., 275: 509-511, 1972.
1867. Goultschin, J. and Shoshan, S., Inhibition of collagen breakdown by diphenylhydantoin, Biochim. Biophys. Acta, 631: 188-91, 1980.
1882. Hanstom, L. and Jones, I. L., The effect of diphenylhydantoin upon degradation of sulphated macromolecules in cat palatal mucosa in vitro, Med. Biol., 57: 177-81, 1979.
2107. Vernillo, A. T. and Schwartz, N. B., Collagen and proteoglycan synthesis in 5,5 diphenylhydantoin (Dilantin) treated chondrocytes, J. Cell. Biol., 83(pt. 2): 116a, 1979.
2571. Hanstrom, L., The effect of diphenylhydantoin on the metabolism of connective tissue macromolecules in oral mucosa and bone in vitro, University of UMEA, Dissertation, 1981.
2581. Hassell, T. M., Evidence for production of an inactive collagenase by fibroblasts from phenytoin-enlarged human gingivae, J. Oral Pathol., 11: 310-17, 1982.

Cunnane, Kent, McAdoo, Caldwell, Lin and Carter, Journal of Investigative Dermatology (1987), 3331 reported that their epidermolysis bullosa patients treated with phenytoin had lower levels of arachidonic acid in plasma and erythrocyte phospholipids than did untreated EB patients. The authors cite that phenytoin has been used with some success in treating recessive dystrophic epidermolysis bullosa. According to the authors, their results suggest that the beneficial effects of PHT may occur in part by decreasing blood levels of arachidonic acid.

3331. Cunnane, S.C., Kent, E.T., McAdoo, K.R., Caldwell, D., Lin, A.N., and Carter, D.M., Abnormalities of plasma and erythrocyte essential fatty acid composition in epidermolysis bullosa: Influence of treatment with diphenylhydantoin, J. Invest. Dermatol., 89: 395-9, 1987.

Fine and Johnson, Archives of Dermatology (1988), 3332 treated four children (two with generalized atrophic benign epidermolysis bullosa [GABEB] and two with Herlitz disease) with two 16-20-week treatment periods with phenytoin separated by an 8-12-week drug-free period. Oral dosages of phenytoin were adjusted to achieve a blood level of 8 mg/l. No other medications were used. Each patient was assessed before PHT therapy and at 2-4-week intervals during treatment. Serial counts were made of lesions (blisters, crusts and erosions) and surface areas of granulation tissue, when present, were also serially measured. Changes in the percentage of surface area involved with scarring, as well as changes in extracutaneous disease activity, were similarly assessed.

Both patients with GABEB showed excellent responses during each course of phenytoin, with average reductions in lesion counts of 70% and 38%. The healing times also appeared to be reduced. During the "wash-out" period, total lesional counts returned toward pretreatment levels. PHT did not appear to benefit the two patients with the Herlitz form of EB. Both GABEB patients received PHT for an additional two years with continued excellent response.

3332. Fine, J.D. and Johnson, L., Efficacy of systemic phenytoin in the treatment of junctional epidermolysis bullosa, Arch. Dermatol., 124: 1402-6, 1988.

Pappu-Katikaneni and Wiest, Pediatric Research (1988), 3333 report the phenytoin dosing requirements for a patient having junctional epidermolysis bullosa. A decrease in blister formation was observed when the patient received 39 mg/kg/day of phenytoin. The authors suggest that the loss of drug in blister fluid represents an extra pathway of PHT elimination and could account for the excessive dosage requirements in this patient.

3333. Pappu-Katikaneni, L.D. and Wiest, D.B., Phenytoin (PHT) dosing requirements and blister fluid concentrations (BFC) in a junctional epidermolysis bullosa (JEB) patient, Pediatr. Res., 23(4):262A, 1988.

Lin, Stern, Caldwell-Brown and Carter, Clinical Research (1989), 3334 report the results of the oral phenytoin treatment of twenty-six patients with recessive dystrophic epidermolysis bullosa. Patients received either phenytoin or placebo for five to seven months. After a 2-month washout period, the patients who received phenytoin were switched to placebo, and vice versa, for an additional five to seven months. Blood phenytoin levels were monitored in an attempt to maintain levels of 8 µg/ml. The phenytoin-treated patients showed improvement in the size of involved sites, number of blisters and erosions, although the difference was indicative of a trend rather than statistical significance.

3334. Lin, A.N., Stern, R.S., Caldwell-Brown, D., and Carter, D.M., Phenytoin for recessive dystrophic epidermolysis bullosa, Clin. Res., 37(2): 625A, 1989.

Caldwell-Brown, Stern, Lin and Carter, New England Journal of Medicine (1992), 3335 continued their evaluation of phenytoin's therapeutic effectiveness in thirty-six patients with recessive dystrophic epidermolysis bullosa in a randomized, double-blind, placebo-controlled, crossover trial. Each treatment was given for five to seven months separated by a two-month period. The total number of blisters, and erosions on the entire body, the size of three plaques containing blisters and erosions, and the number of blisters and erosions in three plaques at the beginning and end of each treatment period were measured in each patient.

Twenty-two patients completed both courses of therapy; seven patients completed one course; and seven patients withdrew before completing a single course. The number of blisters and erosions on the entire body showed a 7% decrease with phenytoin and a 6% increase with placebo. The area of the three designated plaques decreased by 0.4% with phenytoin and increased by 0.2% with placebo. The number of blisters and erosions in the designated plaques decreased by 12% with phenytoin and increased by 31% with placebo. Although a trend favoring the use of phenytoin was evident, it was not statistically significant and the authors concluded that phenytoin is not effective in patients with recessive dystrophic epidermolysis bullosa. The authors caution that their study does not indicate whether or not phenytoin may be effective in some subsets of this disease.

3335. Caldwell-Brown, D., Stern, R.S., Lin, A.N., and Carter, D.M., Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa, N. Engl. J. Med., 327(3): 163-167, 1992.

Masgrau-Peya, Lacour and Saloman, Dermatology (1995), 3336 evaluated 8 patients (2 males, 6 females) aged 1 through 40 years suffering from local epidermolysis bullosa simplex (EBS). During a period of 6 - 36 months, a phenytoin cream was applied topically twice daily at the sites of bulla formation (hands and feet). While in all cases, there was an increase in the rate of wound healing, it was faster in 3 of the 8 patients. For one 2-year-old girl who was unable to walk due to severe EBS, the application of PHT overnight led to marked improvement and allowed physical activity. There was no PHT detected in two patients whose plasma levels were measured. The authors conclude that their open trial of topical PHT showed that patients with a mild form of EBS had a quicker rate of healing of their lesions and felt improved over a long period of time. They note that phenytoin is inexpensive and suggest further controlled trials.

3336. Masgrau-Peya, E., Lacour, M., and Salomon, D., Topical phenytoin accelerates healing in epidermolysis bullosa simplex, Dermatology, 190(3):254, 1995.

Fine, International Journal of Dermatology (1986), 3337 reports on various clinical aspects, pathology and recent advances in epidermolysis bullosa (EB) research and highlights PHT as a notable form of topical therapy for some cases of EB. In a study of seventeen patients with recessive dystrophic EB where patients were treated with oral PHT, twelve patients were shown to have at least a 45% reduction in blistering and a correlation between reduction of blistering and higher PHT levels was noted. It was suggested that PHT is beneficial in patients with recessive dystrophic EB due to its effects on collagenase synthesis.

3337. Fine, J.D., Epidermolysis bullosa, clinical aspects, pathology, and recent advances in research, Int. J. Dermatol., 25: 143-57, 1986.

Nawaz, Matta, Jacobsz and Al-Salem, Pediatric Surgery International (2000), 3338 report on the use of phenytoin in a six-day-old full-term female newborn with both junctional epidermolysis bullosa (EB) and congenital pyloric atresia (CPA). Surgical correction of the pyloric atresia was performed successfully, and with phenytoin treatment, the patient's skin condition showed immediate signs of improvement. She was discharged from the hospital at age 35 days.

3338. Nawaz, A., Matta, H., Jacobsz, A., and Al-Salem, A., Congenital pyloric atresia and junctional epidermolysis bullosa: a report of two cases, Pediatr. Surg. Int., 16(3):206-8, 2000.

See also Refs.

3339. Fine, J.D. and Johnson, L., Efficacy of systemic phenytoin in the treatment of junctional epidermolysis bullosa (JEB), J. Clin. Pharmacol., 27(9): 723, 1987.

3340. Pearson, R.W. and Paller, A.S., Dermolytic (dystrophic) epidermolysis bullosa inverse, Arch. Dermatol., 124: 544-7, 1988.

3341. Kern, I.B., Eisenberg, M., and Willis, S., Management of oesophageal stenosis in epidermolysis bullosa dystrophica, Arch. Dis. Child., 64: 551-6, 1989.

3342. Popov, N., Contemporary problems in epidermolysis bullosa in view of four cases under observation, Pediatriya (Sofia), 27(4): 64-72, 1988.

3343. Talas, G., Adams, T.S.T., Eastwood, M., Rubio, G., and Brown, R.A., Phenytoin reduces the contraction of recessive dystrophic epidermolysis bullosa fibroblast populated collagen gels, Int. J. Biochem. Cell Biol., 29(1):261-270, 1997.

See Also: Basic Section