THE CUTTING EDGE

SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE ANNA GLASER, MD; ELAINE SIEGFRIED, MD Recurrent Multiforme/ Stevens-Johnson Syndrome Response to Mycophenolate Mofetil

Mark D. P. Davis, MD; Roy S. Rogers III, MD; Mark R. Pittelkow, MD; Department of , Mayo Clinic and Mayo Foundation, Rochester, Minn

The Cutting Edge: Challenges in Medical and Surgical Therapeutics

REPORT OF A CASE A A 26-year-old previously healthy man presented with a 1-month history of progressive mouth sores, eye dis- comfort, and skin . Over the 2 weeks before presen- tation, he had lost more than 10 kg (22 lb) because of B difficulty in swallowing fluids and food, caused by the mouth sores. He had a history of herpes gladiatorum affecting his right shoulder. On physical examination, approximately 90% of his was ulcerated. Bilateral conjunctival hyperemia and targetoid skin macules involving his elbows, palms, upper thighs, and genitalia were observed (Figure 1). Results of 3 sepa- rate biopsies of the skin and mucosa were consistent with the clinical impression of erythema multiforme, showing scattered necrotic , basal cell liq- uefaction, subepidermal and intraepidermal edema, and a chronic inflammatory cell infiltrate (Figure 2). Three direct immunofluorescence studies showed intraepider- C mal cytoids and vascular staining, which were also con- sistent with erythema multiforme. The patient was admitted to the hospital for rehy- dration. He received oral corticosteroid therapy (pred- nisone, 1 mg/kg; 80 mg/d) and antiviral therapy (vala- cyclovir hydrochloride, 1 g twice daily). His condition improved. The prednisone was then decreased to 60 mg/d, and he was discharged from the hospital. Two days later, his mucosal ulcers and skin lesions recurred. The dose of prednisone was again increased to 80 mg/d, with a rapid disappearance of his mucosal ulcers and skin lesions within 2 days. Over the following 10 months, each time the dose of oral prednisone was reduced to below 80 mg/d, Figure 1. Initial presentation of erythema multiforme. A, Conjunctival his disabling mouth sores, eye discomfort, and target- hyperemia; B, extensive oral ulceration; and C, targetoid skin macules. oid skin lesions recurred. The recurrence took place despite continuous an- tiviral therapy over this period (valacyclovir hydrochlo- THERAPEUTIC CHALLENGE ride, 1 g twice daily, taken orally). Repeated cultures and polymerase chain reaction studies of skin and mu- Our goal was to institute treatment with a quick-acting cosa (both scrub cultures and biopsy material from a corticosteroid-sparing drug that would suppress the dis- total of 17 samples submitted over this time period) abling mouth sores in this young man and permit taper- were negative for virus, specifically for ing and discontinuation from the systemic corticoster- virus. oid therapy.

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Figure 2. Histological examination of skin biopsy specimen showing hydropic degeneration of the basal layer of the , scattered necrotic keratinocytes, and a dermal lymphohistiocytic infiltrate (hematoxylin-eosin, original magnification ϫ100 [A] and ϫ200 [B]).

SOLUTION and “target lesions” involving his upper extremities that increased over a 3-day period. These symptoms did not Treatment with mycophenolate mofetil (CellCept; respond to oral corticosteroids in doses as high as 80 Roche Pharmaceuticals, Nutley, NJ) was prescribed at a mg/d in combination with reinitiation of valacyclovir, dose of 1 g twice daily. Inadvertently, the patient started but they did respond within 36 hours to reinstatement with a dose of 1 g only once daily, with no effect on the of mycophenolate mofetil treatment. skin lesions. When he began taking 1 g twice daily, his Six months later, the valacyclovir and the myco- skin and mucosal lesions disappeared completely phenolate mofetil treatments were tapered and discon- within 4 to 5 days. He decreased the dose of prednisone tinued. Nine months later, the incapacitating oral - gradually: decreasing from 60 mg/d to 40 mg/d after ations recurred; they responded to reinstatement of 4 days, further decreasing the dose to 20 mg/d 1 week mycophenolate mofetil and valacyclovir. The patient re- later, then to 10 mg/d for a week, and then stopping mains on this treatment to the present. the corticosteroid therapy completely, without recur- rence of symptoms. COMMENT Two months later, an attempt was made to de- crease the dose of mycophenolate mofetil to 1 g once daily, The observed extensive mucosal (mouth, conjunctivae, but the mucosal and skin lesions reappeared within a few genitalia) ulcerations suggested 2 possible diagnoses: ery- days. The symptoms disappeared when mycophenolate thema multiforme and Stevens-Johnson syndrome. The mofetil (1 g) was again administered twice daily. Three nosology here is controversial and confusing. It has been months later, a similar attempt to decrease the myco- argued that the terms are synonymous1 and that the origi- phenolate mofetil dose was made, with the same result. nal description by Stevens and Johnson was consistent Treatment continued with mycophenolate mofetil and with erythema multiforme major. We termed this pa- valacyclovir hydrochloride, each at 1 g twice daily, with tient’s condition recurrent erythema multiforme/Stevens- no adverse reactions. Johnson syndrome. One year later, the mycophenolate mofetil dose was Within the clinical spectrum of erythema multi- decreased to 1 g once daily for a month and then suc- forme, 2 subgroups have been identified: recurrent cessfully stopped without recurrence of symptoms. The erythema multiforme and persistent erythema multi- antiviral treatment was stopped 2 months later. After forme.2,3 Recurrent erythema multiforme is character- approximately 4 months, the patient again experienced ized by multiple interrupted episodes (as were observed conjunctival hyperemia, incapacitating oral ulcerations, in the patient described herein), whereas persistent

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 erythema multiforme is a rare condition in which Although approved by the US Food and Drug lesions occur without interruption. There is little else to Administration for the prevention of renal allograft distinguish these forms of erythema multiforme from rejection only, according to growing evidence myco- the sporadic form except that they are recurrent or phenolate mofetil may be useful in the management of persistent. lymphocyte-mediated skin diseases. It has been used for Erythema multiforme/Stevens-Johnson syndrome is the management of chronic graft-vs-host disease,19 difficult to treat. A critical question is whether a precipi- chronic plaque-type ,20 therapy-resistant pyo- tating factor can be identified. One of the keys to man- derma gangrenosum,21 autoimmune skin disorders such agement is to withdraw the offending drug or to treat as paraneoplastic ,22 ,23 the offending infection.4,5 In a case-control study, Rou- pemphigus foliaceus,23 cutaneous Crohn disease,23 and jeau et al6 found that the use of antibacterial sulfon- .23 amides, anticonvulsant agents, oxicam nonsteroidal The most common reported adverse effect of my- anti-inflammatory drugs, , chlormezanone, cophenolate mofetil therapy is gastrointestinal distur- and, interestingly, corticosteroids is associated with large bance with subsequent reversible, dose-related hemato- increases in the risk of Stevens-Johnson syndrome or logic effects. A slightly increased incidence in viral and toxic epidermal necrolysis. bacterial infections during mycophenolate mofetil therapy Meticulous skin care, fluid management, nutri- has also been reported. Because there may be an in- tional support, and surveillance for and aggressive treat- creased risk of lymphoma in the long term, the patient’s ment of infection are essential. In the patient presented, condition should be monitored carefully. The drug does the results of viral studies were repeatedly negative, and not produce clinically significant nephrotoxicity or liver antiviral treatment did not suppress the disease. Non- damage; therefore, it may be of value for patients who steroidal anti-inflammatory drugs (taken for a head- cannot take cyclosporine or methotrexate because of kid- ache) were thought to be possible culprits. However, the ney or liver dysfunction. symptoms persisted despite rigorous avoidance of these Mycophenolate mofetil is an effective and rela- drugs. tively safe immunosuppressive agent for treatment of au- The value of systemic corticosteroids in the treat- toimmune and inflammatory skin diseases and may be ment of erythema multiforme is hotly debated. Some an alternative for corticosteroid-dependent patients with relief of systemic symptoms is achieved,7 but there is recurrent or persistent erythema multiforme/Stevens- as yet no convincing evidence that use of corticoste- Johnson syndrome. roids improves overall mortality or long-term morbid- ity. Nevertheless, prednisone is often given for severe Accepted for publication November 27, 2001. symptoms, in adults at a dose of 30 to 60 mg/d. The Corresponding author: Mark D. P. Davis, MD, De- role of antiviral therapy for erythema multiforme is partment of Dermatology, Mayo Clinic, 200 First St SW, also debated, with some authors suggesting that long- Rochester, MN 55905. term prophylactic antiviral treatment is both helpful and justifiable.8-12 Control of recurrent erythema mul- tiforme with thalidomide has been reported.13 There REFERENCES have also been case reports of successful treatment with dapsone,14 therapeutic plasmapheresis,15 inter- 1. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of feron alfa,16 and the addition of intravenous immuno- characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8: globulin to corticosteroid therapy.17 In a pilot study 763-775. 2. Leigh IM, Mowbray JF, Levene GM, Sutherland S. Recurrent and continuous ery- for toxic epidermal necrolysis, 10 consecutive indi- thema multiforme—a clinical and immunological study. Clin Exp Dermatol. viduals with clinically and histologically confirmed 1985;10:58-67. toxic epidermal necrolysis were treated with intrave- 3. Drago F, Parodi A, Rebora A. Persistent erythema multiforme: report of two new nous immunoglobulin; disease progression was rap- cases and review of literature. J Am Acad Dermatol. 1995;33:366-369. 4. Stern RS. Improving the outcome of patients with toxic epidermal necrolysis idly reversed, and the outcome was favorable in all and Stevens-Johnson syndrome. Arch Dermatol. 2000;136:410-411. 18 cases. 5. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal Although further studies are needed to delineate its necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative role, our experience suggests that mycophenolate mofetil drugs decrease the risk of death? Arch Dermatol. 2000;136:323-327. might also be considered as a treatment for persistent ery- 6. Roujeau J-C, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens- Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:1600- thema multiforme. Mycophenolate mofetil is a morpho- 1607. line ester of mycophenolic acid, which was shown in the 7. Martinez AE, Atherton DJ. High-dose systemic corticosteroids can arrest recur- 1970s to be effective in patients with severe psoriasis. My- rences of severe mucocutaneous erythema multiforme. Pediatr Dermatol. 2000; cophenolate mofetil has increased bioavailability com- 17:87-90. 8. Juel-Jensen BE. Treatment of erythema multiforme secondary to herpes sim- pared with mycophenolic acid and therefore an im- plex by prophylactic topical acyclovir. BMJ. 1981;283:1544. proved therapeutic window. The drug reversibly and 9. Cheriyan S, Patterson R. Recurrent Stevens-Johnson syndrome secondary to noncompetitively blocks the de novo synthesis of gua- herpes simplex: a follow up on a successful management program. Allergy Asthma nine nucleotides required for DNA and RNA synthesis Proc. 1996;17:71-73. during T- and B-cell proliferation. Because mycopheno- 10. Dumas V, Thieulent N, Souillet AL, Jullien D, Faure M, Claudy A. Recurrent ery- thema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Der- late mofetil inhibits the de novo pathway of purine syn- matol. 2000;142:1248-1249. thesis that is used by lymphocytes, it seems to be more 11. Cohen PR. Herpes simplex virus-induced recurrent erythema multiforme. JGt specific for B and T lymphocytes than azathioprine. Houst Dent Soc. 1995;66:17-18.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 12. Kerob D, Assier-Bonnet H, Esnault-Gelly P, Blanc F, Saiag P. Recurrent ery- 22. Williams JV, Marks JG Jr, Billingsley EM. Use of mycophenolate mofetil in thema multiforme unresponsive to acyclovir prophylaxis and responsive to vala- the treatment of paraneoplastic pemphigus. Br J Dermatol. 2000;142:506- cyclovir continuous therapy. Arch Dermatol. 1998;134:876-877. 508. 13. Cherouati K, Claudy A, Souteyrand P, et al. Treatment by thalidomide of chronic 23. Nousari HC, Sragovich A, Kimyai-Asadi A, Orlinsky D, Anhalt GJ. Mycopheno- multiforme erythema: its recurrent and continuous variants: a retrospective study late mofetil in autoimmune and inflammatory skin disorders. J Am Acad Der- of 26 patients [in French]. Ann Dermatol Venereol. 1996;123:375-377. matol. 1999;40:265-268. 14. Mahendran R, Grant JW, Norris PG. Dapsone-responsive persistent erythema multiforme. Dermatology. 2000;200:281-282. 15. Matsumoto Y, Naniwa D, Banno S, Sugiura Y. The efficacy of therapeutic plas- Submissions mapheresis for the treatment of fatal hemophagocytic syndrome: two case re- ports. Ther Apher. 1998;2:300-304. 16. Berard F, Pincemaille B, Charhon A, Perrot H. Persistent erythema multiforme Clinicians, local and regional societies, residents, and fel- associated with chronic hepatitis C virus infection: efficacy of interferon alpha lows are invited to submit cases of challenges in man- [in French]. Ann Dermatol Venereol. 1997;124:329-331. agement and therapeutics to this section. Cases should 17. Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir J. Carbamazepine- follow the established pattern. Submit 4 double-spaced induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr copies of the manuscript with right margins nonjusti- Neurol. 2000;22:231-233. fied and 4 sets of the illustrations. Photomicrographs and 18. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by block- illustrations must be clear and submitted as positive color ade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490- transparencies (35-mm slides) or black-and-white prints. 493. 19. Busca A, Saroglia EM, Lanino E, et al. Mycophenolate mofetil (MMF) as therapy Do not submit color prints unless accompanied by origi- for refractory chronic GVHD (cGVHD) in children receiving bone marrow trans- nal transparencies. Material should be accompanied by plantation. Bone Marrow Transplant. 2000;25:1067-1071. the required copyright transfer statement, as noted in “In- 20. Grundmann-Kollmann M, Mooser G, Schraeder P, et al. Treatment of chronic structions for Authors.” Material for this section should plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. JAm be submitted to George J. Hruza, MD, Laser and Der- Acad Dermatol. 2000;42:835-837. matologic Surgery Center Inc, 14377 Woodlake Dr, Suite 21. Michel S, Hohenleutner U, Mohr V, Landthaler M. Therapy-resistant pyoderma 111, St Louis, MO 63017. gangrenosum—treatment with mycophenolate mofetil and cyclosporine A [in German]. Hautarzt. 1999;50:428-431.

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ongratulations to the winner of our September quiz, Parima Laohadtanaphorn, MD, Boston University Medical Cen- C ter, Allston, Mass. The correct answer to our September challenge was unilateral laterothoracic (also known as asymmetric periflexural exanthem of childhood). For a complete discussion of this case, see the Off-Center Fold section in the October ARCHIVES (Jhin MH, Eidelman M, Cohen SR, Husain S. Unilateral eruption in a child. Arch Dermatol. 2002;138:1371-1376). Be sure to visit the Archives of Dermatology World Wide Web site (http://www.archdermatol.com) to try your hand at the Interactive Quiz. We invite visitors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the ARCHIVES. The first visitor to e-mail our Web editors with the correct answer will be recognized in the print journal and on our Web site and will also receive a free copy of the The Art of JAMA II.

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