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The Cutting Edge |

Recurrent Erythema Multiforme/Stevens-Johnson Syndrome:  Response to Mycophenolate Mofetil FREE

Mark D. P. Davis, MD; Roy S. Rogers III, MD; Mark R. Pittelkow, MD
[+] Author Affiliations

Section Editor: George J. Hruza, MD
Assistant Section Editor: Deeanna Glaser, MD
Assistant Section Editor: Elaine Siegfried, MD

More Author Information
Arch Dermatol. 2002;138(12):1547-1550. doi:10.1001/archderm.138.12.1547.
Text Size: A A A
Published online

A 26-year-old previously healthy man presented with a 1-month history of progressive mouth sores, eye discomfort, and skin rash. Over the 2 weeks before presentation, he had lost more than 10 kg (22 lb) because of 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 oral mucosa was ulcerated. Bilateral conjunctival hyperemia and targetoid skin macules involving his elbows, palms, upper thighs, and genitalia were observed (Figure 1). Results of 3 separate biopsies of the skin and mucosa were consistent with the clinical impression of erythema multiforme, showing scattered necrotic keratinocytes, basal cell liquefaction, subepidermal and intraepidermal edema, and a chronic inflammatory cell infiltrate (Figure 2). Three direct immunofluorescence studies showed intraepidermal cytoids and vascular staining, which were also consistent with erythema multiforme.

Place holder to copy figure label and caption
Figure 1.

Initial presentation of erythema multiforme. A, Conjunctival hyperemia; B, extensive oral ulceration; and C, targetoid skin macules.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Histological examination of skin biopsy specimen showing hydropic degeneration of the basal layer of the epidermis, scattered necrotic keratinocytes, and a dermal lymphohistiocytic infiltrate (hematoxylin-eosin, original magnification ×100 [A] and ×200 [B]).

Graphic Jump Location

The patient was admitted to the hospital for rehydration. He received oral corticosteroid therapy (prednisone, 1 mg/kg; 80 mg/d) and antiviral therapy (valacyclovir 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, his disabling mouth sores, eye discomfort, and targetoid skin lesions recurred.

The recurrence took place despite continuous antiviral therapy over this period (valacyclovir hydrochloride, 1 g twice daily, taken orally). Repeated cultures and polymerase chain reaction studies of skin and mucosa (both scrub cultures and biopsy material from a total of 17 samples submitted over this time period) were negative for virus, specifically for herpes simplex virus.

Our goal was to institute treatment with a quick-acting corticosteroid-sparing drug that would suppress the disabling mouth sores in this young man and permit tapering and discontinuation from the systemic corticosteroid therapy.

Treatment with mycophenolate mofetil (CellCept; Roche Pharmaceuticals, Nutley, NJ) was prescribed at a dose of 1 g twice daily. Inadvertently, the patient started with a dose of 1 g only once daily, with no effect on the skin lesions. When he began taking 1 g twice daily, his skin and mucosal lesions disappeared completely within 4 to 5 days. He decreased the dose of prednisone gradually: decreasing from 60 mg/d to 40 mg/d after 4 days, further decreasing the dose to 20 mg/d 1 week later, then to 10 mg/d for a week, and then stopping the corticosteroid therapy completely, without recurrence of symptoms.

Two months later, an attempt was made to decrease the dose of mycophenolate mofetil to 1 g once daily, but the mucosal and skin lesions reappeared within a few days. The symptoms disappeared when mycophenolate mofetil (1 g) was again administered twice daily. Three months later, a similar attempt to decrease the mycophenolate mofetil dose was made, with the same result. Treatment continued with mycophenolate mofetil and valacyclovir hydrochloride, each at 1 g twice daily, with no adverse reactions.

One year later, the mycophenolate mofetil dose was decreased to 1 g once daily for a month and then successfully stopped without recurrence of symptoms. The antiviral treatment was stopped 2 months later. After approximately 4 months, the patient again experienced conjunctival hyperemia, incapacitating oral ulcerations, and "target lesions" involving his upper extremities that increased over a 3-day period. These symptoms did not respond to oral corticosteroids in doses as high as 80 mg/d in combination with reinitiation of valacyclovir, but they did respond within 36 hours to reinstatement of mycophenolate mofetil treatment.

Six months later, the valacyclovir and the mycophenolate mofetil treatments were tapered and discontinued. Nine months later, the incapacitating oral ulcerations recurred; they responded to reinstatement of mycophenolate mofetil and valacyclovir. The patient remains on this treatment to the present.

The observed extensive mucosal (mouth, conjunctivae, genitalia) ulcerations suggested 2 possible diagnoses: erythema multiforme and Stevens-Johnson syndrome. The nosology here is controversial and confusing. It has been argued that the terms are synonymous1 and that the original description by Stevens and Johnson was consistent with erythema multiforme major. We termed this patient's condition recurrent erythema multiforme/Stevens-Johnson syndrome.

Within the clinical spectrum of erythema multiforme, 2 subgroups have been identified: recurrent erythema multiforme and persistent erythema multiforme.2,3 Recurrent erythema multiforme is characterized by multiple interrupted episodes (as were observed in the patient described herein), whereas persistent erythema multiforme is a rare condition in which lesions occur without interruption. There is little else to distinguish these forms of erythema multiforme from the sporadic form except that they are recurrent or persistent.

Erythema multiforme/Stevens-Johnson syndrome is difficult to treat. A critical question is whether a precipitating factor can be identified. One of the keys to management is to withdraw the offending drug or to treat the offending infection.4,5 In a case-control study, Roujeau et al6 found that the use of antibacterial sulfonamides, anticonvulsant agents, oxicam nonsteroidal anti-inflammatory drugs, allopurinol, chlormezanone, and, interestingly, corticosteroids is associated with large increases in the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.

Meticulous skin care, fluid management, nutritional support, and surveillance for and aggressive treatment of infection are essential. In the patient presented, the results of viral studies were repeatedly negative, and antiviral treatment did not suppress the disease. Nonsteroidal anti-inflammatory drugs (taken for a headache) were thought to be possible culprits. However, the symptoms persisted despite rigorous avoidance of these drugs.

The value of systemic corticosteroids in the treatment of erythema multiforme is hotly debated. Some relief of systemic symptoms is achieved,7 but there is as yet no convincing evidence that use of corticosteroids improves overall mortality or long-term morbidity. Nevertheless, prednisone is often given for severe symptoms, in adults at a dose of 30 to 60 mg/d. The role of antiviral therapy for erythema multiforme is also debated, with some authors suggesting that long-term prophylactic antiviral treatment is both helpful and justifiable.812 Control of recurrent erythema multiforme with thalidomide has been reported.13 There have also been case reports of successful treatment with dapsone,14 therapeutic plasmapheresis,15 interferon alfa,16 and the addition of intravenous immunoglobulin to corticosteroid therapy.17 In a pilot study for toxic epidermal necrolysis, 10 consecutive individuals with clinically and histologically confirmed toxic epidermal necrolysis were treated with intravenous immunoglobulin; disease progression was rapidly reversed, and the outcome was favorable in all cases.18

Although further studies are needed to delineate its role, our experience suggests that mycophenolate mofetil might also be considered as a treatment for persistent erythema multiforme. Mycophenolate mofetil is a morpholine ester of mycophenolic acid, which was shown in the 1970s to be effective in patients with severe psoriasis. Mycophenolate mofetil has increased bioavailability compared with mycophenolic acid and therefore an improved therapeutic window. The drug reversibly and noncompetitively blocks the de novo synthesis of guanine nucleotides required for DNA and RNA synthesis during T- and B-cell proliferation. Because mycophenolate mofetil inhibits the de novo pathway of purine synthesis that is used by lymphocytes, it seems to be more specific for B and T lymphocytes than azathioprine.

Although approved by the US Food and Drug Administration for the prevention of renal allograft rejection only, according to growing evidence mycophenolate mofetil may be useful in the management of lymphocyte-mediated skin diseases. It has been used for the management of chronic graft-vs-host disease,19 chronic plaque-type psoriasis,20 therapy-resistant pyoderma gangrenosum,21 autoimmune skin disorders such as paraneoplastic pemphigus,22 pemphigus vulgaris,23 pemphigus foliaceus,23 cutaneous Crohn disease,23 and bullous pemphigoid.23

The most common reported adverse effect of mycophenolate mofetil therapy is gastrointestinal disturbance with subsequent reversible, dose-related hematologic effects. A slightly increased incidence in viral and bacterial infections during mycophenolate mofetil therapy has also been reported. Because there may be an increased risk of lymphoma in the long term, the patient's condition should be monitored carefully. The drug does not produce clinically significant nephrotoxicity or liver damage; therefore, it may be of value for patients who cannot take cyclosporine or methotrexate because of kidney or liver dysfunction.

Mycophenolate mofetil is an effective and relatively safe immunosuppressive agent for treatment of autoimmune and inflammatory skin diseases and may be an alternative for corticosteroid-dependent patients with recurrent or persistent erythema multiforme/Stevens-Johnson syndrome.

Accepted for publication November 27, 2001.

Corresponding author: Mark D. P. Davis, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Huff  JCWeston  WLTonnesen  MG Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8763- 775
Link to Article
Leigh  IMMowbray  JFLevene  GMSutherland  S Recurrent and continuous erythema multiforme—a clinical and immunological study. Clin Exp Dermatol. 1985;1058- 67
Link to Article
Drago  FParodi  ARebora  A Persistent erythema multiforme: report of two new cases and review of literature. J Am Acad Dermatol. 1995;33366- 369
Link to Article
Stern  RS Improving the outcome of patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol. 2000;136410- 411
Garcia-Doval  ILeCleach  LBocquet  HOtero  XLRoujeau  JC Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136323- 327
Link to Article
Roujeau  J-CKelly  JPNaldi  L  et al.  Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;3331600- 1607
Link to Article
Martinez  AEAtherton  DJ High-dose systemic corticosteroids can arrest recurrences of severe mucocutaneous erythema multiforme. Pediatr Dermatol. 2000;1787- 90
Link to Article
Juel-Jensen  BE Treatment of erythema multiforme secondary to herpes simplex by prophylactic topical acyclovir. Br Med J (Clin Res Ed). 1981;2831544
Link to Article
Cheriyan  SPatterson  R Recurrent Stevens-Johnson syndrome secondary to herpes simplex: a follow up on a successful management program. Allergy Asthma Proc. 1996;1771- 73
Link to Article
Dumas  VThieulent  NSouillet  ALJullien  DFaure  MClaudy  A Recurrent erythema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Dermatol. 2000;1421248- 1249
Link to Article
Cohen  PR Herpes simplex virus-induced recurrent erythema multiforme. J Gt Houst Dent Soc. 1995;6617- 18
Kerob  DAssier-Bonnet  HEsnault-Gelly  PBlanc  FSaiag  P Recurrent erythema multiforme unresponsive to acyclovir prophylaxis and responsive to valacyclovir continuous therapy. Arch Dermatol. 1998;134876- 877
Link to Article
Cherouati  KClaudy  ASouteyrand  P  et al.  Treatment by thalidomide of chronic multiforme erythema: its recurrent and continuous variants: a retrospective study of 26 patients [in French]. Ann Dermatol Venereol. 1996;123375- 377
Mahendran  RGrant  JWNorris  PG Dapsone-responsive persistent erythema multiforme. Dermatology. 2000;200281- 282
Link to Article
Matsumoto  YNaniwa  DBanno  SSugiura  Y The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apher. 1998;2300- 304
Link to Article
Berard  FPincemaille  BCharhon  APerrot  H Persistent erythema multiforme associated with chronic hepatitis C virus infection: efficacy of interferon alpha [in French]. Ann Dermatol Venereol. 1997;124329- 331
Straussberg  RHarel  LBen-Amitai  DCohen  DAmir  J Carbamazepine-induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr Neurol. 2000;22231- 233
Link to Article
Viard  IWehrli  PBullani  R  et al.  Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282490- 493
Link to Article
Busca  ASaroglia  EMLanino  E  et al.  Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation. Bone Marrow Transplant. 2000;251067- 1071
Link to Article
Grundmann-Kollmann  MMooser  GSchraeder  P  et al.  Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol. 2000;42835- 837
Link to Article
Michel  SHohenleutner  UMohr  VLandthaler  M Therapy-resistant pyoderma gangrenosum—treatment with mycophenolate mofetil and cyclosporine A [in German]. Hautarzt. 1999;50428- 431
Link to Article
Williams  JVMarks  JG  JrBillingsley  EM Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus. Br J Dermatol. 2000;142506- 508
Link to Article
Nousari  HCSragovich  AKimyai-Asadi  AOrlinsky  DAnhalt  GJ Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol. 1999;40265- 268
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Initial presentation of erythema multiforme. A, Conjunctival hyperemia; B, extensive oral ulceration; and C, targetoid skin macules.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Histological examination of skin biopsy specimen showing hydropic degeneration of the basal layer of the epidermis, scattered necrotic keratinocytes, and a dermal lymphohistiocytic infiltrate (hematoxylin-eosin, original magnification ×100 [A] and ×200 [B]).

Graphic Jump Location

Tables

References

Huff  JCWeston  WLTonnesen  MG Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8763- 775
Link to Article
Leigh  IMMowbray  JFLevene  GMSutherland  S Recurrent and continuous erythema multiforme—a clinical and immunological study. Clin Exp Dermatol. 1985;1058- 67
Link to Article
Drago  FParodi  ARebora  A Persistent erythema multiforme: report of two new cases and review of literature. J Am Acad Dermatol. 1995;33366- 369
Link to Article
Stern  RS Improving the outcome of patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol. 2000;136410- 411
Garcia-Doval  ILeCleach  LBocquet  HOtero  XLRoujeau  JC Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136323- 327
Link to Article
Roujeau  J-CKelly  JPNaldi  L  et al.  Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;3331600- 1607
Link to Article
Martinez  AEAtherton  DJ High-dose systemic corticosteroids can arrest recurrences of severe mucocutaneous erythema multiforme. Pediatr Dermatol. 2000;1787- 90
Link to Article
Juel-Jensen  BE Treatment of erythema multiforme secondary to herpes simplex by prophylactic topical acyclovir. Br Med J (Clin Res Ed). 1981;2831544
Link to Article
Cheriyan  SPatterson  R Recurrent Stevens-Johnson syndrome secondary to herpes simplex: a follow up on a successful management program. Allergy Asthma Proc. 1996;1771- 73
Link to Article
Dumas  VThieulent  NSouillet  ALJullien  DFaure  MClaudy  A Recurrent erythema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Dermatol. 2000;1421248- 1249
Link to Article
Cohen  PR Herpes simplex virus-induced recurrent erythema multiforme. J Gt Houst Dent Soc. 1995;6617- 18
Kerob  DAssier-Bonnet  HEsnault-Gelly  PBlanc  FSaiag  P Recurrent erythema multiforme unresponsive to acyclovir prophylaxis and responsive to valacyclovir continuous therapy. Arch Dermatol. 1998;134876- 877
Link to Article
Cherouati  KClaudy  ASouteyrand  P  et al.  Treatment by thalidomide of chronic multiforme erythema: its recurrent and continuous variants: a retrospective study of 26 patients [in French]. Ann Dermatol Venereol. 1996;123375- 377
Mahendran  RGrant  JWNorris  PG Dapsone-responsive persistent erythema multiforme. Dermatology. 2000;200281- 282
Link to Article
Matsumoto  YNaniwa  DBanno  SSugiura  Y The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apher. 1998;2300- 304
Link to Article
Berard  FPincemaille  BCharhon  APerrot  H Persistent erythema multiforme associated with chronic hepatitis C virus infection: efficacy of interferon alpha [in French]. Ann Dermatol Venereol. 1997;124329- 331
Straussberg  RHarel  LBen-Amitai  DCohen  DAmir  J Carbamazepine-induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr Neurol. 2000;22231- 233
Link to Article
Viard  IWehrli  PBullani  R  et al.  Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282490- 493
Link to Article
Busca  ASaroglia  EMLanino  E  et al.  Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation. Bone Marrow Transplant. 2000;251067- 1071
Link to Article
Grundmann-Kollmann  MMooser  GSchraeder  P  et al.  Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol. 2000;42835- 837
Link to Article
Michel  SHohenleutner  UMohr  VLandthaler  M Therapy-resistant pyoderma gangrenosum—treatment with mycophenolate mofetil and cyclosporine A [in German]. Hautarzt. 1999;50428- 431
Link to Article
Williams  JVMarks  JG  JrBillingsley  EM Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus. Br J Dermatol. 2000;142506- 508
Link to Article
Nousari  HCSragovich  AKimyai-Asadi  AOrlinsky  DAnhalt  GJ Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol. 1999;40265- 268
Link to Article

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