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Improvement of Pyoderma Gangrenosum and Psoriasis Associated With Crohn Disease With Anti–Tumor Necrosis Factor Monoclonal Antibody

Mei-Heng Tan, MD; Marsha Gordon, MD; Oscar Lebwohl, MD; James George, MD; Mark G. Lebwohl, MD

Arch Dermatol. 2001;137:930-933.

ABSTRACT
Background  Infliximab is an anti–tumor necrosis factor monoclonal antibody IgG effective in the treatment and maintenance of remission of active refractory Crohn disease and associated draining enterocutaneous fistulae. Multiple infusions of infliximab show promising results in patients with rheumatoid arthritis. Currently, there is limited clinical experience with infliximab, and no published reports exist on its use in cutaneous disorders.

Observations  We describe 2 patients with Crohn disease and pyoderma gangrenosum and 1 patient with Crohn disease and psoriasis who were treated with infliximab for recalcitrant Crohn fistulae, with concurrent improvement in their skin diseases.

Conclusions  These cases suggest that infliximab, a promising therapeutic agent for refractory Crohn disease and fistulae, may also be effective in the treatment of pyoderma gangrenosum and psoriasis associated with Crohn disease.

INTRODUCTION

Jump to Section  • Top  • Introduction  • Report of cases  • Comment  • Author information  • References

INFLIXIMAB (Remicade; Centocor, Inc, Malvern, Pa) is a novel chimeric anti–tumor necrosis factor (anti–TNF-) monoclonal antibody composed of constant regions of the human IgG1 spliced to the murine variable antigen-binding region of a high-affinity human anti–TNF- antibody. Infliximab binds specifically, with high affinity to soluble and transmembrane forms of TNF-, neutralizing its effects in vivo.¹ It has been approved recently for human use by the Food and Drug Administration and is effective in the treatment and remission of moderate to severely active refractory Crohn intestinal disease^2-3 and associated fistulae.⁴ Multiple infusions have shown promising results in patients with rheumatoid arthritis.^5-6

Tumor necrosis factor is a proinflammatory cytokine that has multiple biological activities, including the recruitment of inflammatory cells to local tissue sites of inflammation. Patients with Crohn disease have increased levels of TNF-, TNF-–producing lamina propria cells,^7-8 and soluble TNF receptors.⁹ Treatment with infliximab decreases TNF- levels in inflamed areas of the intestine, decreases the infiltration by inflammatory cells, and lowers interleukin 6 (IL-6) and C-reactive protein concentrations, resulting in a rapid reduction in mucosal inflammation.¹⁰

Pyoderma gangrenosum is a destructive inflammatory skin disease frequently associated with Crohn disease. Disturbances of immunoregulation and immunologic effector functions are involved in some patients with pyoderma gangrenosum; however, no consistent pattern of disturbed cellular immune response has emerged.¹¹ Treatment with steroids and immunosuppressive agents is fraught with potential adverse effects and not always successful.

Psoriasis is an inflammatory disease of the skin. Proliferation of keratinocytes is dramatically increased, and the transit time of basal cells to the stratum corneum is reduced from 28 days in normal epidermis to 2 to 4 days in lesional plaques.¹² Recently, therapy for psoriasis has begun to focus on a number of immunomodulatory agents.

Currently, there is limited clinical experience with infliximab, and to our knowledge, no published reports exist on its use in cutaneous disorders. We describe 2 patients with Crohn disease and pyoderma gangrenosum and 1 patient with Crohn disease and psoriasis who were treated with infliximab.

REPORT OF CASES

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CASE 1

A 39-year-old man with Crohn disease diagnosed in 1978 had a subtotal colectomy in July 1979 and developed painful inflammatory skin lesions within 2 months and fistulae 2 years later. In addition to sulfasalazine and prednisone for treatment of Crohn disease, he received mercaptopurine, tacrolimus, cyclosporine, metronidazole, total parenteral nutrition, and intralesional triamcinolone acetonide for pyoderma gangrenosum. Thalidomide, although of some benefit, was discontinued secondary to sensorimotor neuropathy. Treatment with mycophenolate mofetil was ineffective. Physical examination revealed pustules and widespread ulcerations with violaceous undermined borders and purulence on the upper and lower extremities, chest, and back (Figure 1). Cribriform scars were present. He received 5 infliximab infusions for recalcitrant rectal fistulae at 5 mg/kg over a 1-year period. His pyoderma gangrenosum and fistulae improved dramatically (Figure 2). Decreased pain, erythema, and swelling occurred within the first 12 to 24 hours of each infusion. Complete resolution of most ulcers occurred 1 week after the first infusion. Additional improvement was noted 1 week after each subsequent infusion. Improvement in the Crohn fistulae lasted 2 months, and in the pyoderma gangrenosum for 6 months after the third infusion, after which infliximab therapy was reinstated.

View larger version (37K): [in this window] [in a new window] Figure 1. Forearm pyoderma gangrenosum before treatment.

View larger version (36K): [in this window] [in a new window] Figure 2. Resolving pyoderma gangrenosum after 5 infliximab infusions.

CASE 2

A 50-year-old woman with Crohn disease diagnosed in 1983 was treated with multiple ileocolic resections with ileostomy. Pyoderma gangrenosum and fistulae had been present in the perianal region, abdomen, and legs for 5 years. There were multiple coalescing ulcers in the perianal area, left groin, lower abdomen below the stoma, and left lower leg. Previous treatment included intralesional triamcinolone acetonide, clobetasol propionate ointment, and various dressings. In addition, cyclosporine, mercaptopurine, sulfasalazine, prednisone, rifampin, amoxicillin, and minocycline hydrochloride were ineffective. Thalidomide was effective but its use was discontinued due to peripheral sensory neuropathy. Infliximab, 5 mg/kg, was infused in February 1999, with improvement of lesions within a week followed by complete and partial closure within 1 month. The effects lasted for 2 months after which lesions deteriorated. A second infusion was given 3 months later with similar improvement.

CASE 3

A 51-year-old man with refractory Crohn disease diagnosed in 1973 reported a long-standing, scaly, pruritic eruption, which was diagnosed as psoriasis in 1987. Therapy for Crohn disease included sulfasalazine, ampicillin, metronidazole, and azathioprine. Grenz ray therapy, calcipotriene, tazarotene, and superpotent topical corticosteroids for the psoriasis were ineffective. Plaques on his extremities had remained stable for more than a decade. Physical examination revealed mild diffuse abdominal tenderness, draining perianal fistula, and sharply demarcated erythematous, scaling plaques overlying both lower limbs (Figure 3). He presented in October 1998 with increasing abdominal pain and fistula drainage. Infliximab, 5 mg/kg, was infused. Healing of the fistula commenced within 1 week, with its complete closure within 2 days and a slight improvement in his psoriasis noted days after a second infusion 1 month later. Subsequently, 3 infusions of infliximab were given a year later for fistula recurrence. Healing of the fistula and a decrease in scale, thickness, erythema, and pruritus of his cutaneous lower limb plaques occurred within 2 weeks. Complete closure of the fistula occurred within 4 weeks, and complete resolution of the cutaneous lesions in all but a 1-cm², dime-sized area on the posterior right calf occurred within 5 weeks (Figure 4). His skin has remained clear, and he is currently applying clobetasol propionate ointment twice weekly as maintenance therapy.

View larger version (71K): [in this window] [in a new window] Figure 3. Lower limb psoriasis before treatment with infliximab.

View larger version (73K): [in this window] [in a new window] Figure 4. Resolved psoriatic plaques on the anterior shins after 5 infliximab infusions.

COMMENT

Jump to Section  • Top  • Introduction  • Report of cases  • Comment  • Author information  • References

Pyoderma gangrenosum is a rare destructive inflammatory skin disease that consists of painful nodules and pustules, which break down forming ulcers with raised inflammatory borders and boggy necrotic bases. Pyoderma gangrenosum is frequently associated with systemic disease in which autoimmune mechanisms are suspected or are known to occur, such as ulcerative colitis, Crohn disease, gammopathy, and arthritis, but also exists in the absence of any apparent disorder. The phenomenon of pathergy, the development of new lesions or aggravation of existing ones following trivial trauma, is frequently present in pyoderma gangrenosum and suggests altered, exaggerated, and uncontrolled inflammatory responses to nonspecific stimuli.¹¹ Abnormalities of neutrophil function have been reported,^13-14 and evidence suggests that disturbances of immunoregulation and immunologic effector functions are involved in some patients with pyoderma gangrenosum. However, no consistent pattern of a disturbed cellular immune response has emerged.^{11, 13}

Mild forms of pyoderma gangrenosum respond to intralesional corticosteroids. Topical treatments, such as 2% disodium cromoglycate solution, hyperbaric oxygen, and topical cyclosporine, have been reported to be beneficial. Systemic glucocorticoids halt the progression of existing ulceration and prevent the development of new lesions; however, there is a continual need for suppression of the inflammatory process, and adverse effects occur in up to 50% of patients. Pyoderma gangrenosum may respond to sulfa drugs, such as sulfasalazine, dapsone, and sulfapyridine, which have an antineutrophilic action. However, their precise mechanism of action in pyoderma gangrenosum is not known. Immunosuppressive agents, including cyclosporine, tacrolimus, mercaptopurine, azathioprine, methotrexate, cyclophosphamide, and chlorambucil, are helpful in many but not all cases. Pyoderma gangrenosum has also been reported to respond to colchicine, intravenous immunoglobulin, thalidomide, mycophenolate mofetil, plasmapheresis, and clofazimine.¹¹

Mild forms of psoriasis respond to topical corticosteroids. Treatment is limited by potential adverse effects, such as tachyphylaxis, skin atrophy, and hypothalamic-pituitary-adrenal axis suppression. Other topical medications include tars, salicylic acid, anthralin, calcipotriene, and tazarotene. Phototherapy with UV-B and psoralen–UV-A are used for more widespread involvement. Evidence of an immune-mediated etiology for psoriasis is suggested by the dramatic efficacy of cyclosporine, a drug whose primary effect is the suppression of T lymphocytes¹⁵ and the efficacy of IL-2 diphtheria toxin, a drug that destroys activated T lymphocytes by specifically targeting their IL-2 receptors.¹⁶ Information suggests that antigen-presenting cells of the epidermis must deliver at least 2 signals to receptors on the surface of resting T lymphocytes. Once delivered, cytokine gene expression and T-cell activation take place, initiating the sequence of events that leads to proliferation of keratinocytes and the skin changes typical of psoriasis.¹⁷ Recently, therapy has begun to focus on immunomodulatory agents, which show increasing promise. Systemic therapies include methotrexate and cyclosporine. However, their use is limited by serious adverse effects such as hepatotoxicity and nephrotoxicity. Agents such as IL-2 fusion toxin and CTLA4Ig, which prevents the activation of T cells,¹⁷ have shown potential in the treatment of psoriasis.

Tumor necrosis factor is a proinflammatory cytokine produced by macrophages, lymphocytes, and polymorphonuclear neutrophils. It has multiple biological activities involved in apoptosis, tumor necrosis, metabolism, and activation of granulocytes, lymphocytes, eosinophils, fibroblasts, chondrocytes, and endothelial cells.¹⁸ It induces edema and participates in granuloma formation, activates the coagulation cascade, and is involved in the recruitment of inflammatory cells to local tissue sites of inflammation.^19-20 Patients with Crohn disease have increased levels of TNF- in cells, tissue, and secretory fluids and increased numbers of TNF-–producing lamina propria cells.^7-8 Raised levels of soluble TNF receptors are present in active disease.⁹

Infliximab, also known as chimeric monoclonal anti–TNF- antibody or cA2, is an anti–TNF- monoclonal antibody IgG, a chimer consisting of a human constant region (75%) and a murine variable portion (25%). Infliximab binds specifically and with high affinity to both free and membrane-bound TNF, neutralizing its effects in vivo. Binding of the IgG1 isotype of infliximab activates complement and causes antibody-dependent cell cytotoxicity of activated CD4⁺ T cells and macrophages.¹ Treatment with infliximab decreases TNF- levels in inflamed areas of the intestine, decreases the infiltration of inflammatory cells, and lowers IL-6 and C-reactive protein concentrations, resulting in a rapid reduction in mucosal inflammation.¹⁰ Decreased levels of fibrin degradation products, von Willebrand factor, and thrombin–antithrombin III complex have also been demonstrated.¹⁸ In patients with rheumatoid arthritis, infliximab suppresses symptoms of synovitis and reduces serum markers of inflammation, such as the erythrocyte sedimentation rate and C-reactive protein level.⁵ When used with low-dose methotrexate in patients with rheumatoid arthritis, effects are synergistic.²¹

Infliximab infusions have been associated with immediate hypersensitivity reactions such as urticaria, hypotension, and dyspnea.²² Antibodies to infliximab develop in approximately 13% of patients with Crohn disease treated with the drug³ and increase the likelihood of infusion reactions, shortened half-life, and loss of clinical efficacy.^23-24 The repeated administration of infliximab may be associated with the formation of autoimmune antibodies,²¹ and significant delayed hypersensitivity events, such as myalgia, rash, fever, and polyarthralgia, have been reported on reexposure to infliximab after a long interval.²⁵ The risk of serious infection is reported to not be significantly higher in patients treated with infliximab than placebo-treated groups.²

Long-term risks and benefits remain to be determined. Attention has to be given to the unknown rate of developing malignant neoplasms in patients taking infliximab. As with immunosuppressive agents such as methotrexate and cyclosporine, the development of lymphomas may be a long-term complication with anti–TNF- therapy.³ Further experience is needed to establish if a real risk of developing malignant neoplasms exists. There is currently no information on the effects of other immunosuppressants on the risks or adverse effects of this treatment.

Infliximab is not inexpensive. The average wholesale price of a 100-mg vial is $665.65. At 3 to 4 vials per infusion at 5 mg/kg for a 70-kg patient in an office or hospital setting, cost to the patient can range from $2500 to $4000. On average, patients undergo a series of 3 infusions throughout 6 months, a cost of more than $12 000. In patients who are refractory to other therapies and require frequent and costly hospital admissions, its benefits may make this treatment worthwhile.

The cases presented herein suggest that infliximab, a promising therapeutic agent for refractory Crohn disease and fistulae, may also be effective in the treatment of pyoderma gangrenosum and psoriasis associated with Crohn disease. Because these cutaneous diseases may be refractory to standard therapies, further study of their response to infliximab is warranted.

AUTHOR INFORMATION

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Accepted for publication February 28, 2001.

We thank Donald Rudikoff, MD, for his assistance.

Corresponding author: Mark G. Lebwohl, MD, Department of Dermatology, Box 1047, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029.

From the Departments of Dermatology (Drs Tan, Gordon, and M. G. Lebwohl) and Gastroenterology (Dr George), The Mount Sinai School of Medicine of New York University, and Division of Gastroenterology, Columbia-Presbyterian Medical Center (Dr O. Lebwohl), New York, NY.

REFERENCES

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1. Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti–TNF- monoclonal antibody cA2 binds recombinant transmembrane TNF- and activates immune effector functions. Cytokine. 1995;7:251-259. FULL TEXT | WEB OF SCIENCE | PUBMED 2. Targan SR, Hanauer SB, van Deventer SJ, et al for the Crohn's Disease cA2 Study Group. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. N Engl J Med. 1997;337:1029-1035. FREE FULL TEXT 3. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti–tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology. 1999;117:761-769. FULL TEXT | WEB OF SCIENCE | PUBMED 4. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999;340:1398-1405. FREE FULL TEXT 5. Elliott MJ, Maini RN, Feldman M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;344:1105-1110. FULL TEXT | WEB OF SCIENCE | PUBMED 6. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337:141-147. FREE FULL TEXT 7. Breese EJ, Michie CA, Nicholls SW, et al. Tumor necrosis factor alpha–producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology. 1994;106:1455-1466. WEB OF SCIENCE | PUBMED 8. Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumor necrosis factor , IL-6, and IL-1- by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1993;94:174-181. WEB OF SCIENCE | PUBMED 9. Stronkhorst A, Jansen J, Tytgat GNJ, van Deventer SJH. Soluble IL2 and TNF receptor p55 and p75 in Crohn's disease [abstract]. Gastroenterology. 1994;104:779A. 10. Radema SA, van Dullemen H, Mevissen M, Jansen J, Tytgat GNJ, van Deventer SJH. Anti-TNF therapy decreases production of chemokines in patients with Crohn's disease. In: Cytokine Production, Immune Activation, and Neutrophil Migration in Inflammatory Bowel Disease [dissertation]. Amsterdam, the Netherlands: University of Amsterdam; 1996. 11. Wolff K, Stingl G. Pyoderma gangrenosum. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick's Dermatology in General Medicine. 5th ed. New York, NY: McGraw-Hill; 1999:1140-1146. 12. Weinstein GD, Frost P. Abnormal cell proliferation in psoriasis. J Invest Dermatol. 1968;50:254-259. WEB OF SCIENCE | PUBMED 13. Holt PJ, Davies MG, Saunders KC, Nuki G. Pyoderma gangrenosum: clinical and laboratory findings in 15 patients with special reference to polyarthritis. Medicine (Baltimore). 1980;59:114-133. PUBMED 14. Berbis P, Mege JL, Capo C, Kaplanski S, Bongrand P, Privat Y. Hyperimmunoglobulin E and impaired neutrophil functions in a case of pyoderma gangrenosum: effect of clofazimine. J Am Acad Dermatol. 1988;18:574-576. 15. Baker BS, Griffiths CEM, Lambert S, et al. The effects of cyclosporine A on T lymphocyte and dendritic cell sub-populations in psoriasis. Br J Dermatol. 1987;116:503-510. FULL TEXT | WEB OF SCIENCE | PUBMED 16. Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response of psoriasis to a lymphocyte-selective toxin (DAB₃₈₉IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med. 1995;1:442-447. FULL TEXT | WEB OF SCIENCE | PUBMED 17. Abrams JR, Lebwohl MG, Guzzo CA, et al. CTLA4Ig-mediated blockade of T cell costimulation in patients with psoriasis vulgaris. J Clin Invest. 1999;103:1243-1252. WEB OF SCIENCE | PUBMED 18. Mouser JF, Hyams JS. Infliximab: a novel chimeric monoclonal antibody for the treatment of Crohn's disease. Clin Ther. 1999;21:932-942. FULL TEXT | WEB OF SCIENCE | PUBMED 19. Old LJ. Tumor necrosis factor (TNF). Sci Am. 1988;258:59-60, 69-75. WEB OF SCIENCE | PUBMED 20. Van Deventer SJH. Tumor necrosis factor and Crohn's disease. Gut. 1997;40:443-448. FREE FULL TEXT 21. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti–tumor necrosis factor- monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552-1563. FULL TEXT | WEB OF SCIENCE | PUBMED 22. Van Deventer SJH. Immunomodulation of Crohn's disease using TNF- neutralizing monoclonal antibodies. Clin Nutr. 1997;16:271-275. 23. Baert FJ, Rutgeerts PR. Anti-TNF strategies in Crohn's disease: mechanisms, clinical effects, indications. Int J Colorectal Dis. 1999;14:47-51. FULL TEXT | WEB OF SCIENCE | PUBMED 24. Bell S, Kamm MA. Antibodies to tumour necrosis factor as treatment for Crohn's disease. Lancet. 2000;355:858-860. FULL TEXT | WEB OF SCIENCE | PUBMED 25. Infliximab Extended Interval Retreatment Protocol [data on file]. Malvern, Pa: Centocor, Inc; November 10, 1998.

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