Improvement of Pyoderma Gangrenosum and Psoriasis Associated With CrohnDisease With Anti–Tumor Necrosis Factor α Monoclonal Antibody FREE

INFLIXIMAB (Remicade; Centocor, Inc, Malvern, Pa) is a novel chimericanti–tumor necrosis factor α (anti–TNF-α) monoclonalantibody composed of constant regions of the human IgG1κ spliced tothe murine variable antigen-binding region of a high-affinity human anti–TNF-αantibody. Infliximab binds specifically, with high affinity to soluble andtransmembrane forms of TNF-α, neutralizing its effects in vivo.¹ It has been approved recently for human use by theFood and Drug Administration and is effective in the treatment and remissionof moderate to severely active refractory Crohn intestinal disease^2- 3 and associated fistulae.⁴Multiple infusions have shown promising results in patients with rheumatoidarthritis.^5- 6

Tumor necrosis factor α is a proinflammatory cytokine that hasmultiple biological activities, including the recruitment of inflammatorycells to local tissue sites of inflammation. Patients with Crohn disease haveincreased levels of TNF-α, TNF-α–producing lamina propriacells,^7- 8 and soluble TNF receptors.⁹ Treatment with infliximab decreases TNF-α levelsin inflamed areas of the intestine, decreases the infiltration by inflammatorycells, 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 frequentlyassociated with Crohn disease. Disturbances of immunoregulation and immunologiceffector 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 agentsis fraught with potential adverse effects and not always successful.

Psoriasis is an inflammatory disease of the skin. Proliferation of keratinocytesis dramatically increased, and the transit time of basal cells to the stratumcorneum is reduced from 28 days in normal epidermis to 2 to 4 days in lesionalplaques.¹² Recently, therapy for psoriasishas begun to focus on a number of immunomodulatory agents.

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

A 39-year-old man with Crohn disease diagnosed in 1978 had a subtotalcolectomy in July 1979 and developed painful inflammatory skin lesions within2 months and fistulae 2 years later. In addition to sulfasalazine and prednisonefor treatment of Crohn disease, he received mercaptopurine, tacrolimus, cyclosporine,metronidazole, total parenteral nutrition, and intralesional triamcinoloneacetonide for pyoderma gangrenosum. Thalidomide, although of some benefit,was discontinued secondary to sensorimotor neuropathy. Treatment with mycophenolatemofetil was ineffective. Physical examination revealed pustules and widespreadulcerations with violaceous undermined borders and purulence on the upperand lower extremities, chest, and back (Figure1). Cribriform scars were present. He received 5 infliximab infusionsfor recalcitrant rectal fistulae at 5 mg/kg over a 1-year period. His pyodermagangrenosum and fistulae improved dramatically (Figure 2). Decreased pain, erythema, and swelling occurred withinthe first 12 to 24 hours of each infusion. Complete resolution of most ulcersoccurred 1 week after the first infusion. Additional improvement was noted1 week after each subsequent infusion. Improvement in the Crohn fistulae lasted2 months, and in the pyoderma gangrenosum for 6 months after the third infusion,after which infliximab therapy was reinstated.

A 50-year-old woman with Crohn disease diagnosed in 1983 was treatedwith multiple ileocolic resections with ileostomy. Pyoderma gangrenosum andfistulae had been present in the perianal region, abdomen, and legs for 5years. There were multiple coalescing ulcers in the perianal area, left groin,lower abdomen below the stoma, and left lower leg. Previous treatment includedintralesional triamcinolone acetonide, clobetasol propionate ointment, andvarious 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 sensoryneuropathy. Infliximab, 5 mg/kg, was infused in February 1999, with improvementof lesions within a week followed by complete and partial closure within 1month. The effects lasted for 2½ months after which lesions deteriorated.A second infusion was given 3 months later with similar improvement.

A 51-year-old man with refractory Crohn disease diagnosed in 1973 reporteda long-standing, scaly, pruritic eruption, which was diagnosed as psoriasisin 1987. Therapy for Crohn disease included sulfasalazine, ampicillin, metronidazole,and azathioprine. Grenz ray therapy, calcipotriene, tazarotene, and superpotenttopical corticosteroids for the psoriasis were ineffective. Plaques on hisextremities had remained stable for more than a decade. Physical examinationrevealed mild diffuse abdominal tenderness, draining perianal fistula, andsharply demarcated erythematous, scaling plaques overlying both lower limbs(Figure 3). He presented in October1998 with increasing abdominal pain and fistula drainage. Infliximab, 5 mg/kg,was infused. Healing of the fistula commenced within 1 week, with its completeclosure within 2 days and a slight improvement in his psoriasis noted daysafter a second infusion 1 month later. Subsequently, 3 infusions of infliximabwere given a year later for fistula recurrence. Healing of the fistula anda decrease in scale, thickness, erythema, and pruritus of his cutaneous lowerlimb plaques occurred within 2 weeks. Complete closure of the fistula occurredwithin 4 weeks, and complete resolution of the cutaneous lesions in all buta 1-cm², dime-sized area on the posterior right calf occurred within5 weeks (Figure 4). His skin hasremained clear, and he is currently applying clobetasol propionate ointmenttwice weekly as maintenance therapy.

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

Mild forms of pyoderma gangrenosum respond to intralesional corticosteroids.Topical treatments, such as 2% disodium cromoglycate solution, hyperbaricoxygen, and topical cyclosporine, have been reported to be beneficial. Systemicglucocorticoids halt the progression of existing ulceration and prevent thedevelopment of new lesions; however, there is a continual need for suppressionof 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 precisemechanism of action in pyoderma gangrenosum is not known. Immunosuppressiveagents, including cyclosporine, tacrolimus, mercaptopurine, azathioprine,methotrexate, cyclophosphamide, and chlorambucil, are helpful in many butnot 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. Treatmentis limited by potential adverse effects, such as tachyphylaxis, skin atrophy,and hypothalamic-pituitary-adrenal axis suppression. Other topical medicationsinclude tars, salicylic acid, anthralin, calcipotriene, and tazarotene. Phototherapywith UV-B and psoralen–UV-A are used for more widespread involvement.Evidence of an immune-mediated etiology for psoriasis is suggested by thedramatic efficacy of cyclosporine, a drug whose primary effect is the suppressionof T lymphocytes¹⁵ and the efficacy of IL-2diphtheria toxin, a drug that destroys activated T lymphocytes by specificallytargeting their IL-2 receptors.¹⁶ Informationsuggests that antigen-presenting cells of the epidermis must deliver at least2 signals to receptors on the surface of resting T lymphocytes. Once delivered,cytokine gene expression and T-cell activation take place, initiating thesequence of events that leads to proliferation of keratinocytes and the skinchanges typical of psoriasis.¹⁷ Recently, therapyhas begun to focus on immunomodulatory agents, which show increasing promise.Systemic therapies include methotrexate and cyclosporine. However, their useis limited by serious adverse effects such as hepatotoxicity and nephrotoxicity.Agents such as IL-2 fusion toxin and CTLA4Ig, which prevents the activationof T cells,¹⁷ have shown potential in the treatmentof psoriasis.

Tumor necrosis factor α is a proinflammatory cytokine producedby macrophages, lymphocytes, and polymorphonuclear neutrophils. It has multiplebiological activities involved in apoptosis, tumor necrosis, metabolism, andactivation of granulocytes, lymphocytes, eosinophils, fibroblasts, chondrocytes,and endothelial cells.¹⁸ It induces edema andparticipates in granuloma formation, activates the coagulation cascade, andis involved in the recruitment of inflammatory cells to local tissue sitesof inflammation.^19- 20 Patientswith Crohn disease have increased levels of TNF-α in cells, tissue,and secretory fluids and increased numbers of TNF-α–producinglamina propria cells.^7- 8 Raisedlevels of soluble TNF receptors are present in active disease.⁹

Infliximab, also known as chimeric monoclonal anti–TNF-αantibody or cA2, is an anti–TNF-α monoclonal antibody IgG, a chimerconsisting of a human constant region (75%) and a murine variable portion(25%). Infliximab binds specifically and with high affinity to both free andmembrane-bound TNF, neutralizing its effects in vivo. Binding of the IgG1isotype of infliximab activates complement and causes antibody-dependent cellcytotoxicity of activated CD4⁺ T cells and macrophages.¹ Treatment with infliximab decreases TNF-α levelsin inflamed areas of the intestine, decreases the infiltration of inflammatorycells, and lowers IL-6 and C-reactive protein concentrations, resulting ina rapid reduction in mucosal inflammation.¹⁰Decreased levels of fibrin degradation products, von Willebrand factor, andthrombin–antithrombin III complex have also been demonstrated.¹⁸ In patients with rheumatoid arthritis, infliximabsuppresses 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 withrheumatoid arthritis, effects are synergistic.²¹

Infliximab infusions have been associated with immediate hypersensitivityreactions such as urticaria, hypotension, and dyspnea.²²Antibodies to infliximab develop in approximately 13% of patients with Crohndisease treated with the drug³ and increasethe likelihood of infusion reactions, shortened half-life, and loss of clinicalefficacy.^23- 24 The repeated administrationof 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 reexposureto infliximab after a long interval.²⁵ Therisk of serious infection is reported to not be significantly higher in patientstreated with infliximab than placebo-treated groups.²

Long-term risks and benefits remain to be determined. Attention hasto be given to the unknown rate of developing malignant neoplasms in patientstaking infliximab. As with immunosuppressive agents such as methotrexate andcyclosporine, the development of lymphomas may be a long-term complicationwith anti–TNF-α therapy.³ Furtherexperience is needed to establish if a real risk of developing malignant neoplasmsexists. There is currently no information on the effects of other immunosuppressantson the risks or adverse effects of this treatment.

Infliximab is not inexpensive. The average wholesale price of a 100-mgvial is $665.65. At 3 to 4 vials per infusion at 5 mg/kg for a 70-kg patientin an office or hospital setting, cost to the patient can range from $2500to $4000. On average, patients undergo a series of 3 infusions throughout6 months, a cost of more than $12 000. In patients who are refractoryto other therapies and require frequent and costly hospital admissions, itsbenefits may make this treatment worthwhile.

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

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, NewYork, NY 10029.