Pyoderma gangrenosum

Abstract

We describe a patient with pyoderma gangrenosum (PG) whose lesions responded to etanercept therapy. This disease has been recognized for diverse underlying pathology and associated immune disturbances. Although the role of cytokines in pathogenesis is not fully understood, tumor necrosis factor alpha (TNF-[alpha]) may facilitate induction and maintenance of the disease. This is supported by the successful use of infliximab, a recombinant anti-TNF-[alpha] monoclonal antibody, in cases of PG associated with inflammatory bowel disease (IBD). Etanercept is a divalent recombinant fusion protein that binds soluble TNF-[alpha]. To our knowledge, the utility of etanercept for PG has not been reported.

A patient with recalcitrant and widespread PG that was unresponsive to systemic corticosteroids was treated with etanercept. Rapid and complete clearing of the skin lesions was observed, and steroid taper to 5 mg/day was sustained for two months. Treatment was well-tolerated with no adverse reactions reported. CONCLUSIONS: Etanercept therapy offered rapid and complete resolution of all PG lesions. Such response supports the use of etanercept as a steroid-sparing agent in recalcitrant disease and suggests the role of TNF-[alpha] in pathogenesis of PG.

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Introduction

Pyoderma gangrenosum (PG) is a painful neutrophilic dermatosis, first described in terms of ulceration, border demarcation and scarring tendencies (1). Presentation may range from cutaneous confinement to systemic disease (2). While pathogenesis remains unknown, immune dysregulation appears to be fundamental in PG. Disturbances in cellular, humoral and nonspecific immunity have been reported in certain cases--specifically, abnormalities in serum complement, neutrophil function and immune complex deposition (3). These defects may be illustrated by the diverse immunologic diseases associated with PG (4). Most notably, 36-50% of all patients with PG have inflammatory bowel disease (IBD) (5). Lesions in IBD-related PG are typically ulcerative (3) while the bullous variant may be associated with underlying hematologic or myeloproliferative disease in approximately 27% (6).

Recently, the use of anti-TNF-[alpha] therapy for recalcitrant PG has been explored. Although the rarity of PG has limited controlled investigation of true efficacy measurements, several cases of IBD-associated PG responsive to infliximab appear in the peer review literature. Tan et al. observed serendipitous regression of PG lesions in two patients with Crohn's disease (CD) receiving infliximab (7). More recently, Regueiro et al. reported complete healing of skin lesions in all 13 patients treated with infliximab (3). Complete or partial remission with infliximab treatment was described in an additional 10 of 12 patients from three other case series (8,9). Of the 31 cases of infliximab-treated PG in the literature, the majority received concomitant immunomodulator therapy and/or required multiple infliximab infusions (3,7,9).

Etanercept is a recombinant anti-TNF-[alpha] fusion protein whose efficacy in the treatment of PG has not yet been defined (10). In the following case report, we present a patient with PG refractory to corticosteroid therapy, who responded favorably to etanercept. After an extensive review of the literature using online PubMed, MDConsult and OVID searches, we believe this is the first report of etanercept treatment for PG and the first instance of anti-TNF-[alpha] therapy for PG unassociated with IBD.

Case Report

A 34-year-old female presented to the emergency department with an oral temperature of 101[degrees]F and constitutional symptoms. Also apparent were nonpruritic, deeply purple inflammatory skin lesions with central ulcerations and global distribution. Physical exam at presentation revealed oral lesions of aphthoid type that were exquisitely painful. Laboratory values obtained upon admission revealed leukopenia (2400) and elevated sedimentation rate (100).

After a seven-day course of high dose corticosteroids (with taper), a severe outbreak (Figure 1) occurred. Punch biopsy revealed features compatible with PG (Figure 2). Two additional flares occurred upon steroid taper to 20 mg and 10/5 mg dosing. Etanercept therapy (25 mg SC two times per week) was then instituted with prednisone at 30 mg daily. Healing was evident within 10 days, and complete resolution was noted at one month of etanercept therapy, without any flares or adverse reactions. While on etanercept, steroid taper to 5 mg daily had been achieved and sustained for a two-month period. However, at 13 weeks, a flare resulted after taper to 2.5 mg daily, prompting high-dose prednisone rescue. At fifteen weeks of therapy, another more severe recurrence associated with a motor vehicle accident warranted SoluCortef 100 mg IM with prednisone at 60 mg. Etanercept was then increased to a 100 mg per week dosing, and healing was immediate. Four months after the most recent outbreak, prednisone has been tapered to 5 mg per day, and the patient remains in complete remission while on maintenance etanercept (100 mg/week) therapy.

It is noteworthy that after almost one year of corticosteroid therapy, our patient has endured significant iatrogenic morbidity, including depression, Cushingoid habitus, skin atrophy and asthma exacerbation upon attempted steroid taper.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Discussion

Because cytokines assume a ubiquitous role in inflammation, they may be a perfect target for pharmacologic modulation in inflammatory diseases such as PG, with diverse underlying immunology. Etanercept is a divalent recombinant fusion product of the p75 TNF receptor and the Fc region of human IgG (11). It binds soluble TNF-[alpha] at a 50- to 1000-fold greater affinity than the physiologic TNF-[alpha] receptor (12). Although similar to infliximab in effect, etanercept lacks the capacity to inactivate membrane-bound TNF-[alpha] precursor but demonstrates the distinct capacity to neutralize TNF-[alpha] (13).

Etanercept is now indicated for numerous autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis and IBD (14). More recently etanercept has been introduced into the field of dermatology. In psoriasis, TNF-[alpha] promotes the recruitment of inflammatory cells into active lesions through inducing chemokine production and expression of endothelial adhesion molecules 15. In PG, TNF-[alpha] has been shown to facilitate neutrophil chemotaxis in a similar manner (16).

Successful use of infliximab for enteropathic Crohn's disease (CD) suggests that anti-TNF-[alpha] treatment may be most effective in inflammatory processes driven predominantly by Th1 cytokines (17,18). Most of the literature-based evidence for efficacy of anti-TNF-[alpha] therapy for PG comes from patients with concurrent CD, whose gastrointestinal and cutaneous lesions responded to infliximab (3,7-9). While etanercept has not been proven effective for CD (19), efficacy in the treatment IBD-associated PG has not been assessed. However, it is possible that underlying Th1 cytokine immunology may have, to some extent, determined the responsiveness of our patient to etanercept.

We present a case of PG that was quite susceptible to etanercept. Obvious healing was noted within ten days, which is comparable to much of the data regarding infliximab therapy for PG. While Regueiro et al. reported a mean time to complete healing of 86 days with infliximab (3), complete resolution occurred in our patient at 30 days of treatment. Etanercept therapy was also well-tolerated without any reported adverse reactions in our case. However, steroid taper was difficult, and our patient suffered several flares of her PG during etanercept treatment. Regueiro et al. reported that corticosteroid taper was achieved in all 13 patients receiving infliximab (5 mg/kg), without requiring additional steroid treatment. However, 11 of the 13 patients were maintained on 6-mercaptopurine or azathioprine. Four of these patients experienced flares that, as in our patient, responded to additional anti-TNF-[alpha] therapy (3).

The ulcers of PG may be exquisitely painful and rapidly enlarging, mandating immediate and effective therapy, often with corticosteroids (20). However, the high doses of steroid therapy used in severe PG are associated with significant morbidity and even death in certain reports (21). Steroid-refractory PG as well as iatrogenic morbidity, both experienced by our patient, necessitate treatment alternatives. While numerous biologics have been used for recalcitrant PG (3,21-25), many agents, including azathioprine and mycophenolate mofetil exhibit a delay in onset of action (26). Fast-acting anti-TNF-[alpha] agents are thus attractive options.

The expense of biologic agents becomes another important concern in long-term management. Annual costs of $12,000--$15,000 are reported for the use of biologics in rheumatoid arthritis (RA). However, many clinicians and patients believe that reduction in disability and deformity is commensurate with monetary cost (27). Like RA, PG is associated with considerable morbidity and mortality (28). In these respects, it may be important to consider disease course and patient preferences in selecting biologic agents for PG.

Conclusion

Here, the authors suggest that etanercept, like infliximab, may be an important therapeutic modality in treatment-refractory PG. To our knowledge, we report the first case of PG responsive to etanercept therapy. Although the initial response to etanercept was dramatic, concomitant low-dose corticosteroid maintenance therapy was necessary. While biologics are very costly, etanercept may be an excellent choice in the appropriate clinical context as a steroid-limiting agent for recalcitrant PG.

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JOSEPH WILSON MCGOWAN IV BS (1), CARL ALLEN JOHNSON MD (2), ANNETTE LYNN MD (3)

1. THIRD-YEAR MEDICAL STUDENT

2. CLINICAL ASSISTANT PROFESSOR OF MEDICINE, ELANTE SKIN CENTER, LEXINGTON, SC

3. CLINICAL PROFESSOR OF MEDICINE

UNIVERSITY OF SOUTH CAROLINA SCHOOL OF MEDICINE, COLUMBIA, SOUTH CAROLINA

ADDRESS FOR CORRESPONDENCE:

Carl Johnson, MD

Elante Skin Center

108 Palmetto Park Blvd., Suite C

Lexington, SC 29072

Phone: (803) 808-0193

Fax: (803) 808-0172

E-mail: jmcgowan@gw.med.sc.edu

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