S128. Letters. The treatment of pyoderma gangrenosum using etanercept

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1 S128 JAM ACAD DERMATOL discontinuation or tapering of these agents clearly are needed. Etanercept is approved for use in adult patients with psoriasis, and a clinical trial in pediatric patients is currently underway. Clinical experience in the 10 pediatric patients described here suggests that etanercept therapy may be efficacious and safe in pediatric patients with moderate to severe plaque psoriasis. In addition, etanercept therapy also improved joint symptoms in the patients who had concomitant psoriatic arthritis. Douglas W. Kress, MD Children s Hospital of Pittsburgh Wexford, Pennsylvania University of Pittsburgh Pittsburgh, Pennsylvania This case series was investigator initiated. Financial support for the manuscript was provided by Amgen Inc and by Wyeth Research. The author wishes to thank Julia R. Gage for assistance in manuscript preparation. Conflicts of interest: Dr Kress has received an honorarium for this case series. He is on the speaker s bureau and is a consultant for Amgen. He has not received research funds from Amgen and does not own Amgen stock. Reprints not available from the author. Correspondence to: Douglas W. Kress, MD Children s Hospital of Pittsburgh Pediatric Dermatology, Pine Center, Ste Perry Highway, Wexford, PA DKress@aol.com REFERENCES 1. National Psoriasis Foundation. Statistics. Available at: Accessed April 6, Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol 2000;17: Lewkowicz D, Gottlieb AB. Pediatric psoriasis and psoriatic arthritis. Dermatol Ther 2004;17: Dadlani C, Orlow SJ. Treatment of children and adolescents with methotrexate, cyclosporine, and etanercept: review of the dermatologic and rheumatologic literature. J Am Acad Dermatol 2005;52: doi: /j.jaad The treatment of pyoderma gangrenosum using etanercept CASE REPORTS Patient 1 To the Editor: After being treated unsuccessfully for several months at the wound clinic, a 44-year-old African American woman presented with a 5-month history of nonhealing, painful ulcers on her legs subsequent to what she stated were mosquito bites. This patient had a history of rheumatoid arthritis (rheumatoid factor 1) and lupus erythematosus (antinuclear antibody 1) since Her medications at the time of presentation included hydrochloroquine sulfate 200 mg twice daily, prednisone 5 mg once daily, and celecoxib 200 mg twice daily. Previous treatments for her leg ulcers included wet dressings and local wound care; neither was successful. Physical examination revealed an ill-appearing woman in moderate distress with moonlike facies. She had multiple severe joint deformities involving her hands and feet (Fig 1, A). The patient was noted to require a wheelchair. On her lower extremities were several large, purulent ulcers with raised erythematous borders (Fig 1, B). Cultures obtained from the wounds revealed no evidence of bacterial growth. A glucose-6-phosphate dehydrogenase level was normal, and a purified protein derivative (PPD) was read as negative. On the basis of these findings, a diagnosis of pyoderma gangrenosum was made. Initial treatment consisted of dapsone 100 mg once daily and prednisone 10 mg once daily. After 4 weeks, the lesions showed no clinical improvement. Etanercept therapy was then commenced using a dose of 25 mg subcutaneously 2 times per week. After 1 month of therapy, a 40% improvement in the ulcers was noted (Fig 2, A), and the patient s pain had resolved completely. In addition, her arthritis was 30% better, and she was able to walk without the use of her wheelchair. Two months after initiating therapy, most of the ulcers had healed completely (Fig 2, B), and her arthritis was 80% to 90% improved. At 4 months, all lesions had closed completely (Fig 2, C). The patient currently remains on etanercept therapy with no recurrence of pyoderma gangrenosum and with significant improvement of her joint symptoms. Patient 2 A 48-year-old woman with a history of rheumatoid arthritis, hypothyroidism, nontraumatic deep vein thrombosis (DVT), and previous nonhealing skin lesions presented to the office complaining of a 2-week history of a rapidly expanding, painful ulcer on her right calf. She stated that the lesions began

2 JAM ACAD DERMATOL VOLUME 54, NUMBER 3 S129 Fig 1. Patient 1. Joint deformities hands (A) and feet (B). secondary to small injuries that had occurred previously. Although unaware of the name of her condition, she reported that previous lesions in the same area of the calf had been difficult to treat. The lesions had been unresponsive to oral antibiotics, and previous dermatologists had only minor success with oral corticosteroids and clofazimine. According to the patient, these lesions would often heal spontaneously off treatment, only to recur a short time later. Examination revealed an 11 cm 3 8 cm, ulcerated lesion of the right medial calf with raised, undermined borders and surrounding erythema. There was a central eschar and small amounts of clear to yellow exudate. Of note was a large area of surrounding cicatrix, indicating areas of previous lesions. A 2.5 cm cm ulcerated lesion of similar appearance also was noted on the left dorsal foot. The patient was placed on 60 mg/d of oral prednisone and laboratory workup was initiated. Westergren sedimentation rate was elevated at 26 mm/h. Complete blood count, comprehensive metabolic profile, urinalysis, antinuclear antibodies, serum protein electrophoresis, thyroid-stimulating Fig 2. Patient 1. Improvement in ulcers after 1 month (A), 2 months (B), and 4 months of treatment (C). hormone, venereal disease research laboratory test, C-antineutrophil cytoplasmic antibody, P-antineutrophil cytoplasmic antibody, and coagulation

3 S130 JAM ACAD DERMATOL Fig 3. Lesions in patient 2: initial presentation of arm (A), initial presentation of foot (B), and 19 days (C), 47 days (D), 75 days (E), 125 days (F), 167 days (G), and 210 days (H) after treatment. studies all were within normal limits. Chest X-ray revealed no acute chest findings, and PPD was negative. Because of the history of DVT, antiphospholipid antibodies were ordered, which showed elevation of cardiolipin immunoglobulin A antibody and phosphatidylserine immunoglobulin G. However, laboratory values repeated 6 weeks later revealed no evidence of elevated antibodies. In addition, an autoimmune workup, including SSA, SSB, SCL-70, double-stranded DNA, RNP, and anti- Smith antibodies, was within normal limits. A biopsy of the lesion on the dorsal foot was nondiagnostic.

4 JAM ACAD DERMATOL VOLUME 54, NUMBER 3 S131 Seven days after her initial visit, prednisone was stopped, and the patient was started on etanercept 25 mg subcutaneously twice a week. This medication was chosen because of the patient s positive history of rheumatoid arthritis. The patient was followed at 2- to 4-week intervals (Fig 3, A-G), and at 75 days of therapy the lesion had decreased in size to 5 cm 3 2 cm, with good granulation tissue noted. The lesion on the dorsal foot resolved completely. Significant improvement of the patient s joint pain also was noted. At 125 days, the lesion had increased in size to 5 cm 3 4 cm. Because of poor compliance, the patient had stopped her therapy for an unknown duration of time. At 167 days, the patient reported increased pain and drainage from the lesion. Two small satellite ulcers were noted surrounding the initial lesion, which measured 4 cm 3 3 cm. Cultures obtained showed heavy growth of Staphylococcus aureus. Cephalexin 500 mg twice daily was initiated and etanercept was continued. The patient reported significant improvement of pain and was discharged after initiation of antibiotics. At 210 days, and with strict compliance with therapy, the lesion had decreased to 4 cm 3 3 cm. The patient continues on etanercept therapy currently. Patient 3 A 38-year-old man presented from the wound clinic complaining of ulcers on the right lower extremity, which had developed secondary to trauma. Prior treatment included prednisone at low doses, oral antibiotics, and debridement, with no clinical improvement. Physical examination revealed multiple large, tender ulcerations of the right lower extremity (Fig 4, A). Cultures were negative. A punch biopsy of the lesion revealed changes consistent with pyoderma gangrenosum. The patient denied any history of inflammatory bowel disease, arthritis, hepatitis, malignancies, or hematologic problems. Initial laboratory analysis revealed a mild normocytic anemia. Screening tests for human immunodeficiency virus and hepatitis were negative. Glucose-6-phosphate dehydrogenase level was normal. The patient was started on prednisone 60 mg once daily, cyclosporine 100 mg once daily, and dapsone 100 mg once daily. Topical tacrolimus ointment also was applied twice daily. After 3 months of therapy, all of the ulcers had healed except for the largest lesion on the right anterior tibial area. After an additional 5 months of therapy with tapering doses of prednisone and continuation of cyclosporine and dapsone, no further improvement was seen in the larger lesion. In addition, elevations in blood urea nitrogen and creatinine were noted, and doses of cyclosporine were reduced. Because of a lack of Fig 4. Patient 3. Ulceration of right lower extremity: initial presentation (A) and after 2 weeks of therapy (B). adequate response and the elevations in kidney function, the above medications were discontinued and etanercept therapy was started at a dose of 50 mg/wk subcutaneously. At 2 weeks of therapy, significant improvement was noted, and at 2 months there was complete resolution of the lesion (Fig 4, B). The patient tolerated etanercept well and currently remains free of any lesions. DISCUSSION Pyoderma gangrenosum was first described in 1930 by Brunsting, Goeckerman, and O Leary, who attributed the lesions to streptococcal/staphylococcal infections. 1 Seventy years later the cause of pyoderma gangrenosum remains unclear. Although several associations with internal disease (Table I) have been observed, no single causative agent, infectious or otherwise, has been identified. Up to 50% of cases are thought to be idiopathic. 2 Lesions often begin as a painful papule or pustule that ulcerates and expands rapidly. Pyoderma gangrenosum is described as having a rolled undermined border with surrounding erythema. The border often is deep red to violaceous. 3 Pathergy, which is the development or worsening of lesions after trauma, is associated with pyoderma gangrenosum and is seen in approximately 40% of patients. 4 Since the initial description, several variants have been described. These variants include ulcerative, pustular, bullous,

5 S132 JAM ACAD DERMATOL Table I. Associated systemic diseases 2 Crohn s disease Ulcerative colitis Systemic lupus erythematosus Multiple myeloma Rheumatoid arthritis Monoclonal gammopathy Leukemia Hepatitis Polycythemia vera Primary biliary cirrhosis and vegetative, and can be seen alone or in combination in a single patient. 2 It also has been reported that arthritis-associated pyoderma gangrenosum appears to be more difficult to treat than idiopathic lesions. 5 Histologically, lesions of pyoderma gangrenosum are characterized by a large neutrophilic infiltrate that causes abscess formation and necrosis. 3 It is important to note that no histopathologic findings are diagnostic of pyoderma gangrenosum. The complete connection between neutrophils and tumor necrosis factor (TNF) has yet to be established; however, evidence of enhanced neutrophil activation due to TNF-a has been uncovered. 6 TNF-a upregulates the expression of adhesion molecules, namely intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, and also induces E-selectin. 7 TNF-a is known to induce the release of chemokines and cytokines from fibroblasts. Levels of interleukin 8 have been shown to increase secondary to TNF-a. 8 Recent studies involving various disease processes have helped establish a relationship between neutrophils and TNF-a. Investigations into the development of urticarial vasculitis have demonstrated that early in the development of these lesions, there is a primarily neutrophilic infiltrate with increased levels of TNF-a. As levels of TNF-a fall, so do the numbers of neutrophils noted in these lesions. 9 Analysis of fluid from blisters of patients with subcorneal pustular dermatosis demonstrates elevated levels of TNF. Subcorneal pustular dermatosis, 1 of the neutrophilic dermatoses, is characterized by subcorneal pustules filled with neutrophils. 10 TNF-a also has been shown to increase the synthesis of granulocyte colony-stimulating factor. 11 Increased levels of granulocyte colonystimulating factor have been found in active lesions of Sweet s syndrome, another of the neutrophilic dermatoses. 12 Although the exact role of TNF-a in pyoderma gangrenosum remains undefined, the neutrophil undoubtedly is a key cell type in these lesions, and chemotaxis of these cells is controlled, in part, by TNF-a. TNF-a is a proinflammatory cytokine with broad effects across many cell lines. It plays an important role in the immune response and can be found at increased levels in a number of inflammatory conditions. 13 Increased levels of TNF-a have been observed in the tissue of chronic wounds. 14 The response of cells to transforming growth factor b has been shown to be impaired by TNF-a. Transforming growth factor b is a protein known to increase the deposition of extracellular matrix. 15 Within the inflammatory cascade, TNF-a displays a positive feedback mechanism. 16 Numerous cells possess receptors for TNF-a. Binding of TNF-a to these receptors causes increased synthesis of TNF-a. 17 This process occurs via the nuclear factor kappa B (NF-kB)esignaling pathway. NF-kB is normally found in the cytoplasm where it is bound to an inhibitory molecule known as IkB. As TNF-a binds to the receptor, IkB is destroyed and NF-k is released. Once released, this factor migrates to the nucleus where it then activates various genes involved in inflammation, including those coding for cytokine formation. 18 Studies also have demonstrated that variability of TNF production may be inherited. This may help explain variations in inflammatory response from patient to patient. 19 The reported treatment options for pyoderma gangrenosum include a number of topical and systemic therapies. 2 Etanercept is a soluble TNF receptor that inhibits both TNF-a and TNF-b. This medication was approved initially for use in rheumatoid arthritis, and now is indicated in psoriatic arthritis, ankylosing spondylitis, and psoriasis. Patients with juvenile rheumatoid arthritis as young as 4 years of age can receive etanercept therapy, and there is no laboratory monitoring required. 20 Patients can be taught to self-administer injections, making the drug a reasonable choice for outpatient therapy. The use of TNF-a inhibitors in pyoderma gangrenosum is not a novel idea. Several studies have shown improvement of pyoderma gangrenosum lesions with infliximab. 21 However, the need for this drug to be infused in the hospital or office setting makes it less than ideal for outpatient therapy. TNF-a inhibitors also have been shown to be effective in a number of other inflammatory conditions such as hidradenitis suppurativa, 22 subcorneal pustular dermatosis, 10 apthous ulcers, 23 and Bechet s disease. 24 CONCLUSION The role of TNF in pyoderma gangrenosum remains unclear. Evidence supports the idea that TNF plays a role in chronic inflammation and the

6 JAM ACAD DERMATOL VOLUME 54, NUMBER 3 S133 migration of neutrophils to these lesions. Multiple isolated disturbances in immune function have been reported in association with pyoderma gangrenosum; however, no single abnormality has been identified as a common denominator. While TNF-a is most likely not the primary disturbance, it is possible that the increased release of this cytokine may be a phenomenon common to all pyoderma gangrenosum lesions regardless of their etiology. There is a need, however, for further evaluation of this theory including tissue TNF levels, serum TNF levels, and further therapeutic trials. We propose the use of etanercept as a possible alternative therapy for lesions of pyoderma gangrenosum unresponsive to conventional therapy. DavidB.Roy,DO a Eugene T. Conte, DO, FAOCD a DavidJ.Cohen,MD b Grandview and Southview Hospitals/Ohio University College of Osteopathic Medicine a Centerville, Ohio Mercer University b Macon, Georgia This case series was investigator initiated. Financial support for the manuscript was provided by Amgen Inc and by Wyeth Research. Conflicts of interest: Dr Roy has no conflicts of interest to disclose. Dr Conte has been a speaker for Amgen, Schering, Genentech, and Allergan. Dr Cohen has been a speaker for Amgen, Genentech, Novartis, and Glaxo, and has conducted research for Amgen, Genentech, 3M, Dermik, Galderma, and Medicis. Reprints not available from the authors. Correspondence to: Eugene T. Conte, DO, FAOCD, ChiefofDermatology Grandview and Southview Hospitals/Ohio University College of Osteopathic Medicine 8940 Kingsridge Dr, Ste 104 Centerville, OH contedrconte@aol.com or DavidB.Roy,DO 1700 Sycamore Ave Kingman, AZ droy2@woh.rr.com REFERENCES 1. Brunsting L, Goeckerman W, O Leary P. Pyoderma gangrenosum: clinical and experimental observations in five cases occurring in adults. Arch Dermatol Syph 1930;22: Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996;34: Hurwitz RM, Haseman JH. The evolution of pyoderma gangrenosum: a clinicopathologic correlation. Am J Dermatopathol 1993;15: Provost TT. Pyoderma gangrenosum. Adv Stud Med 2003;3: Charles CA, Bialy TL, Falabella AF, Eaglstein WH, Kerdel FA, Kirsner RS. Poor prognosis of arthritis-associated pyoderma gangrenosum. Arch Dermatol 2004;140: Shalaby MR, Palladino MA Jr, Hirabayashi SE, Eessalu TE, Lewis GD, Shepard HM, et al. Receptor binding and activation of polymorphonuclear neutrophils by tumor necrosis factor-alpha. J Leukoc Biol 1987;41: Norris P, Poston RN, Thomas DS, Thornhill M, Hawk J, Haskard DO. The expression of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: a comparison of ultraviolet B erythema and delayed hypersensitivity. J Invest Dermatol 1991; 96: Sites D, Terr A, Parslow T, editors. Basic and clinical immunology. Norwalk (CT): Appleton and Lange; Kano Y, Orihara M, Shiohara T. Cellular and molecular dynamics in exercise-induced urticarial vasculitis lesions. Arch Dermatol 1998;134: Voigtlander C, Luftl M, Schuler G, Hertl M. Infliximab (antitumor necrosis factor alpha antibody): a novel, highly effective treatment of recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson disease). Arch Dermatol 2001;137: Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch Dermatol 2002;138: Kawakami T, Ohashi S, Kawa Y, Takahama H, Ito M, Soma Y, et al. Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of Sweet syndrome and patients with active Behcet disease: implication in neutrophil apoptosis dysfunction. Arch Dermatol 2004;140: Singh J, Suruchi A. AntiTNF-alpha strategy: present status of this therapeutic paradigm. Indian J Pharmacol 2004;36: Tarnuzzer R, Schultz G. Biochemical analysis of acute and chronic wound environments. Wound Rep Reg 1996;4: Yamane K, Ihn H, Asano Y, Jinnin M, Tamaki K. Antagonistic effects of TNF-alpha on TGF-beta signaling through downregulation of TGF-beta receptor type II in human dermal fibroblasts. J Immunol 2003;171: Beutler B. TNF, immunity and inflammatory disease: lessons of the past decade. J Investig Med 1995;43: Baker SJ, Reddy EP. Modulation of life and death by the TNF receptor superfamily. Oncogene 1998;17: Mak TW, Yeh WC. Signaling for survival and apoptosis in the immune system. Arthritis Res 2002;4(Suppl 3):S Knight JC, Kwiatkowski D. Inherited variability of tumor necrosis factor production and susceptibility to infectious disease. Proc Assoc Am Physicians 1999;111: EnbrelÒ (etanercept). Full prescribing information [package insert]. Thousand Oaks (Calif): Immunex Corp; Tan MH, Gordon M, Lebwohl O, George J, Lebwohl MG. Improvement of Pyoderma gangrenosum and psoriasis associated with Crohn disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 2001; 137:930-3.

7 S134 J AM ACAD DERMATOL 22. Adams DR, Gordon KB, Devenyi AG, Ioffreda MD. Severe hidradenitis suppurativa treated with infliximab infusion. Arch Dermatol 2003;139: Robinson ND, Guitart J. Recalcitrant, recurrent aphthous stomatitis treated with etanercept. Arch Dermatol 2003;139: Sfikakis PP. Behcet s disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis 2002;61(Suppl 2): ii51-3. doi: /j.jaad A novel therapeutic approach to erythema annulare centrifugum To the Editor: Superficial erythema annulare centrifugum (EAC) is a figurate erythema. Migration or radial expansion of the characteristic geometric and polycyclic plaques occur with leading edges advancing 2 to 3 mm per day.1 Evaluation of cutaneous lesions by light microscopy reveals parakeratosis and spongiosis within the epidermis and a tightly cuffed lymphohistiocytic perivascular infiltrate with focal extravasation of erythrocytes in the papillary dermis.2 Most cases are idiopathic or thought to represent hypersensitivity to an antigen or disease state. There is no standard of care, and treatment must begin with exclusion of known precipitating factors. Topical steroids and antihistamines typically are not beneficial, but topical calcipotriol and tacrolimus have recently yielded success.3,4 Systemically administered prednisone often results in cutaneous clearing, but relapse is common after drug cessation. A 57-year-old white man with a medical history remarkable for well-controlled hypertension, asthma, and osteoarthritis presented with a 1-year history of pruritic, generalized, polycyclic plaques located predominantly on the trunk and extremities (Figure 1A). The patient had received a previous diagnosis of psoriasis, which led to unsuccessful topical steroid, narrowband ultraviolet light, and methotrexate treatment. Multiple courses of systemic prednisone were successful, but the condition returned upon drug withdrawal. Previous biopsy revealed parakeratosis, spongiosis, and a superficial perivascular lymphocytic infiltrate. Additional biopsies taken at the time of presentation revealed similar light microscopy findings; immunostains characterized the inflammatory infiltrate as predominately T lymphocytic. Direct, immunofluorescent, T-cell receptor study, and periodic acid-schiff stains were noncontributory. Cultures for dermatophytic infection revealed no growth. Complete blood count, comprehensive metabolic Fig 1. At week 0 (A), patient has not yet begun etanercept treatment. The front (A1) and back (A2) portions of his upper thigh show signs of severe EAC. Within 4 weeks after initiating etanercept (B), the lesions on the patient s legs have resolved significantly.