Diagnostic Dilemma: Pyoderma Gangrenosum

Department Editor: Tania Phillips, MD, FRCPC Overall Learning Objectives: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Recognize that the diagnosis of pyoderma gangrenosum is a diagnosis of exclusion. 2. Describe the various treatment modalities of pyoderma gangrenosum. 3. Recognize that there are no specific laboratory or histologic clues for pyoderma gangrenosum. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Chakrabarty and Phillips disclose no financial conflicts. Accreditation: HMP Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing education activity for .1 CEUs available to participating podiatrists. Method of Participation: Read the article, take, submit, and pass post-test by October 15, 2003. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: October 15, 2002 Expiration date: October 15, 2003 Presentation A 65-year-old Caucasian woman with a history of Crohn’s disease presented with a three-month history of painful, boggy ulcers on the left anterior abdomen and right upper thigh. She had a recent flare up of her Crohn’s disease a few months prior to the development of the ulcers and was hospitalized. The patient was treated with 6-mercaptopurine, which was discontinued due to abdominal discomfort. Lack of response to sulfasalazine was noted by enlargement of the abdominal ulcer. Her past medical history has been significant for type 2 diabetes mellitus, hypertension, status-post cardiac pacemaker, and aortic insufficiency. Her past surgical history included a complete hysterectomy and cholecystectomy. There was no history of known drug allergies. Her current medication list included glyburide, enalapril, furosemide, mesalamine, prednisone, tacro-limus ointment, and oral cyclosporin. She ceased taking coumadin, once her cardiologist advised her of having a normal cardiac rhythm. The patient did not mention any personal or family history of skin diseases. Physical Examination Physical examination revealed a moderately obese woman with a Cushingoid body habitus. Vital signs were all stable. Her head, neck, chest, and back were normal. Purpuric lesions have been present on both forearms. There were several tender, subcutaneous nodules on the abdomen and bilateral lower extremities. On the left lower abdomen, there was a deep ulcer, measuring 10cm x 10cm, covered with fibrinous debris and an erythematous border (Figures 1 and 2). There was a 3cm x 3cm black necrotic ulcer on the right lateral thigh. Background redness in a reticular pattern suggested livedoid reticularis on the bilateral lower extremities. Initial differential diagnosis mentioned disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, coumadin necrosis, and pyoderma gangrenosum (PG). Investigations Antinuclear antibody (ANA) was 1:640 speckled. Complement levels, erythrocyte sedimentation rate, protein C and protein S levels, complete metabolic profile, thyroid function tests, and total protein electrophoresis were normal. C-ANCA and P-ANCA were negative (antibody titer Pathogenesis. PG is a rapidly evolving ulcerative skin disease of unknown origin. Approximately 50 percent of cases are associated with a systemic disease.1,2 In the United States, the inflammatory bowel diseases, notably ulcerative colitis, are commonly associated with PG.3 Other associated causes include rheumatoid arthritis, myeloproliferative disorders, diverticulitis, paraproteinemia, active chronic hepatitis, and Behçet’s syndrome. Takayasu’s arteritis, a large vessel granulomatous arteriopathy, is the most common underlying disorder associated with pyoderma gangrenosum in Japan.4 The exact pathogenesis of PG is unclear. There are no specific laboratory or histologic features.1 The diagnosis is one of exclusion after a thorough patient evaluation and clinical laboratory tests.5 Clinical features. The lesions associated with PG usually occur on the lower extremities and trunk. The lesions begin as hemorrhagic, painful pustules that develop into ulcers with boggy-red, irregular, undermined borders.6,7 A halo of erythema appears around the advancing ulcer edges. The base of the ulcer is purulent with necrotic debris and hemorrhagic exudate. Pustules may be seen around the edges of the ulcer. The majority of lesions are solitary, but multiple lesions may coalesce into a larger one. Older lesions resolve as new lesions appear. The healing of the ulcer may start from the center and progress peripherally. The patient may appear ill depending upon the underlying condition. Clinical variants of PG are mentioned as classical, atypical, peristomal, and mucosal forms.8 Classical PG is frequently described with inflammatory bowel disease and arthritis. The atypical form of PG is associated with hematologic disorders, such as leukemia. The peristomal PG is commonly described in patients with stomas after oncologic surgery. Treatment In patients with early-stage localized PG, local therapy is effective.9 Topical application of sodium cromoglycate has shown to be beneficial.9 Intra-lesional steroids, such as triamcinolone hexacetonide, injected into the ulcer edges are known to provide significant improvement for early lesions of PG. Topical applications of 5-aminosalicyclic acid, macrophage colony-stimulating factor, and benzoyl peroxide have had successful outcomes. Topical tacrolimus has showed promising results in the treatment of PG. An open case study revealed that topical tacrolimus was more effective than clobetasol ointment as monotherapy for PG lesions, especially for ulcers greater than 2cm in diameter.10 Local wound care, prevention of wound infections, and moisture-retentive dressings are the important basics of daily PG management. For patients without an underlying disorder, systemic corticosteroids with or without an immunosuppressive are the gold standard of therapy.9 Rapid withdrawal can precipitate a recurrence of PG. Alternative agents include dapsone, minocycline, clofazimine, and intravenous immunoglobulins. Low-dose oral steroid and an immunosuppressive may be required for long-term maintenance. Cyclosporine A is a promising steroid-sparing immunosuppressive in refractory cases of PG.9 With nearly 50 percent of PG associated with systemic diseases, an underlying cause should be sought.11 For example, a complete gastrointestinal tract work up is highly recommended for patients with gastrointestinal symptoms. Sulfasalazine is known to be effective for inflammatory bowel diseases. There is one case report documenting the favorable response to intravenous infliximab in a 46-year-old patient with active Crohn’s disease and PG.12 Infliximab is a chimeric antibody against tumor necrosis factor. Currently, there are no randomized, double-blinded, placebo trials documenting the most effective method in the management of PG.5,8 The low incidence of the disease makes it difficult to conduct large-scale randomized trials.9 There are many options available from the therapeutic armamentarium. Individual decision-making plays an important role in patients suffering from pyoderma gangrenosum. Necessary laboratory studies involve complete blood count, sedimentation rate, urinalysis, complete metabolic profile, serum protein electrophoresis, antinuclear antibodies, rheumatoid factor, and rapid plasma reagin.1 A biopsy from the ulcer margin should be sent for histology and cultures. The prognosis of PG remains unpredictable.5 Untreated cases may last from months to years. Management The ulcer on the abdomen was initially treated with intralesional triamcinolone acetonide 40mg/mL and sulfasalazine 500mg tablet four times a day. The sulfasalazine caused nausea and vomiting and, therefore, was discontinued. The patient was started on oral prednisone 60mg daily. Consequently, the patient had difficulty managing her diabetes. The oral immunosuppressive, cyclosporine 150mg twice a day, allowed better control of her blood sugar by reducing the dosage of the prednisone to 20mg daily. The patient has also been started on the topical agent, tacrolimus 0.1 percent. Laboratory values have not revealed any abnormal liver or kidney dysfunction. Vital signs, such as blood pressure, are stable. The patient reports no clinical distress from the current treatment regimen and is currently being followed. How to obtain educational credits by reading this article Successful completion entails scoring at least 70 percent on the questions, completing the entire evaluation form (on the next page), tearing it out or copying it, and sending it to the correct address listed below. Certificates will be mailed to those who successfully complete the learning assessment by October 15, 2003. Fax the completed form to (610) 560-0501 or mail the completed form to: Trish Levy, CME Director HMP Communications 83 General Warren Blvd. Suite 100 Malvern, PA 19355 Questions 1. What percentage of pyoderma gangrenosum cases have an underlying disorder? A. 35 percent B. 50 percent C. 65 percent D. 100 percent 2. What are specific laboratory and histologic clues to pyoderma gangrenosum? A. Thyroid function tests B. Alpha-1-antitrypsin C. Wound culture D. No specific histologic clues 3. How is the diagnosis of pyoderma gangrenosum decided? A. Based on laboratory tests B. By diagnosis of exclusion C. Based on physical examination D. None of the above 4. What is the current gold standard therapy of pyoderma gangrenosum? A. Clofazimine B. Intravenous immunoglobulins C. Dapsone D. Systemic steroids with or without immunosuppressives 5. How do you treat pyoderma gangrenosum associated with a systemic disorder? A. Topical application of sodium cromoglycate B. Topical application of benzoyl peroxide C. Topical tacrolimus D. Treat the underlying disorder 6. Pyoderma gangrenosum does not have randomized, double-blinded placebo trials because of: A. The low incidence of pyoderma gangrenosum B. The difficulty in diagnosing the disease C. The lack of researcher interest D. None of the above 7. Which topical immunosuppressive has been shown to be more effective than topical steroids in an open-ended study? A. Azathioprine B. Cyclosporine A C. Tacrolimus D. None of the above 8. The most common underlying disease associated with PG is: A. Inflammatory bowel disease B. Lymphoma C. Carcinoma of the colon D. Carcinoa of the lung Answer Form and Evaluation (Print off or submit online) Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions above) Circle or click one letter for each answer: 1. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D 6. A B C D 7. A B C D 8. A B C D Evaluation (circle or click one) Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning objectives: 4 3 2 1 Effectiveness of the teaching/learning methods: 4 3 2 1 This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1. Recognize that the diagnosis of pyoderma gangrenosum is a diagnosis of exclusion. YES NO 2. Describe the various treatment modalities of pyoderma gangrenosum. YES NO 3. Recognize that there are no specific laboratory or histologic clues for pyoderma gangrenosum. YES NO What questions do you still have?________________________________________________________ How will you use what you have learned from this activity?________________ All tests must be received by 10/15/03.