Collagenase ointment and topical timolol gel for treating idiopathic pyoderma gangrenosum
Authors: Deede Y. Liu, Ryan Fischer, Garth Fraga, Daniel J. Aires
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: A 77-year-old woman was admitted to a university hospital for evaluation and treatment of a painful and rapidly growing 7.5- × 9-cm ulcer on her right medial ankle. Physical examination showed ulceration with central granulation tissue and surrounding violaceous rim (Fig 1, A). Biopsy demonstrated dermal neutrophilic inflammation with edematous undermining of the epidermis. Fite, Grocott methenamine silver, and Brown-Brenn stains by histochemistry were negative for infectious mycobacteria, fungi, and routine bacteria. Pyoderma gangrenosum (PG) was established as the diagnosis. Past medical history was noncontributory. Workup was negative for underlying malignancy, inflammatory bowel disease, and other autoimmune processes. After intralesional steroid injection (Kenalog 5 mg/mL, 1 mL total volume), the patient was discharged with a 2-week oral prednisone taper and a topical regimen consisting of clobetasol ointment with topically applied crushed dapsone under occlusive Biatain absorbent polyurethane foam dressings. For the first month the lesion responded well, and by day 33 the ulcer had decreased to 6 × 6 cm. At this time, the patient was given a second intralesional steroid injection and was started on timolol maleate 0.5% gel applied topically to the entire border of the ulcer daily while continuing both topical clobetasol and dapsone. However, progress ceased during the second month and on day 61 the ulcer was still 6 × 6 cm (Fig 1, B). The patient wished to discontinue topical dapsone due to discomfort and declined systemic medications. We prescribed daily topical collagenase 250 U/g ointment (Santyl) to the entire ulcer bed, in addition to continued daily topical timolol gel. Over the next 30 days, the wound became more shallow and steadily decreased in size from 36 cm2 to 10 cm2. After 36 more days of topical collagenase and timolol gel under occlusion, the ulcer was completely reepithelialized (Fig 1, C). There are currently no specific or uniformly effective therapies for PG; most are directed at reducing inflammation. One alternative approach focuses on enhancing keratinocyte migration to speed reepithelialization. Keratinocytes express beta2-adrenergic receptors, and can also produce beta-adrenergic receptor agonists that decrease keratinocyte migration.1Pullar C.E. Grahn J.C. Liu W. Isseroff R.R. Beta2-adrenergic receptor activation delays wound healing.FASEB J. 2006; 20: 76-86Crossref PubMed Scopus (86) Google Scholar Topical beta2-adrenergic receptor antagonists such as timolol have shown efficacy in treating chronic venous leg ulcers2Lev-Tov H. Dahle S. Moss J. Isseroff R.R. Successful treatment of a chronic venous leg ulcer using a topical beta-blocker.J Am Acad Dermatol. 2013; 69: e204-e205Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar and other recalcitrant wounds.3Braun L.R. Lamel S.A. Richmond N.A. Kirsner R.S. Topical timolol for recalcitrant wounds.JAMA Dermatol. 2013; 149: 1400-1402Crossref PubMed Scopus (40) Google Scholar, 4Tang J.C. Dosal J. Kirsner R.S. Topical timolol for a refractory wound.Dermatol Surg. 2012; 38: 135-138Crossref PubMed Scopus (35) Google Scholar Topical timolol gel is also widely used in ulcerated infantile hemangiomas.5Thomas J. Kumar P. Kumar D.D. Ulcerated infantile haemangioma of buttock successfully treated with topical timolol.J Cutan Aesthet Surg. 2013; 6: 168-169Crossref PubMed Google Scholar Of note, our patient used the timolol gel and not the solution. Improving removal of necrotic tissue and exuberant granulation could present another alternative approach to enhance wound healing. In PG, manual debridement is contraindicated due to pathergy risk. Collagenase ointment contains the metalloproteinases collagenase I and collagenase II, and may also have other anti-inflammatory properties. It has been shown to improve outcomes in burns and chronic wounds. To our knowledge, use of enzymatic debridement has not been previously reported in PG. In light of the negative side effects of chronic systemic steroid use and the frequently recalcitrant nature of PG, daily topical timolol gel applied to the ulcer border and collagenase ointment applied to the ulcer base may present a useful alternative for treatment of chronic idiopathic PG.