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Evidence-Based Dermatology: Critically Appraised Topic |

Is Topical Monotherapy Effective for Localized Pyoderma Gangrenosum? FREE

Laurence Le Cleach, MD; Philippe Moguelet, MD; Pascal Perrin, MD; Olivier Chosidow, MD, PhD
Arch Dermatol. 2011;147(1):101-103. doi:10.1001/archdermatol.2010.393.
Text Size: A A A
Published online

Clinical Question: Is topical treatment alone effective for localized pyoderma gangrenosum (PG), and if yes, is one more effective than the others?

In May 2008, a 32-year-old woman was seen with a painful infiltrated erythematous lesion 11 cm in diameter, studded with purulent necrotic pits, on the anterior right shin (Figure, A). It had started as an erythematous infiltrated lesion 3 months previously and had been stable for 1 month. Pyoderma gangrenosum was diagnosed based on the clinical appearance, negative findings on bacterial culture, and histologic examination of a skin biopsy specimen. No systemic underlying disease was found during investigations, including a colonoscopy.

Place holder to copy figure label and caption
Figure.

The patient's pyoderma gangrenosum lesion before treatment (May 2008) (A) and after topical treatment (September 2008) (B).

Graphic Jump Location

There is little evidence on the efficacy of PG treatment because there is only 1 randomized controlled trial to date comparing the effects of infliximab vs placebo.1 Systemic corticosteroids and cyclosporine are usually recommended as first-line treatments.2 Given the stability of this solitary lesion, we decided to consider the option of topical monotherapy for our patient. The objective of this article was to determine from the available evidence whether a topical agent would be an effective and safe treatment in this setting.

We searched MEDLINE and the Cochrane Controlled Trials Register for each topical agent cited in reviews and textbooks on PG treatment, including hyaluronic acid, becaplermin, topical corticosteroids, clobetasol, betamethasone, intralesional corticosteroids, topical cyclosporine, mesalamine, topical nitrogen mustard, sodium cromoglycate, benzoyl peroxide, pimecrolimus, tacrolimus, and pyoderma gangrenosum. We selected all trials, case series, and case reports describing PG treatment with a topical agent as monotherapy. In addition, we searched for relevant publications in each article's reference list.

We found no randomized controlled trial. Except for topical corticosteroids and calcineurin inhibitors, we found 1 to 10 reported cases for each topical or intralesional treatment. We considered these data too limited to conduct a valuable analysis.

We found 16 publications on PG treatment with topical tacrolimus or topical corticosteroids without an associated systemic treatment:

Topical tacrolimus: 2 prospective case series and 4 case reports38;

Topical corticosteroids: 2 retrospective series and 7 case reports917; and

One trial comparing topical clobetasol propionate treatment with topical tacrolimus treatment.18

One case report13 was excluded because it lacked information on treatment dosage and disease response.13

Although case series are subject to patient selection bias and case reports preferentially describe positive outcomes,19 they often provide preliminary evidence for efficacy of new treatments. We analyzed 4 case series and 10 case reports using a checklist for quality assessment of these types of communications.19

Diagnostic criteria were clearly identified and met by patients in 9 articles3,7,1012,1417 of 14. Although an institutional review board approved 1 prospective case series,4 patient consent was not documented in any of the publications. No reference to the natural course of the disease or its outcome based on standard treatment was clearly stated in any study. The clinically important outcome of complete healing was mentioned in all publications.

The aesthetic appearance of the scar and the patient's perception of the treatment outcome, which are also important, were not mentioned in any of the publications. Potential risks and adverse effects of treatment were discussed in only 1 article.6 The authors abstained from unfounded claims about safety or efficacy in 12 of 14 reports.4,5,712,1417 In the case series, inclusion and exclusion criteria were not given, nor was it stated whether all consecutive cases were included or what were reasons for noninclusion.

The open-label nonrandomized trial compared clobetasol, 0.05%, (n = 13) with tacrolimus, 0.3%, (n = 11) for treatment of peristomal PG.18 However, the study design did not allow statistical comparison between treatments. Patients recruited initially were treated with clobetasol, whereas those recruited later were treated with tacrolimus. There was no discussion of comparability between groups at study inclusion, nor were any clear inclusion criteria listed for the choice of topical vs systemic treatment.

Together, among the open-label trial18 and the aforementioned 15 other relevant publications, 26 patients received topical tacrolimus, and 46 patients received topical corticosteroids. Twelve patients received tacrolimus, 0.3%, once a day, and 7 patients received tacrolimus, 0.1%, once a day, whereas 7 patients had neither the dosage nor the number of applications specified. Among patients who used topical corticosteroids, 24 received clobetasol, 11 betamethasone dipropionate, 2 triamcinolone acetonide paste, 4 hydrocortisone, and 1 acetonide; the type of topical corticosteroid used was unspecified for 4 patients.

All 18 cases of nonperistomal PG were localized, and an underlying disease was present in 8 of 18. Characteristics of lesions and responses to topical treatment are summarized in the Table. Serum tacrolimus levels were available in 17 patients and were always below the therapeutic range. However, the daily amount of tacrolimus used was not reported for any patient. Other than exuberant granulation tissue in 11 patients and burning sensation in 1 patient, no adverse effects were reported. For topical corticosteroid outcomes, the authors of 1 case series9 reported that there were no adverse effects, whereas the other publications mentioned neither the presence nor the absence of adverse effects.

Table Graphic Jump LocationTable. Characteristics of Pyoderma Gangrenosum (PG) Lesions and Their Outcomes by Topical Agent Prescribed

The absence of adverse effects should be balanced by 2 reported cases of PG with serum tacrolimus levels higher than the therapeutic range.20,21 These occurred with topical treatment of high tacrolimus dosages (7.5 g/d or 15 g/d).

Our search was limited to MEDLINE and the Cochrane Controlled Trials Register. A relevant clinical case published in German was excluded.22 Our conclusions are based on a small open trial18 and on 15 aforementioned case reports.

Among local therapies (hyaluronic acid, becaplermin, topical corticosteroids, intralesional corticosteroids, topical cyclosporine, mesalamine, topical nitrogen mustard, sodium cromoglycate, benzoyl peroxide, pimecrolimus, and tacrolimus) reported as potential treatment for PG, our analysis of the literature showed that the best evidence is available for topical corticosteroids and tacrolimus. Most analyzed cases involved peristomal PG, and the others involved localized PG with or without an underlying disease. No apparent differences in complete healing rates were seen between peristomal and nonperistomal PG, with no clear evidence that one type of topical treatment is better than another.

Despite limited available evidence, topical monotherapy with corticosteroids or tacrolimus is a reasonable treatment option for localized and limited PG. However, there is insufficient evidence to advise the frequency of topical application, class of topical corticosteroids, tacrolimus dosage, or use of occlusive dressing. Furthermore, the risk of systemic absorption has to be considered.

We decided to commence topical monotherapy in our patient and chose a topical corticosteroid based on a better risk profile and the lower cost. Clobetasol propionate ointment, 0.05%, was applied once daily for 1 month and every other day for 1 month. At the end of this period, the ulceration was partially healed. The patient was concerned about the development of cutaneous atrophy and depigmentation, and 2 new erythematous nodules had developed on the treated area. Topical tacrolimus has no atrophogenic potential, so we switched treatment from topical clobetasol to topical tacrolimus, 0.1%, ointment once daily without occlusion. The remaining part of the lesion healed completely after 6 weeks (Figure, B). The patient had reported a burning sensation after application during the 2 first weeks of treatment. A recurrence appeared 7 months later on the upper left part of the scar, was again treated with tacrolimus, 0.1%, ointment once daily, and disappeared completely in 2 weeks.

Correspondence: Laurence Le Cleach, MD, Department of Dermatology, Centre Hospitalier Sud Francilien, 59 Blvd Henri Dunant, 91106 Corbeil-Essonnes, France (laurence.lecleach@free.fr).

Accepted for Publication: September 25, 2010.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Le Cleach and Chosidow. Acquisition of data: Le Cleach and Moguelet. Analysis and interpretation of data: Le Cleach, Perrin, and Chosidow. Drafting of the manuscript: Le Cleach. Critical revision of the manuscript for important intellectual content: Moguelet, Perrin, and Chosidow. Study supervision: Moguelet, Perrin, and Chosidow.

Financial Disclosure: Dr Chosidow served as a consultant to Astellas Pharma for a product other than those discussed herein.

Brooklyn  TNDunnill  MGShetty  A  et al.  Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut 2006;55 (4) 505- 509
PubMed Link to Article
Reichrath  JBens  GBonowitz  ATilgen  W Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005;53 (2) 273- 283
PubMed Link to Article
Marzano  AVTrevisan  VLazzari  RCrosti  C Topical tacrolimus for the treatment of localized, idiopathic, newly diagnosed pyoderma gangrenosum. J Dermatolog Treat 2010;21 (3) 140- 143
PubMed Link to Article
Kontos  APKerr  HAFivenson  DPRemishofsky  CJacobsen  G An open-label study of topical tacrolimus ointment 0.1% under occlusion for the treatment of pyoderma gangrenosum. Int J Dermatol 2006;45 (11) 1383- 1385
PubMed Link to Article
Deckers-Kocken  JMPasmans  SG Successful tacrolimus (FK506) therapy in a child with pyoderma gangrenosum. Arch Dis Child 2005;90 (5) 531
PubMed Link to Article
Khurrum Baig  MMarquez  HNogueras  JJWeiss  EGWexner  SD Topical tacrolimus (FK506) in the treatment of recalcitrant parastomal pyoderma gangrenosum associated with Crohn's disease: report of two cases. Colorectal Dis 2004;6 (4) 250- 253
PubMed Link to Article
Vidal  DAlomar  A Successful treatment of periostomal pyoderma gangrenosum using topical tacrolimus. Br J Dermatol 2004;150 (2) 387- 388
PubMed Link to Article
Reich  KVente  CNeumann  C Topical tacrolimus for pyoderma gangrenosum. Br J Dermatol 1998;139 (4) 755- 757
PubMed Link to Article
Lyon  CCSmith  AJGriffiths  CEBeck  MH Peristomal dermatoses: a novel indication for topical steroid lotions. J Am Acad Dermatol 2000;43 (4) 679- 682
PubMed Link to Article
Nybaek  HOlsen  AGKarlsmark  TJemec  GB Topical therapy for peristomal pyoderma gangrenosum. J Cutan Med Surg 2004;8 (4) 220- 223
PubMed Link to Article
Peachey  RD Proceedings: Pyoderma gangrenosum of scalp. Br J Dermatol 1974;90 (1) 106- 108
PubMed
Ko  CBWalton  SWyatt  EH Pyoderma gangrenosum: associations revisited. Int J Dermatol 1992;31 (8) 574- 577
PubMed Link to Article
Ravi  MDSanju  N Pyoderma gangrenosum. Indian Pediatr 2000;37 (11) 1277
PubMed
Rosina  PCunego  SFranz  CZD’Onghia  FSChieregato  G Pathergic pyoderma gangrenosum in a venous ulcer. Int J Dermatol 2002;41 (3) 166- 167
PubMed Link to Article
Sakai  HOtsubo  SIizuka  H Peristomal pyoderma gangrenosum associated with rectal adenocarcinoma. J Dermatol 2006;33 (1) 68- 70
PubMed Link to Article
Sanz-Muñoz  CMartínez-Morán  CMiranda-Romero  A Pyoderma gangrenosum following cesarean delivery [in Spanish]. Actas Dermosifiliogr 2008;99 (6) 477- 480
PubMed Link to Article
Mehta  AJCharman  CR Pyoderma gangrenosum in association with autoimmune neutropenia of infancy. Pediatr Dermatol 2008;25 (6) 620- 622
PubMed Link to Article
Lyon  CCStapleton  MSmith  AJMendelsohn  SBeck  MHGriffiths  CE Topical tacrolimus in the management of peristomal pyoderma gangrenosum. J Dermatolog Treat 2001;12 (1) 13- 17
PubMed Link to Article
Albrecht  JWerth  VPBigby  M The role of case reports in evidence-based practice, with suggestions for improving their reporting. J Am Acad Dermatol 2009;60 (3) 412- 418
PubMed Link to Article
Ghislain  PDDe Decker  ILachapelle  JM Efficacy and systemic absorption of topical tacrolimus used in pyoderma gangrenosum. Br J Dermatol 2004;150 (5) 1052- 1053
PubMed Link to Article
Pitarch  GTorrijos  AMahiques  LSánchez-Carazo  JLFortea  JM Systemic absorption of topical tacrolimus in pyoderma gangrenosum. Acta Derm Venereol 2006;86 (1) 64- 65
PubMed
Petering  HKiehl  PBreuer  CKapp  AWerfel  T Pyoderma gangrenosum: successful topical therapy with tacrolimus (FK506) [in German]. Hautarzt 2001;52 (1) 47- 50
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

The patient's pyoderma gangrenosum lesion before treatment (May 2008) (A) and after topical treatment (September 2008) (B).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Characteristics of Pyoderma Gangrenosum (PG) Lesions and Their Outcomes by Topical Agent Prescribed

References

Brooklyn  TNDunnill  MGShetty  A  et al.  Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut 2006;55 (4) 505- 509
PubMed Link to Article
Reichrath  JBens  GBonowitz  ATilgen  W Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005;53 (2) 273- 283
PubMed Link to Article
Marzano  AVTrevisan  VLazzari  RCrosti  C Topical tacrolimus for the treatment of localized, idiopathic, newly diagnosed pyoderma gangrenosum. J Dermatolog Treat 2010;21 (3) 140- 143
PubMed Link to Article
Kontos  APKerr  HAFivenson  DPRemishofsky  CJacobsen  G An open-label study of topical tacrolimus ointment 0.1% under occlusion for the treatment of pyoderma gangrenosum. Int J Dermatol 2006;45 (11) 1383- 1385
PubMed Link to Article
Deckers-Kocken  JMPasmans  SG Successful tacrolimus (FK506) therapy in a child with pyoderma gangrenosum. Arch Dis Child 2005;90 (5) 531
PubMed Link to Article
Khurrum Baig  MMarquez  HNogueras  JJWeiss  EGWexner  SD Topical tacrolimus (FK506) in the treatment of recalcitrant parastomal pyoderma gangrenosum associated with Crohn's disease: report of two cases. Colorectal Dis 2004;6 (4) 250- 253
PubMed Link to Article
Vidal  DAlomar  A Successful treatment of periostomal pyoderma gangrenosum using topical tacrolimus. Br J Dermatol 2004;150 (2) 387- 388
PubMed Link to Article
Reich  KVente  CNeumann  C Topical tacrolimus for pyoderma gangrenosum. Br J Dermatol 1998;139 (4) 755- 757
PubMed Link to Article
Lyon  CCSmith  AJGriffiths  CEBeck  MH Peristomal dermatoses: a novel indication for topical steroid lotions. J Am Acad Dermatol 2000;43 (4) 679- 682
PubMed Link to Article
Nybaek  HOlsen  AGKarlsmark  TJemec  GB Topical therapy for peristomal pyoderma gangrenosum. J Cutan Med Surg 2004;8 (4) 220- 223
PubMed Link to Article
Peachey  RD Proceedings: Pyoderma gangrenosum of scalp. Br J Dermatol 1974;90 (1) 106- 108
PubMed
Ko  CBWalton  SWyatt  EH Pyoderma gangrenosum: associations revisited. Int J Dermatol 1992;31 (8) 574- 577
PubMed Link to Article
Ravi  MDSanju  N Pyoderma gangrenosum. Indian Pediatr 2000;37 (11) 1277
PubMed
Rosina  PCunego  SFranz  CZD’Onghia  FSChieregato  G Pathergic pyoderma gangrenosum in a venous ulcer. Int J Dermatol 2002;41 (3) 166- 167
PubMed Link to Article
Sakai  HOtsubo  SIizuka  H Peristomal pyoderma gangrenosum associated with rectal adenocarcinoma. J Dermatol 2006;33 (1) 68- 70
PubMed Link to Article
Sanz-Muñoz  CMartínez-Morán  CMiranda-Romero  A Pyoderma gangrenosum following cesarean delivery [in Spanish]. Actas Dermosifiliogr 2008;99 (6) 477- 480
PubMed Link to Article
Mehta  AJCharman  CR Pyoderma gangrenosum in association with autoimmune neutropenia of infancy. Pediatr Dermatol 2008;25 (6) 620- 622
PubMed Link to Article
Lyon  CCStapleton  MSmith  AJMendelsohn  SBeck  MHGriffiths  CE Topical tacrolimus in the management of peristomal pyoderma gangrenosum. J Dermatolog Treat 2001;12 (1) 13- 17
PubMed Link to Article
Albrecht  JWerth  VPBigby  M The role of case reports in evidence-based practice, with suggestions for improving their reporting. J Am Acad Dermatol 2009;60 (3) 412- 418
PubMed Link to Article
Ghislain  PDDe Decker  ILachapelle  JM Efficacy and systemic absorption of topical tacrolimus used in pyoderma gangrenosum. Br J Dermatol 2004;150 (5) 1052- 1053
PubMed Link to Article
Pitarch  GTorrijos  AMahiques  LSánchez-Carazo  JLFortea  JM Systemic absorption of topical tacrolimus in pyoderma gangrenosum. Acta Derm Venereol 2006;86 (1) 64- 65
PubMed
Petering  HKiehl  PBreuer  CKapp  AWerfel  T Pyoderma gangrenosum: successful topical therapy with tacrolimus (FK506) [in German]. Hautarzt 2001;52 (1) 47- 50
PubMed Link to Article

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