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Pyoderma Gangrenosum - Treatment

Pyoderma Gangrenosum - Treatment

Pyoderma Gangrenosum - Treatment

ABSTRACT

For introduction and assessment: See "Pyoderma Gangrenosum - Introduction and Assessment"

Treatment summary:

See 'Algorithm for Management of Pyoderma Gangrenosum'

Currently, there is no definitive guideline or gold standard in management of pyoderma gangrenosum, as data from controlled clinical trials are scarce. As a result, management is guided primarily by small non-randomized controlled studies, and clinical experience. 

Hospital admission: indications include severe/ fulminant pyoderma gangrenosum, need for systemic immunosuppression, spreading or systemic infection 

An adequate treatment plan aims to: 

  • Treat the cause:
    • Aberrant inflammatory response is managed with therapeutic agents and avoidance of triggers. See topical and systemic therapies
    • Underlying associated disorders (e.g. inflammatory bowel disease, hematological disorders, etc) should be addressed, although the course of these disorders may not directly correlate with that of pyoderma gangrenosum.[1]
    • Factors and co-morbidities that commonly impede wound healing should be addressed as well (e.g. with nutrition optimization, smoking cessation, glycemic control).
  • Address patient's concerns
    • Pain management is crucial to relieve patient's anxiety and avoid depression, decreased quality of life and wound healing impairment. See pain management.
  • Provide effective wound care:

Plan reassessment:

  • If lesions do not show signs of improvement after therapeutic agents have been initiated, the initial treatment plan should be reassessed, differential diagnoses re-evaluated, and adjunctive therapies considered. If clinical condition worsens after introduction of immunosuppressants, these should be discontinued and other differential diagnoses should be ruled out. See details in section 'Plan Reassessment' 

Adjunctive interventions: 

  • Data supporting adjunctive interventions are limited. Adjuncts include systemic targeted therapy with biologic agents, wound coverage with cellular and/or tissue products or autologous skin grafting, negative pressure wound therapy. See adjunctive therapies.

When to refer to specialists:

  • Dermatologists: for systemic treatment
  • Rheumatologist, hematologist: if associated rheumatological or hematological diseases are present
  • Gastroenterologist: if gastrointestinal symptomatology is prominent or problematic.
  • Wound care specialist: for non-healing wounds
  • Ostomy specialist: if in a periostomal location
  • Surgeon: if post-surgical onset
  • Other specialists as needed to help rule out other differential diagnoses

ICD-10 Coding: See section 'Coding' in topic "Pyoderma Gangrenosum - Introduction and Assessment"

TREATMENT

Overview

This topic covers management of pyoderma gangrenosum. For a framework on assessment of pyoderma gangrenosum including epidemiology, risk factors, etiology, pathophysiology, history, physical examination, diagnosis, differential diagnoses, documentation and ICD-10 coding, see "Pyoderma Gangrenosum - Introduction and Assessment". 

Background

Pyoderma gangrenosum is a rare but serious primary ulcerating condition of the skin that falls into the category of neutrophilic dermatoses. The course of the disease varies from limited to aggressive, and it is often associated with systemic diseases, of which the most frequent are inflammatory bowel disease, inflammatory arthritis, and hematological disorders.[1] Development of a treatment plan requires comprehensive assessment including history, physical exam and biopsy of the lesion. See topic "Pyoderma Gangrenosum - Introduction and Assessment". 

Currently, there is no definitive guideline or gold standard in management of pyoderma gangrenosum. The paucity of studies and lack of validated outcome measures makes it difficult to conduct pyoderma gangrenosum clinical trials and establish high quality evidence guidelines. Common outcome measures such as resolution of ulcers are not ideal for assessing response to treatment because even after the pathogenic inflammation has resolved pyoderma gangrenosum lesions take weeks or months to heal. Also, co-morbidities not associated with the pathogenic immune response such as obesity, diabetes, edema, and others may contribute to the inability of an ulcer to heal. The low incidence of the disease has also made randomized clinical trials problematic.[2] As a result, management is guided primarily by small non-randomized controlled studies, and clinical experience. 

Nevertheless, an adequate treatment plan aims to: 

  • Treat the cause and other factors impeding healing
  • Assess patient's and caregiver's concerns
  • Provide customized local wound care

If the lesions do not show signs of improvement after therapeutic agents have been initiated, the initial treatment plan should be reassessed, differential diagnoses re-evaluated, and adjunctive therapies considered. If clinical condition worsens after introduction of immunosuppressants, these should be discontinued and other differential diagnoses should be ruled out. See section 'Plan Reassessment' below.

See Algorithm for Management of Pyoderma Gangrenosum (Algorithm 1)

Algorithm 1. Management of Pyoderma Gangrenosum (click on this link to enlarge)


Treatment goals

Regardless of the therapeutic agent used, the goal of therapy is the same: reduce the aberrant inflammatory response to promote wound healing while minimizing adverse drug events.[1]

Treat the cause and co-factors impeding healing

Aberrant inflammatory response and resulting pyoderma gangrenosum ulcers are managed with therapeutic agents (topical, systemic, and adjunct targeted immuno-modulatory therapies), avoidance of triggers, adequate pain control, and appropriate wound care. Underlying associated disorders (e.g. inflammatory bowel disease, hematological disorders, etc) should be addressed, although the course of these disorders may not directly correlate with that of pyoderma gangrenosum.[1] Factors and co-morbidities that commonly impede wound healing (e.g. nutrition optimization, smoking cessation, glycemic control) should be addressed as well.

Management with therapeutic agents

The disease presents itself in mild/indolent to more severe/fulminant forms. Depending on the clinical presentation, therapeutic agents used in the management of pyoderma gangrenosum will include topical, intralesional and/or systemic drugs.

Limited/mild Pyoderma gangrenosum
  • 2CFor patients with mild pyoderma gangrenosum (e.g., single lesions smaller than 2 x 2 cm), as first line therapy, clinicians might opt for high potency topical corticosteroids, intralesional corticosteroids, or topical calcineurin inhibitors (Grade 2C).[1][3][4]
    • Rationale: Patients with limited pyoderma gangrenosum have been reported to respond to topical or intralesional therapy without the need for systemic therapy.[1] Corticosteroids (topical or intralesional) or calcineurin inhibitors (topical) have been used as first line therapy. Other reported treatments include topical sodium cromoglycate, nicotine, 5-aminosalicylic acid, intralesional cyclosporine, and topical dapsone.[4][5][6][7][8] 
    • Dosage: topical corticosteroids (e.g., clobetasol propionate 0.05% 1-2 times daily), intralesional corticosteroids (e.g., intralesional triamcinolone diacetate, between 6 and 40 mg/mL in the peri-wound), or topical calcineurin inhibitors (tacrolimus 0.03% or 0.1%,1-2 times daily).[1][3][4]
    • Response: A prospective cohort study reported that almost half (43.8%) of 66 patients with limited pyoderma gangrenosum who received topical therapy healed within 6 months (clobetasol proprionate 0.05% was the most commonly prescribed drug).[3] If topical treatment fails, systemic treatment is initiated.
More extensive/ severe Pyoderma gangrenosum
  • 2CFor patients with more extensive or severe pyoderma gangrenosum, or patients with limited pyoderma gangrenosum that does not respond to topical therapy, systemic immunosuppressants are warranted and hospitalization should be considered. Selection of a systemic immunosuppressant should be individualized based on potential side effects, severity of the disease and medical comorbidities (Grade 2C). [9]
    • Rationale: More severe presentations of pyoderma gangrenosum warrant management with systemic medications. Among options, corticosteroids and cyclosporine are best studied. Their rapid onset of action makes them excellent choices for initial therapy. To date however, there has been only one randomized controlled trial evaluating systemic immunosuppressants for pyoderma gangrenosum. The study compared corticosteroid and cyclosporine and found that both treatment arms had similar overall healing rates (47% at six months), but serious adverse reactions, such as infections, were more common in the prednisolone group.[10] Topical agents described above are frequently used in association with systemic therapy.
    • Dosage: Oral prednisone can be administered at 0.5-1 mg/Kg/day. For hospitalized patients, initial doses can be administered intravenously, to accelerate response. Intravenous methylprednisolone can be started with 100 mg (daily in single dose) for several days, then tapered down to 60-80 mg/day for several days before switching to oral prednisone at 40-60 mg/day and tapering as tolerated.[11] For severe presentations, intravenous pulse corticosteroid at 1000 mg (1g) /day for 5 days may be used as initial therapy, although some still consider this high dosage as an experimental treatment modality.[1][12][11] An alternative to cyclosporine may be oral tacrolimus although it has not been well studied in the setting of pyoderma gangrenosum.[13] Other oral and intravenous medications that have been reported to successfully treat pyoderma gangrenosum include: azathioprine, sulfasalazine, dapsone, thalidomide, minocycline, clofazimine, methotrexate, mycophenolate mofetil, tacrolimus, and cyclophosphamide [14][15][16][17][18][19][20][21][12][22][23][24][25][26][27]
    • Response: Signs of clinical improvement after initiation of systemic treatment typically are seen 24-72 hours after initiation of treatment. Disappearance of pain is the most remarkable feature, other features include halt of enlargement, less induration, or less erythema.[28]  
    • Coordination of care: Suffice it to say that the initiation of systemic medications to treat pyoderma gangrenosum is best left to Dermatology or Rheumatology specialists that are familiar with the various immunosuppressants and biologic agents. Prompt referral for systemic treatment of pyoderma gangrenosum should occur as soon as the likelihood of diagnosis is confirmed.[29] Consultation with Gastroenterology may be considered if gastrointestinal symptomatology is prominent or problematic.

Address Patient's Concerns

Pain

  • Pyoderma gangrenosum can be extremely painful, especially when lesion is progressing. Pain management is crucial to relieve patient's anxiety and avoid depression, decreased quality of life and wound healing impairment.[1] 
  • Pain can be managed with topical agents, systemic acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opiates. 

Local Wound Care

The role of wound care in the management of pyoderma gangrenosum follows the rational path that patients receive traditional wound care after they have been successfully immunosuppressed.

Cleansing

  • Ulcers should be gently cleansed with a pH-neutral, non-irritating, non-toxic solution during each dressing change. Gently cleanse with sterile saline, water, 0.5-1% acetic acid, or wound cleanser. Tap water from a reliable source does not increase infection rate.[30] 

Debridement 

  • To minimize trauma to the ulcer bed and minimize chances of pathergy (exarcerbation of pyoderma gangrenosum upon tissue injury), if debridement of pyoderma gangrenosum lesions is needed to reduce bacterial load or excessive necrotic debris, it should be limited to obvious nonviable tissue and undertaken utilizing options such as non-surgical debridement (including enzymatic or autolytic debridement), conservative sharp debridement, ultrasonic debridement or hydrosurgery technique.[1][31] 
  • For extensive wounds with or without necrosis, surgical debridement may be necessary for debridement and/or obtaining coverage.[11] Should surgery be necessary in patients with pyoderma gangrenosum, the use of pre- and peri-operative steroids may be of benefit. Certainly, before initiation of steroid therapy, discussion with appropriate consultants should include dosage of medication and goals of treatment, establishing parameters for monitoring and completing treatment. 

Infection management and bioburden control

  • If signs of localized infection (e.g, increased exudate, redness, size, pain) are present, wound culture is collected with a validated method (e.g., Levine), and topical antimicrobial agents (e.g. antimicrobial dressings) are initiated.[32] Common antibacterial agents are silver dressings and cadexomer iodine, which prevent/limit infections and limit maceration.[33] Dressings with methylene blue and gentian violet have also been used for pyoderma gangrenosum. 
  • Non-healing ulcers may also benefit from topical antimicrobial agents. 
  • Spreading or systemic infection warrants initiation of systemic antibiotics in associating with topical antimicrobial agents, after wound culture is obtained.

Moisture management and dressing selection

Selection of primary and secondary dressings should follow established wound bed preparation principles.[34][35][36][37] For customized, wound-specific recommendations and customized wound documentation, use Wound Prep and Dress Tool. For practical information on dressing indications, contraindications, application, Medicare coverage and brands see "Dressing Essentials" and "Dressing Brands Quick Reference". General recommendations regarding dressings for pyoderma gangrenosum are listed below. 

  • There are no high quality studies to recommend one dressing over another in the management of pyoderma gangrenosum ulcers.
    • For exudative wounds, absorptive dressings such as gelling fibers and alginates and foam are suggested. 
    • For wounds with none to minimal exudate, transparent film maintains moisture and offers protection.
    • For periostomal wounds, specialized non-adherent pouch systems offer minimal risk for exacerbating wounds from adhesive-related trauma.[33][38] Two-piece pouch systems minimize disruption to skin re-epithelialization and help ensure appropriate intervals of pouch changes. It is important that ostomy appliance be properly fit, to prevent leakage of intestinal contents on the surrounding skin.[33]

Plan Reassessment

  • For patients with limited pyoderma gangrenosum, if signs of improvement are not obvious within 2 or 3 weeks of topical therapy, clinicians may consider initiation of systemic therapy.
  • For patients who are being assessed for more extensive/ severe pyoderma gangrenosum and have been started on systemic therapy while workup results are pending, local signs (e.g. pain, erythema) are expected to improve within 24-72 hours of initiation of systemic therapy. If no improvement is seen, an assessment of the overall picture including labs is warranted. If findings indicate a worsening clinical picture, steroids should be discontinued, and mimickers such as atypical or necrotizing infections ruled out.[11]
  • Patients with rapidly progressing lesions and/or extensive systemic involvement, or failure to respond to outpatient management may benefit from hospitalization, in order to allow close observation, intravenous antibiotics, wound and pain management and multidisciplinary care.[11]
  • If the ulcer does not resolve with treatment, it is important to consider a new biopsy of the edge of the active ulcer.[39] See how to conduct a comprehensive assessment in the topic "Pyoderma Gangrenosum - Introduction and Assessment"

Prognosis

  • While signs of improvement may be noticed within days of initiation of therapy, complete healing may take months.[3][40] With adequate treatment, complete healing can be expected in more than half of the cases.[41][40]  As ulcers take time to heal following successful suppression of the aberrant pathogenic immune response, the persistence of an ulcer does not necessarily mean that a pyoderma gangrenosum patient has failed to respond to immunosuppressive therapy. Other factors such as edema, induced by high dose prednisone and cytotoxic immunosuppression therapy can inhibit wound healing; diabetes induced by prednisone therapy; heavy bacterial colonization can delay wound healing in a patient otherwise appropriately immunosuppressed.

Adjunctive Therapies

Systemic targeted therapy (biologics)

Over the past ten years, new parenteral protein drugs have changed the treatment options for patient with immune-mediated disease. These “biologic” medications are highly sophisticated proteins that target key components of the immune system.[42] Unfortunately, there has been very little consistency in the published biologic treatment regimens for pyoderma gangrenosum, and evidence supporting use of biologics is currently limited. 

  • If pyoderma gangrenosus response to immunosuppressants (corticosteroids, tacrolimus, cyclosporine) is suboptimal, second-line therapy with TNF blockers may be considered. 
    • More clinical trials are needed to better define the efficacy of biologicals in pyoderma gangrenosum.[1] However, pyoderma gangrenosum has been reported to respond to many biologic medications, most commonly the TNF blockers: infliximab (strongest evidence among biologics)[15]etanercept [43][44][45][46], adalimumab [47][48][49]IL-1 antagonists and IL-12/23 antagonists represent other theoretically possible therapies. New biologics are continuously being developed and it is likely that some will prove useful in the management of pyoderma gangrenosum. It is difficult to predict long-term risks of starting patients on biologic medications.[42] Patients need to be screened prior to the initiation of a biologic therapy and monitored serially for reactivation or infection while on therapy.
  • Intravenous immunoglobulin (IVIG) has also been used to treat pyoderma gangrenosum.[50][51][52] Adverse drug reactions include anaphylaxis, aseptic meningitis and headaches.

Wound Coverage

Cellular and/or Tissue Products
  • Grafting with Cellular and/or Tissue Products (i.e. skin substitutes) such as bioengineered dressings or allografts can provide options for slow healing, medium-sized ulcers that are devoid of an inflammatory border. Data however has been lacking in supporting outcomes using these techniques. A case report described use of one patient successfully treated with a porcine urinary bladder matrix and negative-pressure wound therapy.[53]
Surgical Wound Coverage
  • For extensive wounds with or without necrosis, surgical wound coverage may be needed.[11] Autologous skin grafts have been used with variable outcomes but a significant disadvantage of this technique is the creation of a new wound at the donor site which may exhibit pathergy.[54] Surgical management alone has not been shown to be an effective strategy for management of pyoderma gangrenosum. Trauma from surgery may induce formation of new ulcers or cause enlargement of the existing lesions. However, if the patient is on immunosuppressive treatment, potential pathergy should not preclude surgical coverage as an option.[11] 
  • Negative Pressure Wound Therapy (NPWT) has been used in preparation of the wound bed prior to autologous skin grafting, and to secure partial-thickness skin grafts after they have been positioned on the wound.[55]

Other adjunctive therapies

The potential benefit of Negative Pressure Wound Therapy as well as Hyperbaric Oxygen Therapy as adjunctive therapy has been mentioned in several small case studies and individual case reports but sufficient wider trials are necessary to support endorsement of these therapies.[54]


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