PYODERMA GANGRENOSUM: AN INFLAMMATORY BASED WOUND

Tracey C. Vlahovic, DPM FFPM RCPS (Glasg)Clinical Professor, Dept of Podiatric Medicine, Temple University School of Podiatric Medicine, Philadelphia, PA

CONFLICTS OF INTEREST: NONE

I will be discussing the off-label use of various medications

DDX of non‐healing wounds “DIIDNTHEAL”

Diabetes Infection Inflammation –not in original mnemonic Drugs – steroids, antimetabolites Nutritional Tissue necrosis – local or systemic ischemia Hypoxia Excessive tension ‐post‐surgical or dynamic location Another wound – competition between several areas Low temperature – i.e. on extremities Adapted from Stillman, RM. Wound Care:emedicine

General Surgery

Inflammatory Leg Ulcers Differential Diagnosis

1. Vascular Disease

Arterial insufficiency

Venous insufficiency

Calciphylaxis ‐ particularly painful and rapidly evolving. Similar to PG.

2. Other inflammatory diseases:

Vasculitis – Small vessel, medium vessel (Polyarteritis nodosa), Large vessel (Wegener’s), Behcet’s, Antiphospholipidsyndrome, etc.

Panniculitis

3. Malignancy

Especially squamous cell carcinoma

4. Infection

Bacterial – Staph, strep

Deep Fungal

Atypical mycobacterial

Tertiary Syphilis (gummas)

Deep viral

Anthrax

5. Necrobiosis Lipoidica Diabeticorum

6. Trauma

Insect or spider bites can develop into PG.

Pyoderma Gangrenosum (PG) Clinical features

• Leg is the most common site: 80% in some studies

• Age: 4th-5th decade most common

• Female predominanceincluding pediatric, post-operative and peristomal subsets

PG Clinical Features

Neutrophilic dermatosis

Purple or violaceous border

“Any wound not at the medial leg…”

Time to appropriate diagnosis delayed

PG clinical features: Pathergyand Pain

Ulceration appearing at the sites of trauma- 1/5 to 1/2 of cases- Thought to be due to abnormal neutrophil

activation- Be cautious when injecting these wounds!!!

- Extreme pain- Pain clinic referral is essential for most patients.

Diagnosis of PG

Typical clinical pattern:

• irregular, cribriform, violaceous and/or undermined

border.

• painful

• Rapid progression

Other causes of ulceration have beenexcluded.History of pathergy

Clinical findings of cribriform scarring

Presence of systemic disease associated with PG

– Especially inflammatory bowel dx

Pathology findingsRapid response to systemic steroids

PG Associated Conditions

50-75% have associated condition

Inflammatory bowel disease: 9.3-34%

Hematologic disease: 3.9-45.6%

Rheumatologic diseases: 11.8-20%

Endocrine disease: 44.8%

Hepatitis: 9%

Psoriasis 11%

Malignancy 12.4%

Renal dysfunction 4.3%

The remaining are idiopathic in nature

95 Patients with Misdiagnosis of PG

86 had histopathology: 46showed alternative dx

– Vascular occlusive or venousdisease

– Vasculitis– Cancer– Primary infection– Drug-induced or exogenous

tissue injury– Other inflammatory

disorders

• 5 died from infection• 4 died from progression of

disease

Skin Ulcers Misdiagnosed as

Pyoderma Gangrenosum

Weenig, R. et al.NEJM 2002;347:1412-1418

Workup of Leg Ulcers:Biopsy Early

• Biopsy :–Grayish border ifpossible

–Edge of ulcer in undermined area• do not biopsy the interior of the ulcer bed

• Send for hematoxylin and eosin(H&E)stain• Prepare to have specimen sent to a dermatopathologist

–Send tissue culture for:• Bacterial, Mycobacterial, Fungal culture

• Consider viral culture

PG workup, continued

History, ROS, and exam:

Look for hx, signs or symptoms of IBD, CTD, pathergy

PG can occur in extracutaneous areas: Eyes, lungs, liver, spleen,

GI tract , CNS, bone and heart

LABS for All patients:

Complete Metabolic panel and CBC with Diff

Hepatitis B and C studies, HIV

Guided by history and exam:

ANA survey, ANCA, Antiphospholipid antibodies

PT/PTT

CXR

RPR or VDRL

Colonoscopy or other stool studies?

PG Workup, Other Testing

• Consider age appropriate cancer workup.– PG may be paraneoplastic – particularly

myelodysplastic syndrome, myeloma, paraproteins,leukemia.

– especially considering patient may need immunesuppression.

• STRONGLY consider vascular studies to evaluate bloodflow.– Especially in patients over50.

» This may be PG but is the vascular supply sufficient toheal the ulcer?

How to Treat PG?A Logical Approach

• 5 major treatmentconsiderations:

Treat the inflammation (topical, systemic, or both)

Treat the ulcer.

Address the biofilm or any trueinfection.

Treat the pain.

Treat the underlying disease, ifpresent.

PG Therapies

• Systemic:– Oral Prednisone

– Anti-TNF biologics– Methotrexate– Cyclosporine– Minocycline/Doxycycline– Dapsone– IVIG

– Ustekinumab– Anti-IL-1 biologics

• Local (topical) – Corticosteroids

• Topical or intralesional

– Calcineurin inhibitors

– Cyclosporine eye drops

– DapsoneTopical or crushed tablets

Small slow growing PG: topical therapies:Locally acting anti‐inflammatories

Topical or intralesional steroids

Topical calcineurin inhibitors

Topical antibiotics

Others:

Topical 1% sodium cromoglycate

Topical 0.5% nicotine cream

Topical 5‐aminosalicylic acid

Topical benzoyl peroxide

Topical PDGF

Topical dapsone: Crush tablets or topical gel

PG: Treat the inflammation: Topical cyclosporine

Restasis® 0.05% (Allergan)

Pyoderma gangrenosum (PG) ulcer, 1 case reported

Reduction in pain, size

Oral cyclosporine—the difference?

Urtea-Botero et al AAD Poster 2013

First presentation11/2012

Start of topical cyclosporine3/2013

6/2013

PG: Treat the inflammation: Topical Dapsone gel, 5%

Aczone® (Allergan) Durham et al AAD 2013 poster

Antimicrobial and anti-inflammatory

1 case reported, following Achilles rupture, patient developed PG

Applied QD,

reduction in pain

and size

What about traditional wound care modalities?Enzymatic Debridement NPWT

May be too irritating for frequent use

Can be very painful

Can rotate into every other or every third dressing change

Monitor for inflammation/pathergy

No controlled trials

May cause pathergy; consider use in non-inflammatory, stable PG wounds

Proceed with caution and frequent monitoring

Pretreat with: Corticosteroids, Dapsone,Pentoxyphylline

Consider lower setting for NPWT

May combine with STSG

JEADV 2016 Pichler et alGhersi, M. M. et al. Arch Dermatol 2007;143:1249-1251

PG: Treat the Inflammation

• Is systemic therapyrequired?

–No specificguidelines or protocol• Mostcases require aggressive immune suppression

• Small, slowly growing – try topical treatment

• Moderate sizeand slowly growing– try topical or less potentially toxic regimensfirst

• Rapidly enlarging – start with aggressive therapy immediately

Moderate-slow growing PG: Treat the Inflammation

• Systemic therapies plus topicals–Immune modulatory (less suppressive)

• Anti‐inflammatory oral antibiotics: tetracyclines, macrolides, sulfonamides

• Specific anti‐neutrophil agents: dapsone and/or colchicine.

• No published data for PG but consider:–Pentoxyphylline

» improve circulation + weak inhibitor ofTNF

–NSAIDS

Inflamed large or rapidly growing PG: systemic plus topical Start with rapidly acting induction therapy Prednisone 0.5 – 1.0 mg/kg/day or Infliximab 5‐10 mg/kg day

1,14, 42 then q4‐8 wks Plan to wean as quickly as possible as the PG improves

Start a steroid sparing agent(s) as well or soon thereafter Topical steroid, calcineurin inhibitor or other topical agent Add dapsone or colchine for anti‐neutrophil effect Dapsone helps with pneumocystis prophylaxis in patients on

steroids Tetracycline derivative (doxycycline) for anti‐inflammatory

and antibacterial effects Add more aggressive immune suppression May add other biologic

PG: Treat the Inflammation

• Which steroid sparing agent?– No specific trials forguidance

• Combination therapy better thanmonotherapy?

– Seems to be relatively equal evidence for the efficacy of:

• Mycophenolate mofetil

• Azathioprine

• Methotrexate

• TNF‐inhibitors

• Dapsone

Choose the one(s) with which you are most

comfortable. No specific trials for combination

therapy

Try to use combinations that have been studied in other

diseases

Biologic for PG: Infliximab

Only drug that has been studied in randomized, double-blind, placebo-controlled trial forPG

Brooklyn et al. Gut. 2006 Apr;55(4):505-9

-Half received drug at week 0-If no improvement at wk 2, open label drug wasoffered-69% of 29 pts improved-21% remission at 6weeks

Not a true biologic for PG: apremilast

8/4/2017 12/2017, start of apremilast 7/2/2018

PG: Should I debride?

When is surgical intervention necessary?

In general, discourage repetitive debridement +/‐ grafting

Scenarios for surgery:

Excess necrotic tissue is causing systemic illness

Extensive infection

Once PG activity is controlled, may consider graft

High risk of recurrence in graft donor site as well as in the original site

PG: Hydrosurgical debridement and grafting

Wounds 2018 30 (3): 57-61

Treatment of PG: An Algorithm

Small and stable

Large and rapidly

progressing

Topical therapyTopical plus less

aggressive systemic

Topical plus more aggressive

systemicTopical steroids Intralesionalsteroids CalcineurinInhibitors Topical dapsoneTopical AbxPDGF

GraftingAppropriate wound care

Antibiotics DapsoneColchicine

PentoxyphyllineNSAIDSAntimalarials

AdalimumabEtanerceptUstekinumabSecukinumabIVIG

Systemic steroids Calcineurin inhibitors Infliximab

Methotrexate Azathioprine

WHAT IS THEUNDERLYING

CAUSE?

PG: Summary Biopsy edge of ulcer for pathology and culture. It is a diagnosis of exclusion Remember vascular studies– does patient have the

circulation to heal the ulcer(s)? Get pain management involved when needed Treat the biofilm ‐ colonizing bacteria may be driving

some of the immune response Topical therapy alone may be sufficient for small lesions. Systemic therapy:

Oral Steroids for initial therapyConsider steroid sparing agents quickly.

Most steroid sparing agents take 12‐ 16 weeks to reach full effect. Give it a chance!!

Be flexible – different therapies for different patients. Wean medications slowly after healing as recurrence is

possible

References

Patel, S, Fitzmarice C, Duong C, et al. Effective Strategies for the Management of PyodermaGangrenosum: A comprehensive review. Acta Derma Venereol 2015;95:525‐531.

Bhat R. Pyoderma Gangrenosum: An update. Indian Dermatology Online Journal 3 (1) Jan –April 2012.

Tamir A, Landan M, Brenner S. Topical treatment with 1% Sodium Cromolate in PyodermaGangrenosum. Dermatology 1996;192:252‐254.

Tsele E,Yu R, Chu A. Pyoderma Gangresosum – response to topical Nitrogen Mustard. ClinExper Dermatol 1992;17:437‐440.

Miller J, Yentzner B, Clark A et al. Pyoderma gangrenosum: an review and update of new therapies. J Am Acad Dermatol 2010 Apr;62(4):646‐54.

Sinnya s, Hamza S. Pyoderma gangrenosum of the breast treated with intravenous immunoglobulin. J Dermatol Case Rep. 2013 Jun 30;7(2):64‐8.

Suzuki K, Sieczka E, Tranbaugh R, Hoffman D. Pyoderma gangrenosum masquerading as a sternal wound infection following cardiac surgery. Int J Surg Case Rep. 2015;6C:163‐5

Fedi MC, Quercetani R, Lotti T. Recalcitrant pyoderma gangrenosum responsive to cyclosporine. Int J Dermatol. 1993 Feb. 32(2):119.

Daniels NH, Callen JP. Mycophenolate mofetil is an effective treatment for peristomalpyoderma gangrenosum.Arch Dermatol. 2004 Dec. 140(12):1427‐9

Okhovat JP, Shinkai K. Pyoderma gangrenosum. JAMA Dermatol. 2014 Sep. 150(9):1032

Reichrath J, Bens G, Bonowitz A, Wolfgang T. Treatment recommendations for pyodermagangrenosum: An evidence‐based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005 Aug. 53(2):273‐83.

Thank you!!! traceyv@temple.edu