Department of Medicine

PYODERMA GANGRENOSUM
LEARNING OUTCOMES

Define pyoderma gangrenosum

List the causes of pyoderma gangrenosum
Identify the signs and symptoms of pyoderma
gangrenosum
Formulate a differential diagnosis for pyoderma
gangrenosum
Choose appropriate investigations for pyoderma
gangrenosum
Outline the management of pyoderma gangrenosum
List the complications of pyoderma gangrenosum
 DEFINITION

Pyoderma gangrenosum (PG) is a rare inflammatory

disease of unknown etiology characterized by sterile
neutrophilic infiltration of the skin. Similar neutrophilic
infiltrations may occur in other organs. It is considered to be
one of the groups of neutrophilic dermatoses and clinical
and histological overlap with some of these may occur.
PG is divided into four major subtypes:
Ulcerative (classic) PG (the most common variant)
Bullous (atypical) PG
Pustular PG
And vegetative /superficial PG
EPIDEMIOLOGY

The prevalence of pyoderma gangrenosum (PG) is

unknown. Estimates have suggested that approximately
three cases of PG per million of the population occur per
year, with most large referral centres seeing one to two
cases per year.

It mainly affects adults between the ages of 40 and 60

years.
RISK FACTORS

In around 50% of patients PG is associated with a

variety of systemic disorders including:
Myeloproliferative disorders,
Monoclonal gammopathies (mainly IgA type)
IBD
Rheumatoid arthritis

However it is NOT a manifestation or complication of

these diseases and its clinical course is usually
unrelated to their severity or activity.
SYMPTOMS

PG presents with pustules or nodules that progress to

ulcers with central necrosis.
The lesions are exquisitely tender and heal with
cribriform scarring.
Lesions progress rapidly and cutaneous destruction
evolves over days rather than weeks.
Symptoms of systemic disease may be present:
Malignancy related symptoms: weight loss and fatigue
Symptoms of hematologic disease: bruising, symptoms of VTE
Symptoms relating to the musc. system: joint pains, swelling
Gastrointestinal tract: abdominal pain, diarrhoea.
 SIGNS
The most common initial clinical lesion is an inflammatory
pustule or nodular furuncle (these lesions are usually single
but may be multiple).
They erupt on apparently normal skin (the most common
site being the leg), or sometimes at the site of trauma or
surgery.
The enlarging initial lesion develops a surrounding areola or
zone of erythema that extends into the surrounding skin.
As it enlarges, the centre degenerates, crusts, and erodes,
converting it into an eroding ulcer the development of which
is accompanied by an alarming increase in the severity of
the pain.
SIGNS

The ulcer often has a bluish/violaceous edge (due to

undermining by the necrotizing inflammatory process)
and the base is covered with purulent material.
Ulcerative PG may erode deeply with exposure of
muscle or tendon in some cases.
Ulcerative Pyoderma gangrenosum
Ulcerative Pyoderma gangrenosum
Bullous Pyoderma gangrenosum
Vegetative pyoderma gangrenosum
 DIFFERENTIAL DIAGNOSIS
Vasculitis/Antiphospholipid-antibody syndrome
Wegeners granulomatosis
Malignancy
Cutaneous infection
Vascular occlusion disorders
Venous stasis ulcers
Exogenous tissue injury
Drugs
Ulcerative inflammatory disorders (eg, cutaneous Crohns
disease and ulcerative necrobiosis lipoidica) may be
mistaken for PG
 Diagnostic criteria
Major criteria (must have both):
Rapid progression of a painful, necrolytic cutaneous ulcer with an
irregular, violaceous, and undermined border (1 to 2 cm per day or
50 percent increase in size within one month)
Other causes of cutaneous ulceration have been excluded (usually
necessitates skin biopsy and laboratory investigations)
Minor criteria (must have two):
History suggestive of pathergy or clinical finding of cribriform scarring
Systemic disease associated with PG (inflammatory bowel disease,
arthritis, IgA gammopathy, or malignancy)
Histopathologic findings (sterile dermal neutrophilia, mixed
inflammation, lymphocytic vasculitis)
Treatment response (rapid response to systemic steroid treatment)
 INVESTIGATIONS
Diagnostic:
-Skin biopsy (exclude other disorders that may present with
similar clinical findings)
Underlying aetiology:
-A specimen from the ulcer should be sent for culture to evaluate
for bacterial, fungal, and atypical mycobacterial infections
-Complete blood count (to evaluate for underlying hematologic
disorders)
-Comprehensive metabolic panel (to evaluate for hepatic or renal
dysfunction and glucose abnormalities prior to initiation of systemic
glucocorticoids or immunosuppressive agents)
-Antinuclear antibody titre (to evaluate for the presence of
systemic lupus erythematosus or collagen vascular disorders in
association with PG)
Investigations
-Anti-neutrophilic cytoplasmic antibodies (to evaluate for
granulomatous vasculitis as a cause of ulceration)
-Hypercoagulability studies (antiphospholipid antibody screen
to evaluate for antiphospholipid syndrome as a cause of
ulceration)
-Hepatitis panel (to evaluate for associated hepatitis B or C,
particularly for patients in whom immunomodulatory therapy is
considered)
-Serum protein electrophoresis (to evaluate for paraproteins)
-Colonoscopy (to evaluate for underlying inflammatory bowel
disease unless another cause of PG is identified)
-CXR
-Additional tests to evaluate for associated disorders and
disorders in the differential diagnosis are ordered based upon
clinical suspicion for specific diseases.
Investigations
Therapeutic screening and screening for complications
(for immunosuppressive therapy)
-Chest radiography (to evaluate for presence of extracutaneous
involvement and for possible infection prior to the initiation of
immunosuppressive therapy)
-Renal profile (baseline and monitoring)
-LFT (baseline and monitoring)
-HIV and viral hepatitis screen (before starting
immunosuppressive therapy)
-Mantoux or Quantiferon test: to rule out TB (before starting
immunosuppressive therapy)
-Swab C&S for secondary infection (and guide treatment)
-Pregnancy test
-G6PD screening before starting dapsone
MANAGEMENT
Symtomatic management:
Wound care and dressing

Theraputic managament:
Topical treatments
High potency topical steroids (applied to the periphery of an active PG
lesion can reduce inflammation)
Tacrolimus (isolated pustular lesions, superficial ulcerations)
Intralesional treatments
Systemic treatments
Systemic corticosteroids
Dapsone
Antibacterial agents (Clofazimine, minocycline)
Cyclosporine
Mycophenolate mofetil
Cyclophosphamide
Biologic treatments
Infliximab, adalimumab
Theraputic management- Medications

Topical therapies
Corticosteroids (anti-inflammatory, immunosuppressive, and
vasoconstrictive effects)
Quick short term relief
Relief of itching and inflammation
Less effective with long term use (tachyphylaxis)
Skin atrophy and telangiectasia with LT use
Oral glucocorticoids

Mechanism of action: direct binding of the

glucocorticoid/glucocorticoid receptor complex, or by an
interaction of this complex with other transcription
factors, activating protein-1 or nuclear factor-kappaB.
Side effects of glucocortocoids
Dapsone
The mechanism of action is not well understood.
Oral route

Side effects:
-Hemolysis (screen for G6PD before starting)
-Methemoglobinemia
-Insomnia
-Headache
-Exfoliative dermatitis
-Photosensitive reaction
-Anaemia
Antibacterial agents (clofazimine,
minocycline)

Anti-inflammatory properties but the exact mechanism

is unknown
PO route
Side effects:
-Clozimine-Skin discoloration, GI disturbance, ichthyosis
and dry skin, rash, pruritus (1-5%)

-Minocycline: Skin and mucous membrane pigmentation,

teeth discolouration (in children), vestibular symptoms,
pericarditis, myocarditis, vasculitis, angioedema,
alopecia
Ciclosporin
Immunosuppressant
Calcineurin inhibitor
PO route

Side effects:
May lead to hypertension

May reduce renal blood flow

SHORT TERM management of pyoderma gangrenosum

vs
LONG TERM risk of renal failure, skin cancer
Mycophenolate mofetil
Selective inhibitor of inosine monophosphate
dehydrogenase (IMPDH), inhibits T cell & B cell
proliferation and antibody production

PO route

Side effects
-Hyperglycemia, hypercholesterolemia, Mg
-Dyspnea
-Back pain
-Increased urea
-Leukopenia
Cyclophosphamide
Immunosuppressive agent- Metabolites interfere with
malignant cell growth by cross-linking tumor cell DNA.
PO route

Side effects:
Myelosuppression
Malignancy
Nausea, vomiting
Premature ovarian failure
Haemorrhagic cystitis, bladder cancer
Nausea, vomiting
Pulmonary fibrosis
Heart failure
 Biologic Agents
TNF alpha-inhibitors (infliximab, adalimumab)
Mechanism of action: Agents focused on inhibition of T cell function and
cytokine release (TNF alpha)

Etanercept and adalimumab: SC route

Infliximab given: IV route

Side effects:
Increased risk of infection

Adalimumab may cause lupus

Infliximab may result in reactivation of TB and demyelinating disease

COMPLICATIONS

Active and poorly controlled cutaneous PG causes

significant morbidity:
Loss of mobility
Pain
Exposure to secondary infection
Anaemia of chronic disease
Neutrophilic infiltration of internal organs in PG may lead to
unnecessary surgical procedures

Significant side effects of treatment

 PROGNOSIS
With treatment >50% of patients achieve complete wound healing
within one year
The course of PG does not always parallel that of the related
underlying disease
Effect of treatment of underlying conditions on PG disease
activity is variable
Typically heals with scars, can be disfiguring.
New lesions may develop during or after healing of other lesions.
Relapses can occur after long periods of disease quiescence
Death may occur due to underlying associated disorders (NB
haematological disease) or to complications directly related to
ulcers (e.g. sepsis)
References

1. Fitzpatricks Dermatology in general medicine, 8e, 2012

2. F C Powell, S Collins: Pyoderma gangrenosum; J Clinic in
Dermatology, 2000;18:283-293
3. E Ruocco, S Sangiuliano, AG Gravina, A Miranda, G Nicoletti:
Pyoderma gangrenosum: an updated review; JEADV 2009, 23,
1008 1017
4. J. Miller, B. A. Yentzer, A. Clark, J. L. Jorizzo, S. R. Feldman:
Pyoderma gangrenosum: A review and update on new therapies; J
Am Acad Dermatol 2010;62:646-54
5. UpTodate: Pyoderma gangrenosum
6. DermnetNZ: Pyoderma gangrenosum
MCQ 1

A 40 years old male was diagnosed with a Crohns disease

10 years ago. He presented to GP with a painful necrolytic
ulcer on his right leg that developed over 5 days. Its an
irregular, violaceous with undermined border. What would
support the diagnosis of pyoderma gangrenosum?
A. History of osteoarthritis
B. Positive ulcer swab cultures
C. Sterile dermal neutrophilia on skin biopsy
D. No response to steroid treatment
E. History of trauma
Answer: C
 MCQ 2

A 48 year old female with rheumatoid arthritis developed a

painful necrolytic cutaneous ulcer on her right lateral
malleolus and was diagnosed with pyoderma gangrenosum.
What treatment should be commenced?
A. Biologic treatment with Infliximab
B. Antibacterial treatment with flucloxacillin
C. Cyclosporine
D. Oral corticosteroids
E. Topical antifungal

Answer: D
MCQ 3
A 40 year old male with a history of Crohns disease and
pyoderma gangrenosum presented to the Emergency
Department with worsening right leg ulcer pain, skin
redness and purulent discharge from the wound. What
complication has most likely developed?

A. Flare of Crohns disease

B. Secondary infection
C. Sepsis
D. Side effect of treatment
E. Malignancy
Answer: B
MEQ
A 40 year old male was diagnosed with Crohns disease
10 years ago. He presented to GP with a weight loss and
painful necrolytic ulcer on his right leg that developed over
5 days with an irregular, violaceous border.

Q1. What is the most likely diagnosis? (2 marks)

Pyoderma gangrenosum

Q2. List three investigations and expected findings that would confirm
the diagnosis. (6 marks)
Skin biopsy (sterile dermal neutrophilia, also exclude other skin
disorders)
Anti-phospholipid antibody negative
Anti-neutrophilic cytoplasmic antibodies negative
 MEQ
Q3. List three differential diagnoses for the skin lesion. (6 marks)
Cutaneous Crohns disease
Ulcerative necrobiosis lipoidica
Malignancy

Q4. List 6 systemic treatment options of pyoderma gangrenosum. (6 marks)

Systemic corticosteroids
Ciclosporin
Mycophenolate mofetil
Dapsone
Methotrexate
Cyclophosphamide
Biologic treatment (e.g. infliximab)