1.1.4.2 Pyoderma gangrenosum

EB-21

Dermatitis ulcerosa; phagedenic ulcer.

Incidence:  3 -10 per million per year. Peak of incidence: 20 to 50 years. Women slightly more often affected than men.  Men are more commonly affected in malignancy-associated PG.

Pyoderma gangrenosum (PG) is a rare occurring, chronic, and painful neutrophilic dermatosis that presents with rapidly developing, painful skin ulcers presenting with violaceous undermined borders and peripheral erythema.

More than 50% of patients with PG have an associated systemic disease, including:

1. Inflammatory bowel disease (IBD) (40%). No correlation withn the severity of IBD.
2. Arthritis (12%): Seronegative. Rheumatoid arthritis and ankylosing spondylitis.
3. Hematologic malignancies (7%). Most commonly acute myelogenous leukemia, but a broad spectrum of lymphoproliferative disorders.
4. Drugs:  Interferon-α2b, G-CSF.
5. Autoinflammatory diseases:
   - PAPA syndrome characterized by destructive polyarthritis, severe nodulo-cystic acne and PG. - PASH syndrome (PG, acne and hidradenitis suppurativa)
   - PAPASH syndrome  (pyogenic arthritis, PG, acne and hidradenitis suppurativa) 6- Overlap between PG and Sweet’s syndrome: Usually observed in patients with myeloproliferative disorders.

Presents with a tender nodule, plaque, or sterile pustule that enlarges progressing to sharply marginated painful ulcers with central necrosis, undermined violaceous borders and surrounding  erythema and / or bullous lesions. The ulcer usually increases in size and depth (phagedenism).

Solitary lesion or multiple simultaneous recurrent lesions.  Tends  to develop at areas of previous trauma including surgery (pathergy phenomenon) (25-50%).  As the lesions heal, cribiform or wrinkled (cigarette paper-like) scars often develop.

Extracutaneous sterile neutrophilic infiltrates can be observed in the bones, liver, lungs, pancreas, spleen, kidneys, and central nervous system.

The pretibial area (shins) are most commonly affected but other parts of the skin and mucous membranes are also affected.

Different clinical variants of PG have been defined:

1. Ulcerative (classical) PG: Most commonly occurs at sites of trauma.  Associated disorders: IBD, hematological malignancies, rheumatoid and seronegative arthritis  and monoclonal gammopathy.
2. Bullous PG: Painful bulla(e) that can progress to erosion and/or ulcer.  Associations: Myeloproliferative disorders (70%) and IBD.
3. Pustular PG: Pustules with erythematous borders. Association: IBD.
4. Vegetating PG: low-growing, non-purulent, superficial ulcer; borders are not undermined. No associated disorders.
5. Peristomal PG: Papules that erode into ulcers adjacent to the stoma. Associations: IBD, enteric malignancy, connective tissue disease and monoclonal gammopathy.
6. Postoperative PG: Erythema at the surgical site, wound dehiscence or painful ulcerations that coalesce. Abdominal and breast surgery.

Depends on the cause of the disease.

PG diagnostic workup includes a complete blood count with peripheral blood smear, biochemical survey, serum and urine protein electrophoresis, syphilis serologic tests and  immunological tests (pANCA, cANCA). Skin biopsy for microbiological studies (bacterial, fungal and mycobacterial) should be obtained. 

Additional tests may be indicated in cases with concomitant joint or gastrointestinal symptoms or suspicion of underlying  hematologic malignancies. Age-appropriate cancer screening in selected cases.

The histopathology of PG is nonspecific and changes with the stage of the lesion. Dermal edema, suppurative inflammation and sterile abscess formation. The initial lesions show a deep suppurative folliculitis like pattern with dense neutrophilic infiltrate.

Variable. Chronic, relapsing or self-limiting disease. From mild to aggressive with intense morbidity.

Secondary infection, tissue destruction, intractable pain. Impact on quality of life (depression). Complications secondary to long term immunosuppressive therapy.

Diagnosis of PG is based on history of an underlying disease, typical clinical presentation, histopathology, and exclusion of other diseases that would lead to persistent painful ulcers.

The differential diagnosis should include a wide range of diseases manifested as chronic and persistent cutaneous ulcers:

Vascular occlusive or venous disease, vasculitis (rheumatoid arthritis, ANCAs-related vasculitis, Behçet's disease etc.), hypercoagulable states (anti-phospholipid syndrome), malignant neoplasms (lymphomas, leukaemia), infectious diseases (ecthyma, deep mycoses, atypical mycobacterial infections, late syphilis, necrotizing cellulitis), exogenous tissue injuries (facticial panniculitis),  insect or spider bites, and drug reactions (pustular drug reactions). Pemphigus vegetans.

Oral corticosteroids (0.5–1 mg/kg/day) are the mainstay of treatment for rapid control of the disease and, in other cases, ciclosporin may be used as a steroid-sparing agent either alone or in combination with corticosteroids.

In resistant cases, the combination of steroids with different immunosuppressants or steroid-sparing agents such as dapsone, colchicine, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, clofazimine, thalidomide, tacrolimus, sulfasalazine and minocycline have been proposed.

Anti-tumor necrosis alpha therapy (infliximab, etanercept, adalumimab, certolizumab), could be prescribed in cases of PG associated with IBD. Other systemic treatments include high doses of intravenous immunoglobulin (IVIG),  IL-1 and IL-23 inhibitors  (ustekinumab), anti-IL-23  (tildrakizumab) anti-IL-17 (secukinumab) and IL-1 antagonists (anakinra, canakinumab, gevokizumab),and  small molecules (JAK-STAT inhibitors). 

Appropriate wound dressings of different types according to stage of ulcer. Topical and intralesional treatments (corticosteroids, calcineurin inhibitors) may be used as adjuvant therapies.

PG is included within the spectrum of neutrophilic dermatoses.

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders characterized histologically by a neutrophilic infiltrate with no evidence of underlying infection or vasculitis.

Unpredictable clinical course: from a precipitous onset with rapid spread to a more indolent pattern. Frequent relapses. Potentially life-threatening disease.