1.1.4.2 Pyoderma gangrenosum

Dermatitis ulcerosa, Phagedenic pyoderma, phagedenic ulcer.

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

30-75% of patients with PG have a second underlying immune-mediated disease, most commonly inflammatory bowel disease (IBD) (17-20 %), rheumatoid arthritis (12%) and hematological malignancies (4-8 %).

Pyoderma gangrenosum (PG) is a rare, recurrent, 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:

• Inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) are the systemic diseases most frequently reported in association with PG. High relative risk (odds ratio) of a patient with IBD to develop PG is 29.2, in contrast, only 0.75% of patients with inflammatory bowel diseases had PG. There is no association between the severity of inflammatory bowel disease and the presence of PG.

• Arthritis: Most frequently seronegative arthritis of a single, large joint. Classical forms of rheumatoid arthritis (RA) and ankylosing spondylitis are also associated.

• Hematologic malignancies (7%). Most commonly acute myelogenous leukemia, but a broad spectrum of lymphoproliferative disorders including monoclonal gammopathies, leukemia, lymphoma, and myelodysplastic syndromes have been described in association with PG.

• Drugs: Interferon-α2b, isotretinoin, G-CSF in patients with hematological disorders, propylthiouracil, tyrosine kinase inhibitors (sunitinib, imatinib and gefitinib), and tumor necrosis factor-α inhibitors (infliximab, adalimumab), rituximab.

Autoinflammatory diseases:

• PAPA syndrome is an autosomal dominant inherited disease characterized by non-axial destructive polyarthritis, PG and severe cystic acne. PAPA syndrome is caused by mutations in the PSTPIP1 gene involved in regulation of inflammatory response.

• PASH syndrome (PG, acne and hidradenitis suppurativa) and

• PAPASH syndrome (pyogenic arthritis, PG, acne and hidradenitis suppurativa) are other syndromic forms of PG.

Overlap between PG and Sweet’s syndrome: Usually observed in patients with myeloproliferative disorders.

The pathogenesis of PG is unknown. Trauma (pathergy) may induce the development or worsen previous lesions PG lesions (e.g. biopsy).

Release of cytokines (IL-36, IL-8) and danger signals that can enhance innate immune responses.

Lesions of PG presents with a tender nodule, plaque, or sterile pustule that enlarges, over a course of days, progressing to sharply demarcated painful ulcers with central necrosis. The lesions have undermined violaceous borders and a surrounding zone of erythema. Central necrotic areas with hemorrhagic or purulent exudates develop. The ulcer usually increases in size and depth or extends through the appearance of new peripherally located pustules.

PG may be a solitary lesion but also may manifest as multiple simultaneously recurrent lesions. In 25- 50% of cases, PG arises at areas of trauma (pathergy). As the lesions heal, cribiform or ‘sieve-like’ atrophic scars or wrinkled (cigarette paper-like) scars develop.

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

The lower legs (pretibial area) are most commonly affected but other parts of the skin and mucous membranes including breast, hand, trunk, head and neck and peristomal skin may also be involved.

Different clinical variants of PG have been defined:

1. Ulcerative (classical) PG: Most commonly occurs at sites of trauma, frequently on the anterior lower extremities. Associated disorders: IBD, hematological malignancies, rheumatoid arthritis, seronegative arthritis and monoclonal gammopathy.

2. Bullous PG: Painful bulla/e that can progress to erosions and/or ulcers. Increased incidence on the face and the dorsum of the hands. Overlap with Sweet’s syndrome. Subcorneal, subepidermal and intra-epidermal bullae with dermal neutrophilic infiltrate and microabscess formation. Associations: Myeloproliferative disorders (70%) and IBD.

3. Pustular PG: Pustules with erythematous borders. Association: IBD.

4. Vegetating (granulomatous superficial) PG: Low-growing, non-purulent, superficial ulcer; borders are not undermined. Head and neck. Histologically: Palisading granulomatous reaction. No associated disorders.

5. Peristomal PG: Papules that erode into ulcers with undermined borders adjacent to the stoma. Dermal neutrophilic infiltrates with granulation tissue. Associations: Inflammatory bowel disease (IBD), gastrointestinal malignancy, connective tissue disease and monoclonal gammopathy.

6. Postoperative PG: Erythema at the surgical site, followed by wound dehiscence or painful ulcerations that coalesce. Commonly associated with abdominal and breast surgery.

Occasionally peripheral leukocytosis with neutrophilia and elevated markers of inflammation (erythrocyte sedimentation rate and C-reactive protein).

Laboratory tests are performed to evaluate for associated disorders rather than to establish the diagnosis of pyoderma gangrenosum.

The histopathology of PG is nonspecific and changes with the stage of the lesion. Dermal edema, suppurative inflammation and sterile abscess formation. At the periphery of the lesion, perivascular or perifollicular lymphoid infiltrates may also be present. Additional staining of the biopsy sample is required in order to rule out bacterial and fungal infections.

The initial lesions show a deep suppurative folliculitis with dense neutrophilic infiltrate. Focal leukocytoclastic vasculitis changes may be present. PG with necrotizing granulomatous inflammation has been observed.

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. An Infectious disease should be ruled out. An additional skin biopsy for microbiological studies (bacterial, fungal and mycobacterial cultures, viral or other micro-organism PCR amplification) should be obtained.

PG diagnostic workup includes a complete blood count with peripheral blood smear, biochemical survey, serum and urine protein electrophoresis, stool sampling for occult blood and parasites as well as syphilis serologic tests and immunological studies (rheumatoid factor, ANA, ENA, antiphospholipid antibodies, pANCA, cANCA) for autoimmune diseases.

Additional tests may be indicated in cases with concomitant joint or gastrointestinal symptoms including radiological imaging and/or a colonoscopy to rule out inflammatory arthritis and ulcerative colitis, respectively. Peripheral smear, and bone marrow aspiration or biopsy should be performed, if indicated, to evaluate for hematologic malignancies. Age-appropriate cancer screening in selected cases.

Major criteria

1. Rapid progression of a painful, necrolytic cutaneous ulcer with an irregular, violaceous, and undermined border

2. Exclusion of other causes of cutaneous ulceration

Minor criteria

1. History suggestive of pathergy or clinical findings of cribriform scarring

2. Systemic diseases associated with PG

3. Histopathologic findings

4. Treatment response to systemic steroids

Recently, some new diagnostic criteria for PG have been proposed: PARCELSUS and Delphi diagnostic criteria.

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

• Vascular occlusive or venous disease (including calciphylaxis).

• Vasculitis (rheumatoid arthritis, ANCAs-related vasculitis, Behcet’s disease, etc.).

• Hypercoagulable states (anti-phospholipid syndrome).

• Malignant neoplasms (lymphomas, leukaemia).

• Infectious diseases (ecthyma, streptococcal synergistic gangrene, deep mycoses, atypical mycobacterial infections, late syphilis, deep viral herpetic infections, necrotizing cellulitis).

• Exogenous tissue injuries (factitial panniculitis), insect or spider bites, and

• Drug reactions (pustular drug reactions).

• Primary cutaneous lymphomas

A primary prevention is not possible.

Oral corticosteroids (0.5–1 mg/kg/day) are the mainstay of treatment for rapid control of the disease and, in other cases, cyclosporine A may be used as a steroid-sparing agent either alone or in combination with corticosteroids. In severe and recalcitrant cases, pulsed intravenous methylprednisolone should be considered.

Combinations of steroids with cytotoxic drugs are used in resistant cases. The combination of steroids with dapsone or different immunosuppressants or steroid-sparing agents such as colchicine, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, clofazimine, thalidomide, tacrolimus, sulfasalazine and minocycline has been proposed.

Anti-tumor necrosis alpha therapy (infliximab, etanercept, adalumimab, certolizumab pegol), could be prescribed in cases of PG associated with IBD. Other systemic treatments include high doses of intravenous immunoglobulin (IVIG), biologic drugs such as IL-12 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) or complement Factor C5a inhibitor vilobelimab (IFX-1) have been used with variable success.

Topical treatments including superpotent corticosteroids and calcineurin inhibitors (tacrolimus) and, intralesional therapy (triamcinolone, methotrexate) may be used as adjuvant therapies in conjunction with systemic agents. Topical therapy with wound dressings, skin transplants and the application of bio- engineered skin are useful in selected cases.

The clinical course of PG is unpredictable—from a precipitous onset with rapid spread to a more indolent pattern. Frequent relapses. Potentially life-threatening disease. In some series with a mortality rate of up to 30%.