Pyoderma gangrenosum (PG) is an uncommon, ulcerative cutaneous condition that causes tissue to become necrotic, leading to deep ulcers on the skin, most common on legs. The disease was identified in 1930 and is classified into the autoinflammatory disorders known as neutrophilic dermatoses.
Associated Risk Factors of Pyoderma Gangrenosum
Several high-risk factors are proved to be associated with pyoderma gangrenosum, including:
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Inflammatory bowel disease (ulcerative colitis and Crohn disease)
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Rheumatoid arthritis
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Myeloid blood dyscrasias including leukemia
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Monoclonal gammopathy (usually IgA)
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Chronic active hepatitis
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Granulomatosis with polyangiitis
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PAPA syndrome
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Use of levamisole-adulterated cocaine
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Miscellaneous less common associations
Fig. 1 Proposed schema of PG pathogenesis in current understanding.1
Other organ systems may be involved in patients with pyoderma gangrenosum, such as the lung, heart, central nervous system, gastrointestinal (GI) tract, eyes, liver, spleen, bones, and lymph nodes, where sterile neutrophilic infiltrates can be observed. The potential complications of pyoderma gangrenosum include severe infection, scarring, uncontrolled pain, depression, and loss of mobility. The morbidity of pyoderma gangrenosum is about 1/100,000 and is basically identical in men and women, but prefers to people in 40s~50s age.
Symptoms of Pyoderma Gangrenosum
Pyoderma gangrenosum usually occurred with a small pimple, red bump or blood blister on your skin, which may resemble a spider bite. Within several days, the skin can develop into a large, painful ulcer with a purple or blue edge that may ooze fluid. The ulcer can deepen and widen rapidly to form a larger focus in the area.
Pathogenesis of Pyoderma Gangrenosum
The etiology of pyoderma gangrenosum is incompletely understood, but dysregulation of the immune system (abnormal chemotaxis, neutrophil migration, phagocytosis, bactericidal ability, and abnormal neutrophil trafficking) is believed to be involved. Furthermore, genetic alternation also contributes to the pathophysiology of PG.
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Neutrophil Dysfunction
Compared with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), seronegative arthritis, autoimmune hepatitis, etc., PG is considered one of the rare neutrophilic dermatoses, characterized by aseptic neutrophilic infiltration and systemic inflammation. So neutrophils dysfunction plays an assignable role in the etiology of PG.
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Inflammation
Elevated levels of inflammatory mediators have been found in lesions of PG, suggesting a pathological relationship between abnormal immune reactions and PG. T cells, macrophages, proinflammatory cytokine (IL1β and its receptor, IL-8, IL-23, TNF-α, Fas, FasL, CD40, CD40L, CXCL 1/2/3, CXCL 16, etc.) are reported to be significantly increased in PG lesions.
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Complement
Pyoderma gangrenosum has been reported in association with congenital complement deficiencies, especially the deficiencies of C2, C4, and C7. Deficiencies of C7 is associated with decreased neutrophil chemotaxis, phagocytosis, and opsonization, similar to the immunologic abnormalities described in patients with PG.
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Reference
1. Hobbs, Misty M., and Alex G. Ortega‐Loayza. "Pyoderma gangrenosum: from historical perspectives to emerging investigations." International Wound Journal 17.5 (2020): 1255-1265.
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Questions & Answer
A: Researchers often use cell culture systems to study complement activation in PG. They can culture immune cells and skin cells in the presence of complement proteins and analyze the resulting immune responses. Animal models may also be employed to investigate complement involvement in the development of PG-like skin lesions.
A: Yes, other complement therapeutics are being explored, such as C1 esterase inhibitors, which aim to control complement activation and inflammation in pyoderma gangrenosum. These are still in the experimental stage and require further study.
A: Eculizumab is a monoclonal antibody that inhibits the complement protein C5. By doing so, it prevents the formation of the membrane attack complex, which plays a role in cell damage. This can help reduce inflammation and tissue destruction in pyoderma gangrenosum.
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