Hyperbaric Oxygen Therapy for Pyoderma Gangrenosum As a New Treatment Strategy

INTRODUCTION AND RATIONALE

Pyoderma gangrenosum (PG)

Background information Pyoderma gangrenosum (PG) is a rare, uncommon auto-inflammatory neutrophilic dermatosis characterized by a spectrum of clinical presentations including painful chronic and recurrent cutaneous ulcers with a necrolytic border with variable courses. PG has an overall prevalence of 5 to 10 per 100,000 individuals and an increased mortality rate compared with the general population. Its pathophysiology is complex and not fully understood. PG affects patients of both sexes equally and of any age, although female predominance has also been reported, with a peak incidence between 20 and 50 years of age. Legs are most commonly affected but head, trunk and neck involvement are not uncommon in children, while involvement of the genital and perianal area has been reported in adults as well in infants. There are multiple subtypes of PG, including ulcerative (A), bullous (B), pustular (C), vegetative (D) (pyostomatitis vegetans), peristomal, drug-induced and post-surgical PG (E).

Pathergy, an exaggeration of skin injury occurring after minor trauma, is seen in one-third of patients with PG and can contribute to peristomal and post-surgical PG (PSPG). PSPG occurs at the site of surgery, most commonly reported after breast, chest, or cardiothoracic surgery. PG is considered a "diagnosis of exclusion of clinical features" due to lack of definitive laboratory or histopathological diagnostic criteria and is thus frequently misdiagnosed.

Pathophysiology The pathophysiology of PG represents a complex inflammatory reaction pattern with involvement of multiple pathways that results in a heterogeneous disease presentation and course. The course of PG can vary from relatively indolent to aggressive or fulminant to fatal. Involvement of innate and adaptive immune dysregulation, genetic variants, as well as neutrophilic abnormalities have been described. PG is associated with other neutrophilic or inflammatory disorders such as inflammatory bowel disease (both Crohn's disease and Colitis Ulcerosa), rheumatoid arthritis, suppurative hidradenitis, seronegative arthritis, autoimmune hepatitis, and hematologic disorders, including paraproteinemia, especially IgA, and (neutrophilic) malignancies such as acute and chronic myelogenous leukemia. There are also associations with rare genetic disorders with pyoderma gangrenosum respectively Pyogenic Arthritis Pyoderma Acne (PAPA), Pyoderma Acne Suppurative Hidradenitis (PASH), Pyogenic Arthritis Pyoderma Acne Suppurative hidradenitis (PAPASH), and Pyoderma Acne ulcerative Colitis (PAC).3,7-10 Elevated levels of inflammatory mediators have been found in lesions of PG, suggesting a pathological inflammatory process. PG lesions show significant overexpression of cytokines like IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-17, IL-23, IL-36α, TNF, matrix metalloproteinases, endothelial- and leukocyte-selectins. In the adaptive system the ratio between T regulatory cells and Th17 cells was found to be reduced in PG lesions. There are still several unknown factors, including the initiating trigger for immune dysregulation as well as additional contributory components of the immune system.