Pyoderma gangrenosum (PG) is a rare, chronic, inflammatory disorder that presents with painful skin ulcers. It causes disfiguration, negatively impacts quality of life, and increases mortality. Despite being a disease with significant physical and psychological impact, it remains understudied. The paucity of clinical research in the field is likely due to challenges in diagnosis and unknown treatment outcomes. Misdiagnosis, which is reported in up to 39% of patients, has been one of the main obstacles to proper implementation and enrollment in clinical trials. Because molecular diagnostics remain years away, researchers rely on clinical criteria for diagnosis. Three diagnostic frameworks exist based on clinical findings, however they are not widely applied or accepted. Moreover, the mainstay of treatment for PG is immunosuppression. Monotherapy with systemic corticosteroids or cyclosporine is the classical initial treatment, and only a few clinical trials have evaluated the effectiveness and safety of new therapeutic alternatives such as biologics. Further, combination or concomitant therapy of classic immunosuppression and biologics has been adopted as a new standard of care without high-quality data. Current therapeutic approaches are based on expert opinion guidelines creating additional difficulty in implementing clinical trials and hampering the FDA approval process of potential drugs. Our proposal aligns with the overall long-term goals of our research group: to drive diagnostic and therapeutic innovation in the field of PG – a significantly understudied disease with an increased healthcare burden. Our short-term goals include: 1) to establish which diagnostic framework best performs in a multi-institutional collaborative study, supporting its applicability in medical practice and clinical trials, and 2) to analyze current treatment outcomes in clinical practice. We seek to accomplish our short-term goals utilizing the following specific aims: Aim 1) compare and assess the three diagnostic frameworks in a multi-center prospective study of a well- defined cohort of patients diagnosed with PG and PG-like conditions to determine their performance in diagnosis, and Aim 2) determine the effectiveness of real-world therapeutic approaches currently used as standard of care in a multi-center cohort of patients with PG. Our established PG research team at OHSU has the ability to implement a multi-institutional collaborative effort to ensure the success of this proposal. Collectively, the results of this project will fill the diagnostic and therapeutic gaps in knowledge and define the current landscape of PG in the United States.