Systemic autoinflammatory diseases (SAIDs) are a group of rare but devastating disorders that are characterised by dysregulated activation of the innate immune system. These conditions typically have juvenile onset and differ from autoimmune diseases, as they do not involve autoantibodies or antigen-specific T cells. To date, over 40 monogenic SAIDs have been identified, each linked to mutations in specific genes that regulate immune responses.

Despite significant advances in genetic testing, a large proportion of patients with autoinflammatory symptoms (about 2/3) remain without a definitive genetic diagnosis. These individuals are classified as having undefined SAIDs or SURF (Syndrome of Undifferentiated Recurrent Fever). This diagnostic ambiguity presents a major clinical challenge as it hinderstimely intervention and appropriate treatment selection.

Current therapies, including colchicine, TNF blockers and IL-1 blockers such as Anakinra, Canakinumab and Rilonacept provide symptomatic relief in some SAIDs but are ineffective in other patient groups. Patients with undefined SAIDs risk ongoing inflammatory bouts and long-term organ damage, which can lead to long-term morbidity and mortality if not diagnosed andeffectively treated. Traditional diagnostic tools, including clinical criteria and genetic testing, are often insufficient for early and accurate diagnosis. As a result, many patients continue to suffer without effective treatment options.

Our project will address these challenges by developing an innovative platform for pathway-driven biomarker discovery. This platform will leverage molecular profiling and systems biology to identify predictive biomarkers of therapeutic response. By integrating these biomarkers into clinical decision-making, we aim to enable precision therapy for patients with undefined SAIDs, improving outcomes and reducing disease burden.