GM-CSF AUTOANTIBODIES PRECEDE THE DEVELOPMENT OF CROHN'S DISEASE AND PREDICT COMPLICATED PHENOTYPE AT DIAGNOSIS

Introduction: Inflammatory bowel disease (IBD) is preceded by an asymptomatic period, where immune dysregulation sets the stage for disease onset.The detection of biomarkers associated with this period may offer a means of disease prediction.Prior studies have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a dual role in intestinal inflammation, with both protective and inflammatory properties in IBD.The presence of GM-CSF autoantibodies (autoAbs) at diagnosis have been associated with a more severe course in pediatric IBD (1).Here, we aimed to assess the presence and prognostic value of GM-CSF autoAbs before diagnosis.Methods: Pre-diagnosis samples were obtained from 220 Crohn's disease (CD) and 200 ulcerative colitis (UC) patients and 200 age and gender matched-healthy controls (HC) from the United States Department of Defense Serum Repository.Serum antibodies for GM-CSF were measured for each subject at various timepoints: one corresponding to the nearest sample available around the date of diagnosis (±1 year) and other timepoints collected 2 to 10 years before presentation of symptoms.Each sample was tested for the presence of circulating IgA and IgG autoAbs directed against GM-CSF.Results: 2160 serum samples were tested at time of IBD presentation (or similar date for matched HC) and at ~2-year intervals prior to diagnosis.Seropositivity for GM-CSF IgA or IgG autoAbs was detected in 7-25% CD patients compared to 0-10% with UC and HC, most with titers already present from the earliest collected time point before diagnosis (>6 years, p £ 0.001) (Figure 1A).Pre-existing GM-CSF autoAbs in patients eventually developing CD significantly increased over time (Fig. 1A), were associated with ileal and perianal involvement, and more than doubled the risk of developing complications (obstructing or penetrating disease) at presentation compared to seronegative CD patients (Fig. 1B).Conclusion: AutoAbs to GM-CSF are specifically detectable in a subset of CD patients years before disease onset and represent a predictive biomarker for complicated disease presentation that may inform clinical decision making and pave the way for preventive strategies.