Published online Feb 7, 2018. doi: 10.3748/wjg.v24.i5.623
Peer-review started: November 16, 2017
First decision: November 30, 2017
Revised: December 5, 2017
Accepted: December 12, 2017
Article in press: December 12, 2017
Published online: February 7, 2018
Crohn’s disease (CD) is a chronic inflammatory disease is characterized by a transmural inflammation that targets any region of the gastrointestinal tract. The transmural involvement particularly involving the ileum, often leads to fibrosis, luminal narrowing, and fistulas. In one population based cohort study of adult patients with CD, the cumulative probability of major abdominal surgery was 38% to 58% within 5 to 20 years after diagnosis. Further, disease recurrence resulting in a second surgery for management of CD may occur in 31% to 50% of patients within 10 years of the initial surgery. There remains a need for serological and genetic markers that can reliably identify patients with increased risk for surgical recurrence.
Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that promotes myeloid cell development and maturation. Deficiency of this important hematopoietic growth factor can contribute to mucosal inflammation and immunodeficiency. We and others have previously shown, neutralizing GM-CSF auto-antibodies (Ab) are associated with a reduced bioactivity of GM-CSF, impaired neutrophil bacterial killing, and increased rates of intestinal resection for ileal CD. In the present study, we examined the predictive capacity of GM-CSF Ab in surgical recurrence rates after initial ileocolic resection for ileal CD. We also evaluated other clinical, serologic and genetic prognostic factors that might define the subset of patients with shorter time to surgical recurrence.
The development of biomarkers for diagnosis and prognosis of CD is evolving and serological assays like ASCA, ANCA, Anti-glycan antibodies and GM-CSF Ab are important discoveries. Some assays are reliable predictors for diagnosis and for staging severity. Here we demonstrate that GM-CSF Ab is a reliable biomarker for characterizing severity and reliably predicts patients at greater risk for aggressive disease behavior and the need for surgery.
We reviewed 412 patients which included in the study had ileal or ileocolonic CD and surgical resection of small bowel or ileocecal region for management of disease from a clinical database at tertiary academic hospital. Serum samples were analyzed for serological assays, which included GM-CSF cytokine, GM-CSF Ab, ASCA IgG and IgA, and genetic markers included SNPs rs2066843, rs2066844, rs2066845, rs2076756 and rs2066847 in NOD2, rs2241880 in ATG16L1, and rs13361189 in IRGM. The predictors of surgical recurrence were assessed by the Cox proportional-hazards models.
Of 96% patients underwent initial Ileocecal resection (ICR) or Ileal resection (IR) and subsequently 40% of patients required a second ICR/IR for CD. GM-CSF Ab level was elevated at a median of 3.81 mcg/mL. Factors predicting faster time to a second surgery included elevated GM-CSF Ab and elevated GM-CSF cytokine. Factors predicting longer duration between first and second surgery included use of Immunomodulators, the interaction effect of low GM-CSF Ab levels and smoking, and the interaction effect of low GM-CSF cytokine levels and ATG16L1.
In this study patients with elevated GM-CSF Ab had shorter intervals between the first and second surgery for management of CD. This is the first study to describe this. Therefore routine surveillance of this serological assay may facilitate the identification of patients at risk for disease complications and allow clinicians to optimize medical therapy.
Elevated GM-CSF Ab is a reliable assay for defining patients who are at a greater risk for surgery. A clinical assay is needed.