Impaired granulocyte-macrophage colony-stimulating factor bioactivity accelerates surgical recurrence in ileal Crohn’s disease

Table 1 Demographic characteristics of the subjects

Patient characteristics (n = 412)	n (%)
Gender, Female	242 (58.74)
Race, White	368 (89.3)
Age, mean ± SD	49.88 ± 14.49
Smoking
Current smoker	180 (43.69)
Ex-smoker	27 (6.57)
Never smoker	203 (49.27)
Surgery for CD1
First Ileocolic resection	370 (89.80)
First Ileal resection	26 (6.31)
Second Ileocolic resection	152 (36.89)
Second Ileal resection	13 (3.15)
Exposure to medication
Immunomodulators pre-T1	105 (25.48)
Anti-TNF agent pre-T1	80 (19.41)
Immunomodulators pre-T2	187 (45.39)
Anti-TNF agent pre-T2	120 (29.13)

¹3.2% of patients underwent other intestinal surgeries as noted in the results section of the text. CD: Crohn’s disease.

Table 2 Phenotypes by Montreal classification

	n (%)
Age at diagnosis
A1 (≤ 16)	56 (13.63)
A2 (17-40)	296 (72.57)
A3 (> 40)	60 (14.6)
Disease location
L1 ileal	279 (67.71)
L2 colonic	2 (0.485)
L3 ileocolonic	131 (31.87)
L4 upper GI disease	50 (12.17)
p perianal disease	125 (30.41)
Disease behavior
B1 non-stricturing, non-penetrating	35 (08.49)
B2 stricturing	167 (40.63)
B3 penetrating	197 (47.93)

Table 3 Values for serological assays

Serological assays	Mean ± SD	Median (IQRs)	Range
GM-CSF cytokine, pg/mL	3.18 ± 8.61	1.28 (0.43-3.05)	0.0052-136.5
GM-CSF Ab, mcg/mL	10.64 ± 19.76	3.81 (0.93-11.01)	0.08-241.2
ASCA IgA, U/mL	95.21 ± 77.38	67.51 (27.86-174.4)	1.92-242.8
ASCA IgG, U/mL	69.79 ± 41.09	66.86 (31.76-104.2)	3.17-158.1

GM-CSF Ab: Granulocyte-macrophage colony-stimulating factor auto-antibodies; ASCA: Anti-Saccharomyces cerevisiae antibodies; CD: Crohn’s disease.

Table 4 Risk factors at or after the initial Crohn’s disease surgery associated with time to the second Crohn’s disease surgery

Main effects	HR	95%CI	P value	FDR
Immunomodulators1	0.486	0.306-0.773	0.002	0.026
GM-CSF Ab level	3.493	1.430-8.538	0.005	0.030
GM-CSF cytokine level	2.489	1.292-4.796	0.005	0.030
B2 disease behavior2	1.415	0.517-3.874	0.491	0.624
B3 disease behavior3	0.415	0.146-1.176	0.091	0.145
Smoking4	1.286	0.277-5.981	0.743	0.800
ASCA IgG, U/mL	1.318	0.799-2.174	0.270	0.378
Age at diagnosis	0.983	0.963-1.003	0.094	0.145
Clostridium difficile infection	0.035	0.001-1.092	0.051	0.113
antiTNF-α5	1.272	0.662-2.447	0.461	0.615
ATG16L1 polymorphism	1.793	0.982-3.273	0.052	0.113
IRGM polymorphism	0.092	0.004-2.262	0.136	0.201
ASCA IgA, U/mL	0.976	0.755-1.262	0.852	0.852
NOD2 polymorphisms	1.123	0.741-1.702	0.577	0.673
Interactions
GM-CSF Ab level and smoking	0.612	0.454-0.825	0.001	0.026
GM-CSF cytokine level and ATG16L1	0.652	0.480-0.885	0.005	0.030
GM-CSF Ab level and ASCA IgG, U/mL	0.808	0.674-0.968	0.018	0.081
GM-CSF Ab level and ATG16L1	0.719	0.538-0.962	0.023	0.081
B2 disease behavior and Clostridium difficile	21.57	1.456-319.271	0.023	0.081
B2 disease behavior and smoking	1.601	0.318-8.059	0.560	0.673
B3 disease behavior and smoking	5.117	0.966-27.141	0.050	0.113
GM-CSF Ab level and Clostridium difficile	2.865	1.065-7.715	0.033	0.104
GM-CSF cytokine level and Clostridium difficile	0.902	0.325-2.501	0.840	0.852
Smoking and IRGM	0.406	0.145-1.134	0.079	0.145
ASCA IgG, U/mL and IRGM	1.867	0.908-3.835	0.083	0.145
GMCSF cytokine level and antiTNF-α	0.765	0.562-1.041	0.082	0.145
GM-CSF Ab level and antiTNF-α	0.941	0.703-1.260	0.676	0.757
GM-CSF cytokine level and ASCA IgA, U/mL	0.865	0.750-0.997	0.041	0.113

¹Use of Immunomodulators between first and second CD surgery including: Azathioprine, 6-Mercaptopurine, Methotrexate;

²Stricturing behavior (B2) compared to Inflammatory (B1) disease behavior;

³Penetrating behavior (B3) compared to Inflammatory (B1) disease behavior;

⁴Active smoker before the first CD surgery;

⁵Use of Anti-tumor Necrosis Factor-alpha therapy between first and second CD surgery including: Infliximab, Adalimumab. Cox proportional hazard model; A Cox proportional hazard model was fitted with main effects and first-order interactions of clinical and genotype variables. A stepwise variable selection was performed to select the relevant subset of variables. Within the model, P value was adjusted with the cutoff at FDR < 0.05. Model fitting and selection were generated using R 3.1.1 (http://cran.r-project.org). Table 4 displays the P-values for all fitted terms in the final model. GM-CSF Ab: Granulocyte-macrophage colony-stimulating factor auto-antibodies; ASCA: Anti-Saccharomyces cerevisiae antibodies; CD: Crohn’s disease.