Society: AGA

Background: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (anti-GM-CSF) have been associated with development of Crohn’s disease (CD) and complications at time of diagnosis. There are limited data on anti-GM-CSF as a prognostic biomarker in CD. We evaluated the association of anti-GM-CSF in recently diagnosed patients with clinical outcomes.

Methods: We analyzed anti-GM-CSF titers in serum samples in CD patients from the Ocean State Crohn’s and Colitis Area Registry (OSCCAR). OSCCAR is a prospective, biosample-linked, community-based inception cohort capturing new pediatric and adult CD diagnoses in Rhode Island. OSCCAR patients had longitudinal clinical data collected through structured interviews and standardized central medical record data abstraction with a median follow up of 7 years. The primary outcome was development of disease complications defined as any new stricturing (B2) / penetrating (B3) complication, perianal disease, CD-related surgery, and/or CD-related hospitalization. Anti-GM-CSF IgA and IgG to sargramostim were assayed by ELISA at all timepoints available using serial dilutions. An anti-GM-CSF reciprocal titer >100 was considering positive for the antibodies. Time to event analyses were performed. Spearman’s correlation assessed the association between anti-GM-CSF and anti-microbial antibodies at baseline. Cox regression assessed the association between the primary outcome and baseline log anti-GM-CSF IgA and IgG.

Results: 229 CD patients from OSCCAR had baseline serum assayed for anti-GM-CSF. Mean age (SD) was 29 (17.7) years, 41% were men, disease location was ileal in 22.7% and ileocolic in 31.3%, 79% had inflammatory disease behavior at baseline, and 7% had perianal disease. 11.6% of patients were positive for anti-GM-CSF IgA and 21.2% were positive for IgG. The majority of patients had stable titers over 5 years (Figure 1A). Baseline anti-GM-CSF IgA and IgG titers were associated with younger age, B2/B3 behavior, and perianal disease but not disease location (Figure 1B). Anti-GM-CSF IgA was significantly (p<0.05) correlated with Cbir (r=0.21), ASCA IgG (r=0.51), and ASCA IgA (r=0.59) and anti-GM-CSF IgG was also significantly (p<0.05) correlated with Cbir (r=0.25), ASCA IgG (r=0.61), and ASCA IgA (r=0.54). Anti-GM-CSF IgA and IgG positive patients were significantly more likely to have disease complications over time (IgA HR 1.70 [95%CI 1.01-2.72]; IgG HR 1.73 [95%CI 1.15-2.60]) (Figure 2). In multivariable models controlling for baseline ulcers, upper tract disease, history of bowel resection, and ANCA, both log anti-GM-CSF IgA and IgG were associated with the development of disease complications (IgA aHR 1.21 [95%CI 1.02-1.43]; IgG aHR 1.66 [95%CI 1.0-2.77]).

Conclusion: Anti-GM-CSF IgG and IgA are biomarkers associated with risk of developing disease complications in recently diagnosed CD patients.

Figure 1

Figure 2

Background: Several instruments for the assessment of pouchitis disease activity have been used to define eligibility criteria and outcome measures in clinical trials. However, there remains a need for a validated pouchitis instrument that is suitable for use in novel drug development. In this study, a novel composite index of endoscopic and histologic disease activity, the Atlantic pouchitis index (API), was developed and internally validated for the assessment of pouchitis.

Methods: Baseline and week 10 pairs of both endoscopic videos and histologic images were obtained from 98 patients with chronic antibiotic-refractory pouchitis who participated in a randomized placebo-controlled trial of alicaforsen enema (ClinicalTrials.gov identifier: NCT02525523). Four endoscopists and 3 pathologists scored 59 items for each pair, including 51 component items from 11 indices (4 endoscopic, 4 histologic, 3 composite) identified in a prior systematic review and 8 additional items identified in a prior Research and Development/University of California Los Angeles appropriateness methodology exercise. The intra- and inter-rater reliability of all indices and items was assessed using intraclass correlation coefficients (ICCs) and interpreted according to Landis and Koch benchmarks (slight, 0.00-0.20; fair, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; almost perfect, 0.81-1.00). Responsiveness was evaluated using the area under the receiver operating characteristic curve (AUC). The novel index was developed using linear regression with a 100-mm visual analogue scale (VAS) of pouchitis activity as an anchor.

Results: After reliability and responsiveness were assessed for all measures, the simple endoscopic score for Crohn’s disease (SES-CD) and the Robarts histopathology index (RHI) were selected for inclusion in the API. The total API score can be calculated as API = (3 × SES-CD [0 to 12]) + (1 × RHI [0 to 33]) and ranges from 0 (no disease activity) to 69 (severe disease activity). The API demonstrated almost perfect intra-rater reliability (ICC, 0.88 [95% CI: 0.81, 0.92]), substantial inter-rater reliability (ICC, 0.72 [95% CI: 0.60, 0.79]), and a high correlation with the VAS (r = 0.84 [95% CI: 0.76, 0.89]). This index was highly responsive in detecting meaningful improvements in disease activity, with an AUC (0.95 [95% CI: 0.89, 0.98]) that was higher than the AUCs of existing endoscopic indices (ΔAUC, 0.09-0.24; P≤0.005) (Table).

Conclusion: We developed and internally validated the API, a novel composite index of endoscopic (SES-CD) and histologic disease activity (RHI) that is reliable and significantly more responsive than existing endoscopic pouchitis scoring systems. This promising instrument could be used in clinical trials to evaluate the effectiveness of novel therapies for pouchitis. Further validation is needed in independent datasets.

Malcolm Hogan

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