The present study demonstrated that CAR was independently positively associated with moderate to severe endoscopic activity in patients with UC. No association was found between CAR and other clinical outcomes including MH and clinical remission.
Several previous studies have explored the association between CAR and clinical outcomes in patients with UC. A Turkish study of 149 patients with UC found a relationship between CAR and clinical disease activity whereby CAR value was associated with the difference between moderate and severe disease activity .In a Chinese study of 876 patients with IBD, including 275 patients with UC, CAR was highly useful for identifying patients with active-stage IBD . In an Irish study of 124 patients with acute severe UC, CAR was significantly higher in steroid-refractory patients than in steroid-responsive patients . In an Australian retrospective study of steroid-refractory UC patients, CAR was positively associated with colectomy after infliximab . Taking these results together, CAR is positively associated with clinical activity, endoscopic activity, and poor response to medication in UC patients. The results of the present study are consistent with these previous findings indicating an association between CAR and clinical outcomes.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) study recommended treat-to-target strategies for patients with IBD [18, 19]. While maintaining MH remains the larger goal, the normalization of serum and fecal biomarkers has been identified as a short-term target. The development of an easy, rapid, repeatable, and affordable serum marker for MH is one of the unmet needs related to maintaining MH in the clinical setting. Several novel biomarkers for MH have recently been reported, including the CAR as well as serum globulin, serum indirect bilirubin, neutrophil/lymphocyte ratio, albumin/platelet ratio, and platelet/lymphocyte ratio [20,21,22,23]. Our results indicate that CAR should be used as serum marker for disease activity and poor response to treatment but not for MH.
Only a few studies have explored the influence of disease duration on biomarker accuracy in patients with IBD. In patients with Crohn’s disease, disease duration did not affect the utility of fecal calprotectin as a biomarker . In patients with UC, on the other hand, the immunochemical fecal occult blood test as a biomarker for MH is more accurate in patients with disease duration < 4 years . Similarly, serum albumin was found to be a useful marker for MH in patients with shorter UC duration but not in those with longer UC duration . In the present study, CAR was associated with disease activity only in UC patients with longer disease duration but not in those with shorter disease duration. It remains uncertain why disease duration affects the association between CAR and disease activity in patients with UC. Further research regarding the association between disease duration and serum biomarker accuracy in patients with UC is warranted.
Although the mechanism underlying the link between CAR and disease activity remains unclear, there are several biologically plausible possibilities. Both CRP and albumin are widely used as acute inflammatory markers in clinical settings, and albumin is also used as a marker of malnutrition. During inflammation, cytokines such as TNF α and IL-6 may suppress albumin synthesis in the liver . Chronic and severe inflammation leads to hypercytokinemia, which can lead to malnutrition . It is possible that CAR is related to severe and/or chronic inflammation but not to mild inflammation. This would explain why CAR is associated with disease activity only in patients with long disease duration.
There are several limitations to this study. First of all, it was a cross-sectional study. Therefore, causality between CAR and MH needs to be confirmed by conducting longitudinal and interventional studies. Secondly, many of the patients in this cohort were on long-term treatment and had high clinical remission. Long-term treatment might affect the association between CAR and endoscopic activity. Third, fecal calprotectin is recognized as a reliable marker of MH, however, the calprotectin data was missing in this cohort. Fourth, other clinical scores, including the Clinical Activity Index, were missing in this cohort. Finally, selection bias may have affected the results. The characteristics of this cohort might be different those of Japanese ulcerative colitis. However, the sex ratio, median age (years), and frequency of anti-TNFα monoclonal antibody use (63.9%, 44.0, and 9.0%, respectively) in the Japanese national study were similar to those in this study (57.9%, 48.0, and 6.2%, respectively) .