Circulating microRNA (miRNA) levels are another potential method of assessing disease activity among patients with IBD. In a comparison of patients with active and inactive UC and CD with controls, peripheral blood miRNAs were able to distinguish active UC and CD from healthy controls.69 Although specific patterns were identified to allow for delineation between active UC and CD, in this evaluation there was significant overlap between several of the miRNAs in both CD and UC. The blood expression of miRs-199a-5p, -362-3p, -340*, -532-3p, and miRplus-1271 was elevated in both subtypes of IBD as compared with healthy controls, which may indicate an overall inflammatory state found in both UC and CD.69 In a similar evaluation, 11 miRNAs were elevated in pediatric patients with active CD when compared with healthy controls.70 A later study suggested that several miRNAs could accurately distinguish UC from CD, in addition to differentiating both subtypes of IBD from controls.71 Importantly, the authors of this study noted that among patients with CD, their miRNA profiles were consistent with the earlier patterns indicated by Wu et al69 and Zahm et al.70 When patients with UC were compared with controls, a distinct signature consisting of 31 miRNAs was identified which could differentiate patients with UC from controls with high specificity, sensitivity, and accuracy.72
Tissue miRNA profiling has also been used to differentiate subtypes of IBD and to differentiate patients with IBD from controls.73–79 Wu, et al. were among the first to analyze the potential role of miRNA obtained from colonic biopsies, in their description of the differential expression of 11 miRNAs among patients with active UC.73 A separate study by Wu et al identified 5 miRNAs associated with active CD of the sigmoid colon and 4 miRNAs that were increased among patients with CD affecting the terminal ileum.75 The 5 miRNAs associated with active colonic CD were later studied to assess their ability to differentiate CD from UC and indeterminate colitis. In this evaluation, all 5 miRNAs were statistically different when comparing patients with CD to those with indeterminate colitis, whereas no difference was noted when patients with UC were compared with those with indeterminate colitis.80 The ability to identify similar miRNA expression profiles across multiple studies is encouraging; however, the need for invasive testing with endoscopic examination and biopsy may limit the utility of colonic tissue miRNA profiling as a biomarker.
In an era of increased focus on the potential for personalized medicine, the emphasis on strategies for the development of better biomarkers in IBD will continue to exist. In addition to the identification of specific disease subtypes within IBD, a renewed focus on predictors of the disease course is paramount. Improving the ability to not only diagnose patients with IBD, but also to predict their disease activity and their response to therapy will significantly improve the care of patients with IBD. Additionally, by avoiding costly therapies that may be of minimal benefit, more precise therapy choices may lead to significant reductions in health care costs and resource utilization over time.
Given the lack of sensitivity and specificity associated with ESR and CRP, a significant opportunity exists for the development of disease-specific serologic markers of inflammation. Further attention may be focused on specific genotypes associated with CD or UC as a means of identifying better targets for biomarker development. For example, defensins such as β-defensin 2 and antimicrobial peptides such as cathelicidin may be increased among patients with CD where bacterial DNA is present in blood samples, and mediated through a wild-type NOD2/CARD15 genotype.81
Metabolic profiling has been proposed as another area of great promise in the evaluation of patients with suspected IBD and in the differentiation of UC from CD.82 Multiple specimen types can be analyzed through metabolomic methods, including mucosal biopsies, stool, and urine samples.83–88 One of the more unique metabolomic profiles recently suggested is a breathprint that can differentiate children with IBD from healthy controls. In a study of 117 patients, the authors used selected-ion flow-tube mass spectrometry to identify patterns of volatile organic compounds in the exhaled breath of children with IBD, demonstrating the potential utility for breath testing as a noninvasive method of evaluating a patient with suspected IBD.89
Protein profiling of serum, plasma, and tissue samples may also reveal distinct patterns among those patients with IBD. A variety of techniques for proteomic analysis have been proposed,90,91 with pilot studies indicating that proteomic profiling may be useful in the differentiation of patients with IBD from healthy controls,92,93 and in the differentiation of subtypes of IBD.94 Early studies also suggest that protein profiling may also have a role in the prediction of response to biologic therapy among patients with IBD.95
There has been continued interest in the development of biomarkers to aid in the differentiation between subtypes of IBD given the low sensitivity associated with serologic tests such as pANCA and ASCA. Our ability to explore genetic associations with clinical presentations of disease has improved considerably over the past decade, holding great promise for such evaluations. Recently, the largest genotype–phenotype study of patients with IBD was published.96 In an analysis of 29,838 patients with IBD, 3 gene loci (NOD2, MHC, and MST1 3p21) were identified which were associated with subphenotypes of IBD. These findings led to the recommendation that based on genetic factors, IBD may be better classified into 3 distinct subphenotypes (ileal CD, colonic CD, and UC).96 In an accompanying editorial, more systematic evaluation of the gene–environment connections was suggested as one means of improving our understanding of disease pathogenesis.97 Another recent genetic evaluation identified nearly 200 single-nucleotide polymorphisms that were associated with IBD, many of which overlapped between patients with UC and CD.98
Other efforts have been focused on improving the sensitivity of more established tests with previously detailed high specificity. Given the inability of pANCA alone to distinguish UC from CD, combining pANCA with other biomarkers has been proposed as a means of better delineation of disease subtype. In a study of 484 patients, Targan et al. found anti-CBir1 positivity in 44% of pANCA-positive patients with CD compared with 4% of pANCA-positive patients with UC,99 suggesting that the combination of these markers (pANCA+/anti-CBir1+) may be part of a biomarker signature suggestive of a specific, perhaps more complicated or UC-like phenotype of CD. In another approach, the genetic marker TNFSF15 was combined with ASCA IgA to increase the power of predicting a stenosing or perforating phenotype of CD.100
Perhaps most indicative of the potential power of using a multifaceted biomarker signature or panel was the comparison by Plevy, et al. of a panel of serological markers (ASCA-IgA, ASCA-IgG, ANCA, pANCA, OmpC, and CBir1) to a panel that included the same serological markers as well as inflammatory markers (including CRP), gene variants, and 2 additional serological markers (A4-Fla2 and FlaX).101 In this evaluation, the larger panel improved both the ability to differentiate IBD from non-IBD as well as the discrimination between CD and UC.101 As the utilization of serological biomarkers, genetic analysis, inflammatory and potentially environmental factors would seem to offer the greatest hope for increasing the ability to differentiate patients with IBD from those without IBD as well as to differentiate UC from CD, the creation of multifaceted biomarker signatures is an area that will likely continue to expand in the near future.
Although complicated due to the inherent multifactorial nature, the prediction of an individual patient's disease course is one area where improvement in biomarker performance is most desired. The potential use of biomarkers in the prediction of disease course has been demonstrated for over 15 years, beginning with the association of high ASCA levels with fibrostenosing and penetrating disease among patients with CD.102 Other studies have suggested that the sum of antibodies is an important factor in the evaluation of disease progression among patients with CD.103 Early prospective studies by Dubinsky et al104 demonstrated that the frequency of internal penetrating or stricturing disease increased as the presence of immune response to microbial antigens such as I2, OmpC, CBir1, and ASCA increased. In a larger study of 796 pediatric patients with CD, Dubinsky et al demonstrated that the rate of complicated CD (penetrating, stricturing, or surgery requiring disease) increased as the number and magnitude of reactivity to antibodies increased, with those patients expressing immune reactivity demonstrating a significantly faster disease progression.105 In a study of sera from 100 military personnel with CD, 65 patients were positive for at least 1 CD-associated antimicrobial antibody (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2, or anti-FlaX) at a median of 6 years before a diagnosis of CD.106 Additionally, the proportion of positive antimicrobial antibodies before diagnosis was higher among patients who developed complicated CD when compared with those who developed noncomplicated CD.106 Genotyping may also suggest the potential for a more severe disease course, as the NOD2 genotype has been associated with stricturing small bowel disease among patients with CD and more rapid disease progression.107
After the initial success in identifying serologic and genotypic predictors of disease course, more recent efforts have been focused on combining methods to create even stronger predictive models. In an evaluation of 1721 patients with CD, Kaur et al demonstrated that combining clinical and genetic data led to improved performance in determining an association with perianal CD.108 Additionally, the development of models incorporating genotype, serologic, and clinical information into a multivariable model for prediction of disease progression offers great promise for better predictions of the disease course of patients with CD.109,110 These models are particularly attractive given their web-based nature allowing for real-time discussions of predictions of disease prognosis with individual patients.
In addition to the demonstrated abilities to assess inflammation and mucosal healing, FC has also emerged as a noninvasive assessment of prediction of disease relapse among patients with UC.111 In a study of 70 patients in remission at study entry, an elevated FC was associated with an increased risk of relapse at both 6 and 12 months, whereas histologic inflammation, CRP, and length of remission were not predictive of relapse.111 In patients with severe UC, multiple methods have been proposed for the identification of patients at the greatest risk of colectomy. In one study, an elevated CRP alone was associated with an increased likelihood of colectomy.112 However, a more recent study used a risk matrix model to identify the extent of disease, age, need for systemic steroids, and CRP or ESR at diagnosis as reliable predictors of need for colectomy both individually and in combination.113
Given the success of combination approaches to predicting the disease course of patients with both CD110 and UC,113 it would seem that further development and refining of these prediction models holds the greatest potential for better identification of patients at risk for a more severe disease course, allowing for an earlier and more personalized approach to therapy.
Ideally, biomarkers would be used as a predictive means to guide the initial decisions regarding the initiation of one therapeutic agent over another among patients with active CD and UC. However, to this point, many biomarkers have demonstrated utility in predicting response or remission only after initiation of an agent, which may lead to trials of multiple therapies before a successful maintenance regimen is established. In addition to an increasing focus on the utility of pharmacodynamic and pharmacokinetic monitoring of patients being treated with biological therapy,114–118 multiple biomarkers have been identified (Table 4).
CRP has been used in a variety of studies to predict response to biological therapy.119–122 The overall importance of CRP in the prediction of response to biological therapy has been discussed in many scenarios, with particular questions centered around CRP's role as an independent biomarker predicting clinical response or remission to therapy as opposed to a more general indicator of inflammation.123 CRP has also been described as a predictor of low IFX level, and subsequent loss of response among patients with CD being treated with IFX.124 Among patients being treated with thiopurines, CRP can also serve as a predictor of relapse.125,126 Elevated CRP has also served as a predictor of relapse after withdrawal of IFX therapy in patients being treated with combination therapy.127
Given concerns that blood-based tests such as CRP might reflect an overall state of inflammation, there has been continued interest in the role of fecal tests that may be more directly associated with mucosal inflammation. High FC at baseline have been associated with increased risk of disease relapse among patients with CD,24 whereas FC levels that normalize after induction therapy have been associated with sustained clinical remission among patients with CD and UC.131,132 Lower FC levels have been associated with response to biological therapy and clinical outcomes including clinical remission and mucosal healing.133,134 Perhaps most useful, among patients in remission, FC has been reported to increase earlier and remain elevated before clinical or endoscopic relapse of disease,135 which may indicate a role for prospective or routine monitoring with FC to identify those patients at the greatest risk of relapse.
Genome-wide association studies have been used to identify predictors of response to anti-TNF therapy among patients with IBD. In an evaluation of 94 patients with IBD, Dubinsky et al136 found an association between 6 known susceptibility loci and primary nonresponse to an anti-TNF therapy. In the final predictive model used in this study, only the 21q22.2/BRWDI loci demonstrated a significant association, along with pANCA and a diagnosis of UC.136
Gene expression analysis has also been used as a predictor of response to anti-TNF therapy in patients with both UC66 and CD.67,137 Gene expression analysis offers a particularly attractive tool, as it could be performed before initiation of therapy and thus offers a prediction of response before use of therapy that may ultimately provide a less than desirable treatment effect. Techniques using analysis of “metagenes,” transcript sets that have been derived to reflect ongoing biological change within a mucosal biopsy have also demonstrated utility in the identification of predictors of the response to IFX therapy among patients with UC.138 Whole-blood gene expression analysis techniques are perhaps more attractive, as they allow for prediction of response using a minimally invasive approach as compared with the need for biopsies for gene expression analysis of mucosal tissue. Given the preference for a less invasive, blood-based predictor of response, there are ongoing studies of whole-blood gene expression analysis to identify predictors of response to therapy with IFX and adalimumab.
Further development of biomarkers to assist in the care of patients with UC and CD is an area that is primed for progression in the near future. As we move toward an ultimate goal of precision medicine, where treatment decisions can be individualized through the use of clinical, genetic, and phenotypic information, there will be further emphasis on the initial identification of patients with IBD, as well as predictors of disease course and responses to individual treatment regimens. Given the initial successes in combining multiple testing modalities, there is hope that the ultimate development of a biomarker signature may yield significant advances in our ability to identify those patients with the greatest risk for severe disease, and thus would benefit most from aggressive and individualized therapies. Although the ideal biomarker for the care of patients with UC and CD does not exist at this point, there is hope that we can build on the initial foundations of serologic and stool tests to identify a more sensitive and specific biomarker or biomarker signature with low cost and increased availability.
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