Confocal laser endomicroscopy for functional barrier imaging in Crohn’s disease

Confocal laser endomicroscopy (CLE) is an endoscopic technique for microscopic assessment of the gastrointestinal mucosa, and was introduced into clinical practice in 2004 [1]. Initial studies used the technique to predict the presence of colonic neoplasias, but subsequent studies aimed to assess mucosal inflammation in the gastrointestinal tract. Specifically, CLE has been used for assessment of the intestinal mucosa in patients with inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis. These studies revealed that CLE with fluorescein can be used to detect crypt alteration, hypervascularization, and infiltrating mononuclear cells in patients with IBD [2] [3]. Moreover, CLE with acriflavine was able to detect translocation of commensal bacteria into the inflamed mucosa [3], suggesting that this CLE approach may be suitable for the analysis of altered barrier function in IBD. Finally, in a pilot study of 47 patients with ulcerative colitis and 11 patients with Crohn’s disease, Kiesslich et al. [4] demonstrated that detection of shedding epithelial cells and local barrier defects in the gut epithelium predict clinical relapse of quiescent IBD and can be quantitatively assessed by a new scoring system (Watson score).

In this issue of Endoscopy, Karstensen et al. [5] have extended the above findings on altered barrier function in a larger series of 39 patients with Crohn’s disease, of whom 20 were in clinical remission. In the study, integrated endoscope-based CLE with fluorescein was performed in the colon and ileum. The authors noted increased ileal and colonic fluorescein leakage, ileal microerosions, and colonic vascular alterations in patients with active Crohn’s disease compared with inactive disease. In patients with inactive disease, quantitative assessment of fluorescein leakage and microerosions via the Watson score in the ileum could be used to predict clinical relapse of the disease. In contrast, changes in the colon were more difficult to interpret compared with the ileum, suggesting that further studies are warranted to determine the relevance of functional barrier imaging in colonic Crohn’s disease. With regard to ileal Crohn’s disease, these findings indicate that the presence of an altered barrier function is an early phenomenon in recurrent Crohn’s disease that occurs before clinical symptoms of active disease. Importantly, analysis of intra- and interobserver variability in this study yielded substantial or almost perfect reproducibility of most CLE parameters, suggesting that this approach is a valuable tool for prediction of clinical relapse in ileal Crohn’s disease.

In spite of these promising results, the study has some potential limitations, including the heterogeneity of the Crohn’s disease population (cases with clinically active disease and those in remission), the limited clinical observation period after CLE (12 months), and the definition of clinical relapse (treatment escalation or surgery rather than increase of established clinical activity scores for Crohn’s disease). However, the study makes an important contribution to further define the usefulness of CLE in patients with Crohn’s disease.

Although the potential of CLE to detect signs of active inflammation in both Crohn’s disease and ulcerative colitis, and to potentially discriminate between the lesions of these disease entities has been acknowledged before [2] [4] [6] [7] [8] [9] [10] [11], functional imaging of the epithelial barrier via CLE remains a poorly studied field in IBD. Previous findings indicated that CLE enables detection of epithelial gaps caused by cell shedding, the presence of microerosions, and the occurrence of fluorescein leakage in IBD compared with control patients [3] [4] [12] [13]. It was also shown that quantitative assessment of these changes using the Watson score allows prediction of clinical relapse in patients with IBD. This observation was prospectively explored in the study by Karstensen et al. [5] in a larger series of Crohn’s disease cases. The findings indicate that CLE permits the accurate assessment of functional barrier alterations in Crohn’s disease as a potential marker for prediction of relapse. If these results can be further confirmed by larger prospective trials, one can imagine that CLE will become an important option for evaluation of barrier function in IBD. It is important to emphasize that such analysis of barrier function via CLE is not possible by histologic analysis of endoscopically obtained gut biopsies from IBD patients, thereby opening new avenues for research with CLE that are based on functional imaging in the gastrointestinal tract.

Various studies using both endoscope-based CLE and probe-based CLE have focused on descriptive microscopic imaging in the inflamed and uninflamed mucosa in patients with IBD [3] [4] [10] [11]. These studies demonstrated that CLE with fluorescein is suitable for the structural analysis of intestinal epithelial cells and infiltrating mononuclear cells in IBD. Furthermore, CLE findings in Crohn’s disease showed significantly more discontinuous inflammation, focal cryptitis, and discontinuous crypt abnormalities than in ulcerative colitis. However, ulcerative colitis frequently led to severe, widespread crypt distortion, decreased crypt density, and frankly irregular surface [10]. Another field of interest for CLE-based microscopic tissue analysis in IBD involves the detection of colitis-associated neoplasias. This technique, in combination with chromoendoscopy, has been highly successful in patients with ulcerative colitis [11], but a recent study showed only limited relevance in Crohn’s disease because of the infrequent detection of flat neoplasias in patients with Crohn’s disease [14]. However, in patients with inflammation-associated lesions, CLE may predict the presence of neoplasia with high accuracy.

Recent studies have also highlighted the potential of CLE for molecular imaging in Crohn’s disease and neoplastic disorders of the gastrointestinal tract [15] [16]. In Crohn’s disease, a pilot study revealed that fluorescent anti-tumor necrosis factor (TNF) antibodies (adalimumab) can be used to detect membrane-bound TNF-expressing immune cells in the lamina propria, thereby allowing prediction of response to anti-TNF therapy in active Crohn’s disease. Thus, in addition to descriptive microscopic analysis, CLE in patients with Crohn’s disease has the exciting potential to permit both functional and molecular analyses of the tissue. Accordingly, we can now define three potential areas for CLE indications in IBD that clearly go beyond the possibilities of white-light endoscopy or high resolution endoscopy: descriptive imaging, functional imaging, and molecular imaging ([Fig. 1]). The potential of the CLE technique for functional barrier analysis in IBD was further highlighted by the study from Karstensen et al. [5]. Future studies will be needed to explore these interesting new insights into CLE-based tissue analysis in order to unequivocally define the diagnostic value of CLE in patients with IBD. These studies should also define the relevance of CLE-based functional barrier imaging compared with endoscopic mucosal healing and disease activity scores as current gold standards for assessment of clinical deep remission in Crohn’s disease.

Fig. 1 Usefulness of white light endoscopy, high resolution endoscopy, and confocal laser endomicroscopy in patients with Crohn’s disease. CDEIS, Crohn’s Disease Endoscopic Index of Severity; SES-CD, Simplified Endoscopic Score for Crohn’s Disease; mTNF, membrane-bound tumor necrosis factor.

• References

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