To our knowledge, this is the first study to evaluate the change of stricture stiffness of CD using SWE after biologics treatment. Interestingly, only the SWS indices in the UST naïve group were significantly decreased one year after the treatment, but not in the IFX naïve group and the bio-switch group. On the other hand, the BWT indices in each group were significantly decreased.
Intestinal stricture of CD is characterized by focal asymmetric, transmural, and granulomatous inflammation affecting any segment of the gastrointestinal tract , and could be subdivided into the 3 different types; predominantly fibrotic, inflammatory, and mixed type. [31, 32, 33] It is difficult to determine the type of stricture by clinical manifestations and using serological indicators. The strictures containing considerable fibrosis thought to be associated with intramural SWS indices, which may be higher in the fibrotic strictures compared to purely inflammatory strictures. On the basis of the bowel wall SWS, it may be possible to evaluate the presence of fibrosis at the time of initial diagnosis of stricture presentation. [34, 35] Fibrosis process results from the activation of mesenchymal cells by TNF-α, transforming growth factor-β (TGF-β), vascular growth factor, and insulin-like growth factor-1, matrix metalloproteinases, and other mediators released by leukocytes, epithelial and mesenchymal cells, and the gut microbiota. TGF-β induces myofibroblast transformation from fibroblast and epithelial cells, and myofibroblast produced collagen and fibronectin leading extracellular matrix and causing fibrotic strictures. Thus TGF-β is one of the important molecular targets against fibrotic strictures. The healing process could be different depending on the biologics, because of the different role of target molecules.
UST may suppress the activity of TGF-βactivated by IL-22 and IL-17, because UST blocks IL-23 and also decreases the expression of IL-17A downstream, which may lead to suppression of fibrogenesis and stenotic formation. [7, 36] UST downregulated TNF-α expression indirectly, which slows the healing of ulcerations as compared with anti-TNFαagents.[ 37] Thus, UST may lead to suppression of fibrogenesis and stenotic formation. Interestingly, Murate K, et al reported that UST could be an effective treatment for preventing re-stenosis of the small bowel after endoscopic balloon dilation (EBD) in two cases with small bowel lesions. [38, 39] On the other hands, anti-TNF-α antibodies induced small bowel stenoses in 8 of 15 (53.3%) patients after 6–22 maintenance infusion.  In another prospective study investigating the frequency of small bowel obstruction in CD stricture patients after IFX or adalimumab, 22.2% (2/9) had bowel obstruction requiring surgical resection.  However, the data about the development bowel obstruction after UST is lacking. The further prospective studies are required increasing the number of patients and extending observation period after the biologics therapy.
There were two reports evaluating SE against intestinal lesions of CD treated with anti-TNF therapy. Orlando et al.  evaluated as a method of monitoring outcomes of anti-TNF therapy, no statistically significant difference in strain ratio values at baseline and at 14 and 52 weeks after therapy.[ 42] Our results also indicated no statistically significant difference in SWE indices in the IFX group and the bio-switch group. Only the SWS indices in the UST naïve group were significantly decreased one year after the treatment. The reason of no improvement in the bio-switch group might be due to the fibrotic strictures, which have formed during the longer duration of CD. Our results suggested that early induction of UST could be related with suppression of fibrosis, however immunochemical histologic analysis of stenosis lesion treated UST are required to confirm in the further study.
BWT would be useful to monitor biologics-induced bowel activity improvement in CD.[ 15, 28, 43] There is an increase in echogenicity of the third layer of the intestinal wall (submucosal layer) that is currently thought to be an expression of submucosal fibrosis, whereas hypoechogenicity of the intestinal layers is related to hyperemia and edema. [44, 45] Increased BWT are important components of inflammation,[ 46] and improvement lesions are generally defined as those with improvement (> 1mm) or normalization of BWT.  In this study, the BWT in each group including the bio-switch group decreased significantly after biologics treatments, and both biologics improved simple CDAI regardless bio-naïve status. Therefore, BWT may be a beneficial tool to evaluate activity reflecting mainly inflammation, while SWS might be a better tool to evaluate fibrotic stricture reflecting tissue stiffness.
This study has several limitations. At first, there was no reference standard, such as histological fibrosis analysis using surgical resection organs. Secondary, the number of patients is small and the study is retrospective. The baseline of clinical data among the three groups were not matched and selection bias should be considered. Especially, the baseline CDAI were different between the IFX group and the UST groups. Almost our CD patients with perianal and perirectal lesions were treated by IFX, because IFX is reported to be more effective against perianal lesion compared to UST.  The further prospective study evaluating the development of obstruction after biologics treatment are required to confirm the difference in SWS. The multicenter large-scale study adjusting the clinical data between the UST group and the IFX group is required to conform the results.
In conclusion, only the SWS indices in the UST naïve group were significantly decreased one year after the treatment, but not in the IFX naïve group and the group with switching from IFX to UST. Early induction of UST in patients with CD might lead to suppression of stenotic formation.