Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: A cross-sectional study

Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: A cross-sectional study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: A cross-sectional study Shinya Furukawa, Sen Yagi, Kana Shiraishi, Kenichirou Mori, Tomoyuki Ninomiya, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-60855/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Nov, 2020 Read the published version in BMC Gastroenterology → Version 3 posted 4 You are reading this latest preprint version Show more versions Abstract Background: Mucosal healing (MH) has been indicated as the therapeutic goal for ulcerative colitis (UC). Platelet count is known as an inflammation evaluation. However, the association between platelet count and MH among patients with UC is still scarce. We therefore assessed this issue among Japanese patients with UC. Methods: The study subjects consisted of 345 Japanese patients with UC. Platelet count was divided into quartiles on the basis of the distribution of all study subjects (low, moderate, high, and very high). Several endoscope specialists were responsible for evaluating MH and partial MH, which was defined as a Mayo endoscopic subscore of 0 and 0-1, respectively. Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Age, sex, CRP, steroid use, and anti-Tumor necrosis factor α (TNFα) preparation were selected a priori as potential confounding factors. Results: The percentage of partial MH and MH were 63.2 and 26.1%, respectively. Moderate and very high was independently inversely associated with partial MH (moderate: OR 0.40 [95%CI: 0.19-0.810], very high: OR 0.37 [95%CI: 0.17-0.77], p for trend= 0.034). Similarly, moderate, high, and very high were independently inversely associated with MH (moderate: OR 0.37 [95% CI: 0.18-0.73], high: OR 0.41 [95% CI: 0.19-0.83], and very high: OR 0.45 [95% CI: 0.21-0.94], p for trend = 0.033) after adjustment for confounding factors. Conclusions: Among patients with UC, platelet count was independently inversely associated with MH. Gastroenterology & Hepatology platelet mucosal healing ulcerative colitis Figures Figure 1 Figure 1 Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by a disease course involving relapses and remissions [1]. Mucosal healing (MH) is inversely associated with clinical relapse, rates of hospitalization and surgery, and incidence of colorectal cancer [2-7]. Thus, MH has been indicated as the therapeutic goal for UC. Endoscopy is considered the gold standard for evaluating MH, but frequent endoscopic procedures are invasive, inconvenient, expensive, and occasionally cause complications. Platelet count is considered to be an inflammation marker. Platelet count among active UC patients was higher than that among inactive UC patients [8, 9]. Platelet count among patients with complete MH was lower than that among patients with partial MH [10]. Two studies identified a positive relationship between platelet count and the severity of endoscopic severity among patients with UC [11, 12]. Elevated platelet count was significantly positively associated with relapse among patients with UC [13]. In a Spanish study of patients with IBD, however, platelet count was not associated with endoscopic activity among patients with UC [14]. The association between platelet count and MH among patients with UC is still scarce. Thus, we aimed to evaluate the association between platelet count and MH among Japanese patients with UC. Material And Methods Study population The study subjects consisted of 414 Japanese patients with UC at the Department of Gastroenterology and Metabology at the Ehime University Graduate School of Medicine, and at several affiliated hospital in Ehime prefecture (the Ehime Clinical Network for Alimentary Diseases [ECNAD] study group). All patients were diagnosed with UC based on endoscopic, radiological, histological, and clinical criteria. After 69 patients were excluded due to incomplete data, the final analysis sample in this study consisted of 345 patients assessed for endoscopy examination, medication, and platelet count. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) and was approved by the institutional review board of the Ehime University Graduate School of Medicine (1505011). Consent was obtained mainly for outpatients at each hospital, as well as inpatients for ulcerative colitis. The study was explained and enrolled to all those diagnosed with ulcerative colitis. Well-trained staff obtained written informed consent from all patients enrolled. This study analyzed group was registered during the period from 2015 to 2019. Measurements Information on endoscopic findings, use of drugs for UC, and platelet count and CRP were collected using medical records. Platelet count was determined from routine blood levels obtained from patient files at the time the patients were included in the study. Blood samples were taken the morning after overnight fasting. Blood examination was collected when a colonoscopy is reserved or when the colonoscopy examination is performed. There could be a time difference of about two months. Definition of mucosal healing We evaluated mucosal status by total colonoscopy. The Mayo endoscopic subscore (MES) contains the following four categories [15]: 0, normal or inactive disease; 1, mild disease with erythema, decreased vascular patterns, and mild friability; 2, moderate disease with marked erythema, absence of vascular patterns, friability, and erosions; 3, severe disease with spontaneous bleeding and ulceration. Partial MH and MH were defined as category 0 and 0-1 in this study, respectively. Several endoscope specialists were responsible for evaluating MES and MH, and all endoscopists were blinded to platelet count. Statistical analysis Platelet count was divided into quartiles on the basis of the distribution of all study subjects. Platelet count was classified into four categories: 1) low platelet, 29.6 (×10⁴/μL). Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Multiple logistic regression analyses were used to adjust for potential confounding factors. Age, sex, CRP, steroid use, and anti-TNFα preparation were selected a priori as potential confounding factors. A receiver operating characteristic (ROC) curve was generated, and the area under the curve was calculated to show the utility of the platelet count in indicating mucosal healing. We used Youden’s index to calculate the cutoff value of platelets. Statistical analyses mainly were performed using SAS software package version 9.4 (SAS Institute Inc., Cary, NC, USA). The ROC curve, cutoff value of the platelet count, sensitivity, and specificity were analyzed using JMP 14.2 software (SAS Institute Inc., Cary, NC, USA). All probability values for statistical tests were two-tailed, and P < 0.05 was considered statistically significant. Results Table 1 shows the characteristics of the 345 study participants. The mean age was 50.2 years, and the percentage of male patients was 59.7%. Use of 5-aminoasalicylates, prednisolone, azathioprine, and TNF-α monoclonal antibody preparations were reported to be 91.0%, 20.6%, 15.4% and 5.5%, respectively. The percentage of partial MH and MH were 63.2% and 27.4%, and the mean CRP and platelet count were 0.39 ± 1.13 (mg/dl) and 25.77 ±7.80 (×10⁴/μL). The ROC curve of the platelet count for identifying mucosal healing had an area under the curve of 0.615 (Figure1). Table 2 shows crude and adjusted ORs and 95% CIs for partial MH and MH in relation to platelet count. The percentages of partial MH and MH among low, moderate, high, and very high platelet patients were 78.2%, 60.5%, 62.9%, 51.2%, 43.7%, 20.9%, 19.8% and 19.8%, respectively. After adjustment for age, sex, CRP, use of steroid, and use of TNF-α monoclonal antibody preparations , moderate, and very high platelet counts but not high platelet were independently inversely associated with partial MH (moderate: OR 0.40 [95% CI: 0.19-0.80], and very high: OR 0.37 [95% CI: 0.17-0.77], p for trend p=0.034). Similarly, platelet count was independentlyinversely associated with MH (moderate: OR 0.37 [95% CI: 0.18-0.73], high: OR 0.41 [95% CI: 0.19-0.83], and very high: 0.45 [95% CI: 0.21-0.94], p for trend = 0.033). In sensitive analysis, azathioprine was not associated with platelet count. Discussion In the present study, platelet count was independently inversely associated with partial MH and MH among 345 Japanese patients with UC. Platelet count is known as an inflammation marker. Several studies had showed the association between platelet count and outcome among patients with UC. Platelet count among active stage patients was higher than among those with inactive stage UC and healthy subjects in a Greek study of subjects including those with UC and Crohn’s disease [8] and in a Turkish study of subjects with active UC and inactive UC [9]. In a Japanese study of 68 patients with UC, platelet count was positively associated with endoscopic activity [11]. In a Swish study of 280 subjects including those with UC, a positive association between platelet count and endoscopic activity based on a modified Baron score among patients with UC was found [12]. In a retrospective cohort study of 183 Japanese UC patients with clinical remission, platelet count among patients with complete mucosal healing (Mayo endoscopic subscore 0) was lower than that among those with partial mucosal healing (Mayo endoscopic subscore1). Furthermore, the change of platelet count from baseline was significantly associated with a shift from complete to partial MH [10]. In a prospective observational study of Japanese UC patients with MH, a platelet count at baseline in the relapse group was significantly higher than that among those in the non-relapse group. Additionally, a platelet count at baseline was significantly associated with relapse among patients with UC after adjustment for several confounding factors [13]. In a Spanish study of 123 patients with UC, a positive relationship between fecal calprotectin level, which is a reliable marker for MH, and platelet count was found [16]. The finding in this study was consistent with these studies that showed the association between platelet count and favorable prognosis. On the other hand, however, a similar association between platelet count and endoscopic activity was reported among patients with Crohn’s disease but not among those with UC [14]. The discrepancies regarding platelet count and MH among patients with UC might be explained, at least in part, by differences in year, duration of UC, sample size, and confounding factors considered. The underlying mechanism linking platelet count and MH among patients with UC remains unclear, but there are some biologically plausible options. Clusters of differentiation 154 (CD154) plays a central role in co-stimulation and regulation of the immune response via T cell priming and activation of CD40-expressing immune cells [17]. CD 154 expression was found on platelets [18], and mucosal inflammation might elevate platelet count via CD 154 expression. The platelet-to-lymphocyte ratio (PLR) has emerged as a useful marker revealing shifts in platelet and lymphocyte counts due to acute inflammatory. PLR can be calculated easily from a routine blood test without additional cost. PLR has been reported to be a useful biomarker in the prognosis of various cancers [19]. Several pieces of evidence regarding the association between PLR and UC exist. In a Turkish study of 104 patients with UC and a Korean case control study of 144 subjects including 48 patients with UC and 96 healthy controls, PLR among patients with UC was higher than that in controls, regardless of mucosal remission. PLR among patients with endoscopic active UC was higher than that in patients with endoscopic remission UC [20]. Similarly, in a Korean study, PLR among patients with severe UC was higher than that in patients with mild to moderate UC [21]. In an Italian study of 88 UC patients who started anti-TNF monotherapy, PLR was a useful prognostic biomarker of mucosal healing [22]. Platelet count and PLR might be cost-effective and easy-to-validate parameters for optimal treatment modality. Our findings are consistent with those of previous reports regarding the association between platelets (including PLR) and UC. To date, MH has been indicated as the therapeutic goal for IBD [3, 23, 24]. Endoscopy is necessary to evaluate MH, but repeated endoscopy is extremely burdensome for patients. Monitoring platelet count might be useful both for patients with UC and their physicians. However, further research is needed to confirm the association between platelet and MH in future. Our study has a few limitations. First, this was a cross-sectional study; therefore, we cannot conclude that there is a causal relationship between platelet count and MH. Second, most of the patients in this cohort may have been receiving treatment for a considerable period of time since their physicians may have opted to attempt to control inflammation. The long duration of such treatment might have masked the association between platelet count and MH. Third, data regarding fecal calprotectin was not available in this cohort. Fourth, the time difference between the blood test and the test may have caused a misclassification. However, non-differential misclassification causes a bias of the odds ratio towards the null. Finally, the patients in the current study were not likely representative of Japanese patients with UC. Nevertheless, the median age, male/female ratio, and use of 5-aminoasalicylates, prednisolone, thiopurines, and biologics were similar in the present study (48.0, 59.7%, 91.0%, 20.6%, 15.4%, and 5.5%, respectively) and in a Japanese national study based on UC claims data in 2016 (44.0, 63.9%, 96.2%, 15.5%, 13.8%, and 9.0%, respectively). Conclusions Among Japanese patients with UC, platelet count may be independently inversely associated with partial MH and MH. This study confirmed the positive association between platelet count and MH shown in previous retrospective studies and reinforced a positive dose-response association. Monitoring the platelet count may be useful in the assessment of early response to medication and when endoscopy cannot be repeated, such as in elderly and infant patients with UC. List Of Abbreviations MH: mucosal healing; UC: ulcerative colitis: TNF: tumor necrosis factor; IBD: inflammatory bowel disease; MES: Mayo endoscopic subscore; CD: Clusters of differentiation; PLR: platelet-to-lymphocyte ratio Declarations Ethics approval and consent to participate The study protocol was approved by the institutional review board of the Ehime University Graduate School of Medicine (1505011). Well-trained staff obtained written informed consent from all patients enrolled. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests Funding Not applicable. Authors’ contribution Conception and design: SF, ET, YI, YH, TS; Acquisition of data: KS, SY, KM, NT, KK, YM, SS, MU, NS, SN, SI, HM, KO, MT, AH, HY, MM; Analysis and Interpretation of data: SF, SY, RY, YI, YH; Drafting of the manuscript: SF; Statistical analysis: SF; Supervision: YH. The author (s) read and approved the final manuscript. Acknowledgements The authors would like to acknowledge Yu Hashimoto, Masakazu Hanayama, Kazuhiro Tange, Kanako Konishi, Tomoe Kawamura, Yasunori Yamamoto, and the ECNAD study group for their support. References Langholz E , Munkholm P , Davidsen M , et al. Course of ulcerative colitis: analysis of changes in disease activity over years. 1994; 107: 3-11. Colombel JF , Rutgeerts P , Reinisch W , et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. 2011; 141: 1194-201. Frøslie KF , Jahnsen J , Moum BA , Vatn MH ; IBSEN Group . 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Am J Gastroenterol. 2001; 96: 776-81. Kayahan H, Akarsu M, Ozcan MA, et al. Reticulated platelet levels in patients with ulcerative colitis. Int J colorectal Dis 2007; 22: 1429-35. Nakarai A, Kato J, Hiraoka S, et al. Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing, which can be predicted from the platelet count. World J Gastroenterol. 2014; 20: 18367-74. Uchihara M, Kato J, Tsuda S, et al. Blood biomarker integration of severity and extent of endoscopic inflammation in ulcerative colitis. JGH Open. 2017; 1: 98-104. Schoepfer Am, Beglinger C, Straumann A, et al. Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes. Inflamm Bowel Dis. 2013; 19: 332-41. Nakarai A, Kato J, Hiraoka S, et al. An elevated platelet count increases the risk of relapse in ulcerative colitis patients with mucosal healing. 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PLoS One. 2014; 9: e101119 (Page 13 Lines 6-7 in the revised manuscript). Akpinar MY, Ozin YO, Kaplan M, et al. Platelet-to-lymphocyte Ratio and Neutrophil-to-lymphocyte Ratio Predict Mucosal Disease Severity in Ulcerative Colitis. J Med Biochem. 2018; 37: 155-62 Jeong Y, Jeon SR, Kim HG, et al. The role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in ulcerative colitis. Intest Res. 2020 (In Press) Bertani L, Rossari F, Barberio B, et al. Novel prognostic biomarkers of mucosal healing in ulcerative colitis patients treated with anti-TNF: neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio. Inflamm Bowel Dis 2020; 20: 1579-87 Pineton de Chambrun G, Peyrin-Biroulet L, et al. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol. 2010; 7: 15-29 Baert F , Moortgat L , Van Assche G , Caenepeel P , et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. 2010;138:463-8. Matsuoka T, Igarashi A, Sato N, et al. Trends in corticosteroid prescriptions for ulcerative colitis and factors associated with long-term corticosteroid use: analysis using Japanese claims data from 2006 to 2016. J Crohns Colitis. 2020 (In press). Tables Table 1. Clinical characteristics of the 345 study participants Variable n (%) Age, years, mean ± SD 50.2 ± 16.6 Male (%) 206 (59.7) Disease extent (pancolitis/left-sided/procitis/others) 148/96/93/8 Medication 5-aminoasalicylates (%) 314 (91.0) Prednisolone (%) 71 (20.6) Azathioprine 53 (15.4) TNF-α monoclonal antibody (%) 19 (5.5) Mayo endoscopic subscore, mean ± SD 1.17 ± 0.9 Partial mucosal healing (Mayo endoscopic subscore ≤ 1) (%) 218 (63.2) Mucosal healing (Mayo endoscopic subscore < 1) (%) 90 (26.1) CRP (mg/dl) 0.39 ± 1.13 Platelet ( ×10⁴/μL ), mean ± SD 25.91 ± 7.81 SD, standard deviation; TNF, tumor necrosis factor Table 2 Crude and adjusted odds ratios and 95% confidence intervals for mucosal healing in relation to platelet count Variable (× 10⁴/µL) Prevalence (%) Crude OR (95% CI) Adjusted OR (95% CI) Partial MH (MES ≤ 1) platelet ≤ 20.4 68/87 (78.2) 1.00 1.00 20.4 < platelet ≤ 25.0 52/86 (60.5) 0.43 (0.22–0.83) 0.40 (0.19–0.80) 25.0 < platelet ≤ 29.6 54/86 (62.9) 0.47 (0.24–0.92) 0.54 (0.26–1.13) 29.6 < platelet 44/86 (51.2) 0.29 (0.15–0.56) 0.37 (0.17–0.77) P for trend 0.034 MH (MES < 1) platelet ≤ 20.4 38/87 (43.7) 1.00 1.00 20.4 < platelet ≤ 25.0 18/86 (20.9) 0.34 (0.17–0.66) 0.37 (0.18–0.73) 25.0 < platelet ≤ 29.6 17/86 (19.8) 0.32 (0.16–0.62) 0.41 (0.19–0.83) 29.6 < platelet 17/86 (19.8) 0.32 (0.16–0.62) 0.45 (0.21–0.94) P for trend 0.033 Odds ratios were adjusted for age, sex, CRP, use of prednisolone, and use of TNF-α monoclonal antibody. OR, odds ratio; CI, confidence interval Cite Share Download PDF Status: Published Journal Publication published 16 Nov, 2020 Read the published version in BMC Gastroenterology → Version 3 posted Editorial decision: Accept 08 Nov, 2020 Editor assigned by journal 31 Oct, 2020 Submission checks completed at journal 31 Oct, 2020 Editor invited by journal 31 Oct, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Harumi","middleName":"","lastName":"Yano","suffix":""},{"id":4293061,"identity":"d95eb7e9-2cc9-4e6b-8e1a-a51f90f66457","order_by":17,"name":"Masato Murakami","email":"","orcid":"","institution":"Murakamikinen Hosipital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Murakami","suffix":""},{"id":4293062,"identity":"602797c9-b183-49df-be05-37148960f11a","order_by":18,"name":"Eiji Takeshita","email":"","orcid":"","institution":"Ehime University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eiji","middleName":"","lastName":"Takeshita","suffix":""},{"id":4293063,"identity":"34c4dfa2-fd36-4b93-bb87-6abce6ec8ebf","order_by":19,"name":"Yoshio Ikeda","email":"","orcid":"","institution":"Ehime University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoshio","middleName":"","lastName":"Ikeda","suffix":""},{"id":4293064,"identity":"c129408d-b204-41d5-b986-8147f55b4461","order_by":20,"name":"Yoichi Hiasa","email":"","orcid":"","institution":"Ehime University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoichi","middleName":"","lastName":"Hiasa","suffix":""}],"badges":[],"createdAt":"2020-08-17 10:18:51","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.3.rs-60855/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-60855/v3","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12876-020-01538-y","type":"published","date":"2020-11-16T15:00:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":3435697,"identity":"d5e97bb3-9c59-4a4e-b87a-f5571a6025ea","added_by":"auto","created_at":"2020-11-06 22:01:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51507,"visible":true,"origin":"","legend":"Receiver operating characteristic curve of platelet count for identifying mucosal healing based on the Mayo endoscopic subscore. \nThe receiver operating characteristic (ROC) curve platelet count for identifying mucosal healing had an area under the curve of 0.613. When the cutoff value of the platelet count was 20.4, the sensitivity and specificity were 42.9% and 76.7%, respectively. \n","description":"","filename":"20201031Figure1ROCPLTANDMH.jpg","url":"https://assets-eu.researchsquare.com/files/rs-60855/v3/9df1e2f4771e17da26e85d58.jpg"},{"id":3435693,"identity":"a25b2064-5ecc-4731-bc82-70c489b0fbed","added_by":"auto","created_at":"2020-11-06 22:01:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51507,"visible":true,"origin":"","legend":"Receiver operating characteristic curve of platelet count for identifying mucosal healing based on the Mayo endoscopic subscore. \nThe receiver operating characteristic (ROC) curve platelet count for identifying mucosal healing had an area under the curve of 0.613. When the cutoff value of the platelet count was 20.4, the sensitivity and specificity were 42.9% and 76.7%, respectively. \n","description":"","filename":"20201031Figure1ROCPLTANDMH.jpg","url":"https://assets-eu.researchsquare.com/files/rs-60855/v3/df1e8b72f7086b4b408fdf7b.jpg"},{"id":13612187,"identity":"53e8ee09-5699-47ea-aba8-e39980d842f9","added_by":"auto","created_at":"2021-09-17 06:31:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":420548,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-60855/v3/4916238c-f2aa-4029-bed1-9d415c1de9b8.pdf"}],"financialInterests":"","formattedTitle":"Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: A cross-sectional study","fulltext":[{"header":"Background","content":"\u003cp\u003eUlcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by a disease course involving relapses and remissions [1]. Mucosal healing (MH) is inversely associated with clinical relapse, rates of hospitalization and surgery, and incidence of colorectal cancer [2-7]. Thus, MH has been indicated as the therapeutic goal for UC. Endoscopy is considered the gold standard for evaluating MH, but frequent endoscopic procedures are invasive, inconvenient, expensive, and occasionally cause complications.\u003c/p\u003e\n\u003cp\u003ePlatelet count is considered to be an inflammation marker. Platelet count among active UC patients was higher than that among inactive UC patients [8, 9]. Platelet count among patients with complete MH was lower than that among patients with partial MH [10]. Two studies identified a positive relationship between platelet count and the severity of endoscopic severity among patients with UC [11, 12]. Elevated platelet count was significantly positively associated with relapse among patients with UC [13]. In a Spanish study of patients with IBD, however, platelet count was not associated with endoscopic activity among patients with UC [14]. The association between platelet count and MH among patients with UC is still scarce.\u003c/p\u003e\n\u003cp\u003eThus, we aimed to evaluate the association between platelet count and MH among Japanese patients with UC.\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study subjects consisted of 414 Japanese patients with UC at the Department of Gastroenterology and Metabology at the Ehime University Graduate School of Medicine, and at several affiliated hospital in Ehime prefecture (the Ehime Clinical Network for Alimentary Diseases [ECNAD] study group). All patients were diagnosed with UC based on endoscopic, radiological, histological, and clinical criteria. After 69 patients were excluded due to incomplete data, the final analysis sample in this study consisted of 345 patients assessed for endoscopy examination, medication, and platelet count. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) and was approved by the institutional review board of the Ehime University Graduate School of Medicine (1505011). Consent was obtained mainly for outpatients at each hospital, as well as inpatients for ulcerative colitis. The study was explained and enrolled to all those diagnosed with ulcerative colitis. Well-trained staff obtained written informed consent from all patients enrolled. This study analyzed group was registered during the period from 2015 to 2019.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasurements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformation on endoscopic findings, use of drugs for UC, and platelet count and CRP were collected using medical records. Platelet count was determined from routine blood levels obtained from patient files at the time the patients were included in the study. Blood samples were taken the morning after overnight fasting. Blood examination was collected when a colonoscopy is reserved or when the colonoscopy examination is performed. There could be a time difference of about two months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of mucosal healing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe evaluated mucosal status by total colonoscopy. The Mayo endoscopic subscore (MES) contains the following four categories [15]: 0, normal or inactive disease; 1, mild disease with erythema, decreased vascular patterns, and mild friability; 2, moderate disease with marked erythema, absence of vascular patterns, friability, and erosions; 3, severe disease with spontaneous bleeding and ulceration. Partial MH and MH were defined as category 0 and 0-1 in this study, respectively. Several endoscope specialists were responsible for evaluating MES and MH, and all endoscopists were blinded to platelet count.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlatelet count was divided into quartiles on the basis of the distribution of all study subjects. Platelet count was classified into four categories: 1) low platelet, \u0026lt; 20.4(\u0026times;10⁴/\u0026mu;L) (reference); 2) moderate platelet, 20.4-25.0 (\u0026times;10⁴/\u0026mu;L); 3) high platelet, 25.0-29.6 (\u0026times;10⁴/\u0026mu;L), and 4) very high platelet, \u0026gt; 29.6 (\u0026times;10⁴/\u0026mu;L). Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Multiple logistic regression analyses were used to adjust for potential confounding factors. Age, sex, CRP, steroid use, and anti-TNF\u0026alpha; preparation were selected a\u003cem\u003e priori \u003c/em\u003eas potential confounding factors. A receiver operating characteristic (ROC) curve was generated, and the area under the curve was calculated to show the utility of the platelet count in indicating mucosal healing. We used Youden\u0026rsquo;s index to calculate the cutoff value of platelets. Statistical analyses mainly were performed using SAS software package version 9.4 (SAS Institute Inc., Cary, NC, USA). The ROC curve, cutoff value of the platelet count, sensitivity, and specificity were analyzed using JMP 14.2 software (SAS Institute Inc., Cary, NC, USA). All probability values for statistical tests were two-tailed, and P \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTable 1 shows the characteristics of the 345 study participants. The mean age was 50.2 years, and the percentage of male patients was 59.7%. Use of 5-aminoasalicylates, prednisolone, azathioprine, and \u003cem\u003eTNF-\u0026alpha; monoclonal antibody preparations\u003c/em\u003e were reported to be 91.0%, 20.6%, 15.4% and 5.5%, respectively. The percentage of partial MH and MH were 63.2% and 27.4%, and the mean CRP and platelet count were 0.39 \u0026plusmn; 1.13 (mg/dl) and 25.77 \u0026plusmn;7.80 (\u0026times;10⁴/\u0026mu;L). The ROC curve of the platelet count for identifying mucosal healing had an area under the curve of 0.615 (Figure1).\u003c/p\u003e\n\u003cp\u003eTable 2 shows crude and adjusted ORs and 95% CIs for partial MH and MH in relation to platelet count. The percentages of partial MH and MH among low, moderate, high, and very high platelet patients were 78.2%, 60.5%, 62.9%, 51.2%, 43.7%, 20.9%, 19.8% and 19.8%, respectively.\u003c/p\u003e\n\u003cp\u003eAfter adjustment for age, sex, CRP, use of steroid, and use of \u003cem\u003eTNF-\u0026alpha; monoclonal antibody preparations\u003c/em\u003e, moderate, and very high platelet counts but not high platelet were independently inversely associated with partial MH (moderate: OR 0.40 [95% CI: 0.19-0.80], and very high: OR 0.37 [95% CI: 0.17-0.77], p for trend p=0.034). Similarly, platelet count was independentlyinversely associated with MH (moderate: OR 0.37 [95% CI: 0.18-0.73], high: OR 0.41 [95% CI: 0.19-0.83], and very high: 0.45 [95% CI: 0.21-0.94], p for trend = 0.033). In sensitive analysis, azathioprine was not associated with platelet count.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, platelet count was independently inversely associated with partial MH and MH among 345 Japanese patients with UC.\u003c/p\u003e\n\u003cp\u003ePlatelet count is known as an inflammation marker. Several studies had showed the association between platelet count and outcome among patients with UC. Platelet count among active stage patients was higher than among those with inactive stage UC and healthy subjects in a Greek study of subjects including those with UC and Crohn\u0026rsquo;s disease [8] and in a Turkish study of subjects with active UC and inactive UC [9]. In a Japanese study of 68 patients with UC, platelet count was positively associated with endoscopic activity [11]. In a Swish study of 280 subjects including those with UC, a positive association between platelet count and endoscopic activity based on a modified Baron score among patients with UC was found [12]. In a retrospective cohort study of 183 Japanese UC patients with clinical remission, platelet count among patients with complete mucosal healing (Mayo endoscopic subscore 0) was lower than that among those with partial mucosal healing (Mayo endoscopic subscore1). Furthermore, the change of platelet count from baseline was significantly associated with a shift from complete to partial MH [10]. In a prospective observational study of Japanese UC patients with MH, a platelet count at baseline in the relapse group was significantly higher than that among those in the non-relapse group. Additionally, a platelet count at baseline was significantly associated with relapse among patients with UC after adjustment for several confounding factors [13]. In a Spanish study of 123 patients with UC, a positive relationship between fecal calprotectin level, which is a reliable marker for MH, and platelet count was found [16]. The finding in this study was consistent with these studies that showed the association between platelet count and favorable prognosis. On the other hand, however, a similar association between platelet count and endoscopic activity was reported among patients with Crohn\u0026rsquo;s disease but not among those with UC [14]. The discrepancies regarding platelet count and MH among patients with UC might be explained, at least in part, by differences in year, duration of UC, sample size, and confounding factors considered.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; The underlying mechanism linking platelet count and MH among patients with UC remains unclear, but there are some biologically plausible options. Clusters of differentiation 154 (CD154) plays a central role in co-stimulation and regulation of the immune response via\u0026nbsp;\u003ca href=\"https://en.wikipedia.org/wiki/T_cell\"\u003eT cell\u003c/a\u003e\u0026nbsp;priming and activation of CD40-expressing immune cells [17]. CD 154 expression was found on platelets [18], and mucosal inflammation might elevate platelet count via CD 154 expression.\u003c/p\u003e\n\u003cp\u003eThe platelet-to-lymphocyte ratio (PLR) has emerged as a useful marker revealing shifts in platelet and lymphocyte counts due to acute inflammatory. PLR can be calculated easily from a routine blood test without additional cost. PLR has been reported to be a useful biomarker in the prognosis of various cancers [19]. Several pieces of evidence regarding the association between PLR and UC exist. In a Turkish study of 104 patients with UC and a Korean case control study of 144 subjects including 48 patients with UC and 96 healthy controls, PLR among patients with UC was higher than that in controls, regardless of mucosal remission. PLR among patients with endoscopic active UC was higher than that in patients with endoscopic remission UC [20]. Similarly, in a Korean study, PLR among patients with severe UC was higher than that in patients with mild to moderate UC [21]. In an Italian study of 88 UC patients who started anti-TNF monotherapy, PLR was a useful prognostic biomarker of mucosal healing [22]. Platelet count and PLR might be cost-effective and easy-to-validate parameters for optimal treatment modality. Our findings are consistent with those of previous reports regarding the association between platelets (including PLR) and UC.\u003c/p\u003e\n\u003cp\u003eTo date, MH has been indicated as the therapeutic goal for IBD [3, 23, 24]. Endoscopy is necessary to evaluate MH, but repeated endoscopy is extremely burdensome for patients. Monitoring platelet count might be useful both for patients with UC and their physicians. However, further research is needed to confirm the association between platelet and MH in future.\u003c/p\u003e\n\u003cp\u003eOur study has a few limitations. First, this was a cross-sectional study; therefore, we cannot conclude that there is a causal relationship between platelet count and MH. Second, most of the patients in this cohort may have been receiving treatment for a considerable period of time since their physicians may have opted to attempt to control inflammation. The long duration of such treatment might have masked the association between platelet count and MH. Third, data regarding fecal calprotectin was not available in this cohort. Fourth, the time difference between the blood test and the test may have caused a misclassification. However, non-differential misclassification causes a bias of the odds ratio towards the null. Finally, the patients in the current study were not likely representative of Japanese patients with UC. Nevertheless, the median age, male/female ratio, and use of 5-aminoasalicylates, prednisolone, thiopurines, and biologics were similar in the present study (48.0, 59.7%, 91.0%, 20.6%, 15.4%, and 5.5%, respectively) and in a Japanese national study based on UC claims data in 2016 (44.0, 63.9%, 96.2%, 15.5%, 13.8%, and 9.0%, respectively).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAmong Japanese patients with UC, platelet count may be independently inversely associated with partial MH and MH. This study confirmed the positive association between platelet count and MH shown in previous retrospective studies and reinforced a positive dose-response association. Monitoring the platelet count may be useful in the assessment of early response to medication and when endoscopy cannot be repeated, such as in elderly and infant patients with UC.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003eMH: mucosal healing; UC: ulcerative colitis: TNF: tumor necrosis factor; IBD: inflammatory bowel disease; MES: Mayo endoscopic subscore; CD: Clusters of differentiation; PLR: platelet-to-lymphocyte ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the institutional review board of the Ehime University Graduate School of Medicine (1505011). Well-trained staff obtained written informed consent from all patients enrolled.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: SF, ET, YI, YH, TS; Acquisition of data: KS, SY, KM, NT, KK, YM, SS, MU, NS, SN, SI, HM, KO, MT, AH, HY, MM; Analysis and Interpretation of data: SF, SY, RY, YI, YH; Drafting of the manuscript: SF; Statistical analysis: SF; Supervision: YH. The author (s) read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge Yu Hashimoto, Masakazu Hanayama, Kazuhiro Tange, Kanako Konishi, Tomoe Kawamura, Yasunori Yamamoto, and the ECNAD study group for their support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Langholz%20E%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=8020674\"\u003eLangholz E\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Munkholm%20P%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=8020674\"\u003eMunkholm P\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Davidsen%20M%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=8020674\"\u003eDavidsen M\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Binder%20V%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=8020674\"\u003eet\u003c/a\u003e al. 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Correlation between concentrations of fecal calprotectin and outcomes of patients with ulcerative colitis in a phase 2 trial. 2016; 150: 96-102.\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Shah%20SC%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26829025\"\u003eShah SC\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Colombel%20JF%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26829025\"\u003eColombel JF\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Sands%20BE%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26829025\"\u003eSands BE\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Narula%20N%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26829025\"\u003eet\u003c/a\u003e al. Mucosal healing is associated with improved long-term outcomes of patients with ulcerative colitis: a systematic review and meta-analysis. \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Clin+Gastroenterol+Hepatol.+2016%3B14(9)%3A+1245.\"\u003eClin Gastroenterol Hepatol.\u003c/a\u003e 2016; 14: 1245-55.\u003c/li\u003e\n\u003cli\u003eKapsoritakis AN, Koukourakis MI, Sfiridaki A, et al. Mean platelet volume: a useful marker of inflammatory bowel disease activity. Am J Gastroenterol. 2001; 96: 776-81.\u003c/li\u003e\n\u003cli\u003eKayahan H, Akarsu M, Ozcan MA, et al. Reticulated platelet levels in patients with ulcerative colitis. Int J colorectal Dis 2007; 22: 1429-35.\u003c/li\u003e\n\u003cli\u003eNakarai A, Kato J, Hiraoka S, et al. Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing, which can be predicted from the platelet count. World J Gastroenterol. 2014; 20: 18367-74.\u003c/li\u003e\n\u003cli\u003eUchihara M, Kato J, Tsuda S, et al. Blood biomarker integration of severity and extent of endoscopic inflammation in ulcerative colitis. JGH Open.\u0026nbsp;2017; 1: 98-104.\u003c/li\u003e\n\u003cli\u003eSchoepfer Am, Beglinger C, Straumann A, et al. Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes. Inflamm Bowel Dis. 2013; 19: 332-41.\u003c/li\u003e\n\u003cli\u003eNakarai A, Kato J, Hiraoka S, et al. An elevated platelet count increases the risk of relapse in ulcerative colitis patients with mucosal healing. Gut Liver. 2018; 12: 420-5.\u003c/li\u003e\n\u003cli\u003eMiranda-Garc\u0026iacute;a P, Chaparro M, Gisbert JP. Correlation between serological biomarker and endoscopic activity in patients with inflammation bowel disease. Gastroenterol Hepatol. 2016; 39: 508-15.\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Schroeder%20KW%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=3317057\"\u003eSchroeder KW\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Tremaine%20WJ%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=3317057\"\u003eTremaine WJ\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Ilstrup%20DM%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=3317057\"\u003eIlstrup DM\u003c/a\u003e. Fecal calprotectin predicts complete mucosal healing and better correlates with the ulcerative colitis\u0026nbsp;endoscopic index of severity than with the Mayo endoscopic subscore in patients with ulcerative colitis. \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=N+Engl+J+Med+1987+317+1625-9\"\u003eN Engl J Med.\u003c/a\u003e 1987; 317: 1625-9.\u003c/li\u003e\n\u003cli\u003eLobat\u0026oacute;n T, Rodr\u0026iacute;guez-Moranta F, Lopez A, et al. A new rapid quantitative test for focal calprotectin predicts endoscopic activity in ulcerative colitis. Inflamm Bowel Dis. 2013; 19: 1034-42.\u003c/li\u003e\n\u003cli\u003eGrewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998; 16: 111-35.\u003c/li\u003e\n\u003cli\u003eSch\u0026ouml;nbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001; 58: 4-43.\u003c/li\u003e\n\u003cli\u003eZhou X, Du Y, Huang Z, et al. Prognostic value of PLR in various cancers: a meta-analysis. PLoS One. 2014; 9: e101119 (Page 13 Lines 6-7 in the revised manuscript).\u003c/li\u003e\n\u003cli\u003eAkpinar MY, Ozin YO, Kaplan M, et al. Platelet-to-lymphocyte Ratio and Neutrophil-to-lymphocyte Ratio Predict Mucosal Disease Severity in Ulcerative Colitis. J Med Biochem. 2018; 37: 155-62\u003c/li\u003e\n\u003cli\u003eJeong Y, Jeon SR, Kim HG, et al. The role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in ulcerative colitis. Intest Res. 2020 (In Press)\u003c/li\u003e\n\u003cli\u003eBertani L, Rossari F, Barberio B, et al. Novel prognostic biomarkers of mucosal healing in ulcerative colitis patients treated with anti-TNF: neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio. Inflamm Bowel Dis 2020; 20: 1579-87\u003c/li\u003e\n\u003cli\u003ePineton de Chambrun G, Peyrin-Biroulet L, et al. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol. 2010; 7: 15-29\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Baert%20F%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=19818785\"\u003eBaert F\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Moortgat%20L%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=19818785\"\u003eMoortgat L\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Van%20Assche%20G%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=19818785\"\u003eVan Assche G\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Caenepeel%20P%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=19818785\"\u003eCaenepeel P\u003c/a\u003e, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. 2010;138:463-8.\u003c/li\u003e\n\u003cli\u003eMatsuoka T, Igarashi A, Sato N, et al. Trends in corticosteroid prescriptions for ulcerative colitis and factors associated with long-term corticosteroid use: analysis using Japanese claims data from 2006 to 2016. J Crohns Colitis. 2020 (In press).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style='margin:0in;text-align:justify;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eTable 1. Clinical characteristics of the 345 study participants\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.5e+2pt;border: none;margin-left:4.2pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"MS PGothic\",sans-serif;'\u003e \u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eVariable\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"MS PGothic\",sans-serif;'\u003e \u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003en (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eAge, years, mean \u0026plusmn; SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e50.2 \u0026plusmn; 16.6\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMale (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e206 (59.7)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eDisease extent (pancolitis/left-sided/procitis/others)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e148/96/93/8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMedication\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;text-indent:6.0pt;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e5-aminoasalicylates\u003c/span\u003e\u003cspan style='font-family: \"Times New Roman\",serif;'\u003e\u0026nbsp;(%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;text-indent:24.0pt;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e314 (91.0)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;text-indent:6.0pt;'\u003e\u003cspan style='font-family: \"Times New Roman\",serif;'\u003ePrednisolone (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e71 (20.6)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;text-indent:6.0pt;'\u003e\u003cspan style='font-family: \"Times New Roman\",serif;'\u003eAzathioprine\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e53 (15.4)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;text-indent:6.0pt;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eTNF-\u0026alpha;\u0026nbsp;monoclonal antibody\u0026nbsp;(%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e19 (5.5)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 305.45pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.9pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114.7pt;padding: 0in 4.95pt;height: 17.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMayo endoscopic subscore, mean \u0026plusmn; SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;text-indent:24.0pt;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e1.17 \u0026plusmn; 0.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003ePartial mucosal healing (Mayo endoscopic subscore \u0026le; 1) (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e218 (63.2)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMucosal healing (Mayo endoscopic subscore \u0026lt; 1) (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e90 (26.1)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;padding:0in 4.95pt 0in 4.95pt;height: 17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eCRP (mg/dl)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e0.39 \u0026plusmn; 1.13\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:305.45pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003ePlatelet (\u003cspan style=\"color:black;background:white;\"\u003e\u0026times;10⁴/\u0026mu;L\u003c/span\u003e), mean \u0026plusmn; SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.9pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:114.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 4.95pt 0in 4.95pt;height:17.9pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e25.91 \u0026plusmn; 7.81\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:left;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eSD, standard deviation; TNF, tumor necrosis factor\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:16px;font-family:\"Century\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCrude and adjusted odds ratios and 95% confidence intervals for mucosal healing in relation to platelet count\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable (\u0026times;\u0026thinsp;10⁴/\u0026micro;L)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePrevalence (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCrude OR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePartial MH (MES\u0026thinsp;\u0026le;\u0026thinsp;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eplatelet\u0026thinsp;\u0026le;\u0026thinsp;20.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68/87 (78.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.4\u0026thinsp;\u0026lt;\u0026thinsp;platelet\u0026thinsp;\u0026le;\u0026thinsp;25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e52/86 (60.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.43 (0.22\u0026ndash;0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.40 (0.19\u0026ndash;0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.0\u0026thinsp;\u0026lt;\u0026thinsp;platelet\u0026thinsp;\u0026le;\u0026thinsp;29.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54/86 (62.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.47 (0.24\u0026ndash;0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.54 (0.26\u0026ndash;1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.6\u0026thinsp;\u0026lt;\u0026thinsp;platelet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44/86 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.29 (0.15\u0026ndash;0.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.37 (0.17\u0026ndash;0.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMH (MES\u0026thinsp;\u0026lt;\u0026thinsp;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eplatelet\u0026thinsp;\u0026le;\u0026thinsp;20.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38/87 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.4\u0026thinsp;\u0026lt;\u0026thinsp;platelet\u0026thinsp;\u0026le;\u0026thinsp;25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18/86 (20.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.34 (0.17\u0026ndash;0.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.37 (0.18\u0026ndash;0.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.0\u0026thinsp;\u0026lt;\u0026thinsp;platelet\u0026thinsp;\u0026le;\u0026thinsp;29.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17/86 (19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32 (0.16\u0026ndash;0.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.41 (0.19\u0026ndash;0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.6\u0026thinsp;\u0026lt;\u0026thinsp;platelet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17/86 (19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32 (0.16\u0026ndash;0.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.45 (0.21\u0026ndash;0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eOdds ratios were adjusted for age, sex, CRP, use of prednisolone, and use of TNF-\u0026alpha; monoclonal antibody. OR, odds ratio; CI, confidence interval\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"platelet, mucosal healing, ulcerative colitis","lastPublishedDoi":"10.21203/rs.3.rs-60855/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-60855/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eMucosal healing (MH) has been indicated as the therapeutic goal for ulcerative colitis (UC). Platelet count is known as an inflammation evaluation. However, the association between platelet count and MH among patients with UC is still scarce. We therefore assessed this issue among Japanese patients with UC. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe study subjects consisted of 345 Japanese patients with UC. Platelet count was divided into quartiles on the basis of the distribution of all study subjects (low, moderate, high, and very high). Several endoscope specialists were responsible for evaluating MH and partial MH, which was defined as a Mayo endoscopic subscore of 0 and 0-1, respectively. Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Age, sex, CRP, steroid use, and anti-Tumor necrosis factor α (TNFα) preparation were selected a priori as potential confounding factors. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe percentage of partial MH and MH were 63.2 and 26.1%, respectively. Moderate and very high was independently inversely associated with partial MH (moderate: OR 0.40 [95%CI: 0.19-0.810], very high: OR 0.37 [95%CI: 0.17-0.77], p for trend= 0.034). Similarly, moderate, high, and very high were independently inversely associated with MH (moderate: OR 0.37 [95% CI: 0.18-0.73], high: OR 0.41 [95% CI: 0.19-0.83], and very high: OR 0.45 [95% CI: 0.21-0.94], p for trend = 0.033) after adjustment for confounding factors. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eAmong patients with UC, platelet count was independently inversely associated with MH.\u003c/p\u003e","manuscriptTitle":"Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: A cross-sectional study","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2020-11-06 22:01:32","doi":"10.21203/rs.3.rs-60855/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-11-09T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-01T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-31T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-31T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2020-10-29 20:20:55","doi":"10.21203/rs.3.rs-60855/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2020-10-28T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-28T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\nWe thank the authors for their response. However, I am not convinced that they have sufficiently addressed my concern, and I have further queries about the methodology of the study.\n\nThe authors point out that the main problem with previous reports was that they were 'retrospective', insinuating that this study is different. From what I understand, the previous reports were all also cross-sectional studies with similar design. The \"positive dose-response relationship\" of platelet count and mucosal healing has also already been described in a previous report by Uchihara et al.\n\n1) There is no description regarding chronology of data collection in this paper for it to count as a cross-sectional study. When were the blood tests taken in relation to the timing of colonoscopy?\n2) Please describe how the patients were enrolled in the study (time span of enrollment, whether patients were selected according to a particular criterion or not).\n3) Please describe the extents of colitis in the patients.\n4) In order to make a statement about positive association between platelet count and mucosal healing, please consider plotting ROC curves and calculating the AUC.\n5) Please mention the details of usage of immunomodulators such as azathioprine which is known to affect platelet count.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"decision","content":"Minor revision","date":"2020-10-28T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-26T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-26T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\n.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewersInvited","content":"","date":"2020-10-23T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-10-21T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-20T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-20T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-08-27 16:08:07","doi":"10.21203/rs.3.rs-60855/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2020-10-05T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-25T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"reviewersInvited","content":"","date":"2020-09-03T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-03T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-08-18T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-08-17T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-17T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-08-16T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"786b27a6-5fc0-4453-919f-ef71b0c4ef6e","owner":[],"postedDate":"November 6th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":927106,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2020-11-22T15:01:57+00:00","versionOfRecord":{"articleIdentity":"rs-60855","link":"https://doi.org/10.1186/s12876-020-01538-y","journal":{"identity":"bmc-gastroenterology","isVorOnly":false,"title":"BMC Gastroenterology"},"publishedOn":"2020-11-16 15:00:44","publishedOnDateReadable":"November 16th, 2020"},"versionCreatedAt":"2020-11-06 22:01:32","video":"","vorDoi":"10.1186/s12876-020-01538-y","vorDoiUrl":"https://doi.org/10.1186/s12876-020-01538-y","workflowStages":[]},"version":"v3","identity":"rs-60855","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-60855","identity":"rs-60855","version":["v3"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}