Publications by authors named "Florian Rieder"

135 Publications

Health Maintenance Consensus for Adults With Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 Jul 19. Epub 2021 Jul 19.

Boston University School of Medicine, Boston, Massachusetts, USA.

Background: With the management of inflammatory bowel disease (IBD) becoming increasingly complex, incorporating preventive care health maintenance measures can be challenging. The aim of developing these updated recommendations is to provide more specific details to facilitate their use into a busy clinical practice setting.

Method: Fifteen statements were formulated with recommendations regarding the target, timing, and frequency of the health maintenance interventions in patients with IBD. We used a modified Delphi method and a literature review to establish a consensus among the panel of experts. The appropriateness of each health maintenance statement was rated on a scale of 1 to 5 (1-2 as inappropriate, and 4-5 as appropriate) by each panelist. Interventions were considered appropriate, and statements were accepted if ≥80% of the panelists agreed with a score ≥4.

Results: The panel approved 15 health maintenance recommendations for adults with IBD based on the current literature and expert opinion. These recommendations include explicit details regarding specific screening tools, timing of screening, and vaccinations for adults with IBD.

Conclusions: Patients with IBD are at an increased risk for infections, malignancies, and other comorbidities. Given the complexity of caring for patients with IBD, this focused list of recommendations can be easily incorporated in to clinical care to help eliminate the gap in preventative care for patients with IBD.
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http://dx.doi.org/10.1093/ibd/izab155DOI Listing
July 2021

Disease Activity Indices for Pouchitis: A Systematic Review.

Inflamm Bowel Dis 2021 Jun 28. Epub 2021 Jun 28.

Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.

Background: Several indices exist to measure pouchitis disease activity; however, none are fully validated. As an initial step toward creating a validated instrument, we identified pouchitis disease activity indices, examined their operating properties, and assessed their value as outcome measures in clinical trials.

Methods: Electronic databases were searched to identify randomized controlled trials including indices that evaluated clinical, endoscopic, or histologic pouchitis disease activity. A second search identified studies that assessed the operating properties of pouchitis indices.

Results: Eighteen randomized controlled trials utilizing 4 composite pouchitis disease activity indices were identified. The Pouchitis Disease Activity Index (PDAI) was most commonly used (12 of 18; 66.7%) to define both trial eligibility (8 of 12; 66.7%), and outcome measures (12 of 12; 100%). In a separate search, 21 studies evaluated the operating properties of 3 pouchitis indices; 90.5% (19 of 21) evaluated validity, of which 42.1% (8 of 19) evaluated the construct validity of the PDAI. Criterion validity (73.7%; 14 of 19) was evaluated through correlation of the PDAI with fecal calprotectin (FCP; r = 0.188 to 0.71), fecal lactoferrin (r = 0.570 to 0.582), and C-reactive protein (CRP; r = 0.584). Two studies assessed correlation of the modified PDAI (mPDAI) with FCP (r = 0.476 and r = 0.565, respectively). Fair to moderate inter-rater reliability of the PDAI (k = 0.440) and mPDAI (k = 0.389) was reported in a single study. Responsiveness of the PDAI pre-antibiotic and postantibiotic treatment was partially evaluated in a single study of 12 patients.

Conclusions: Development and validation of a specific pouchitis disease activity index is needed given that existing instruments are not valid, reliable, or responsive.
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http://dx.doi.org/10.1093/ibd/izab124DOI Listing
June 2021

A single-cell atlas of fibroblasts: one size does not fit all.

Nat Rev Gastroenterol Hepatol 2021 Jun 24. Epub 2021 Jun 24.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

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http://dx.doi.org/10.1038/s41575-021-00482-wDOI Listing
June 2021

Real-World Effectiveness and Safety of Ustekinumab in Elderly Crohn's Disease Patients.

Dig Dis Sci 2021 Jun 23. Epub 2021 Jun 23.

Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.

Introduction: The efficacy and safety profile of ustekinumab (UST) in Crohn's disease (CD) is favorable; however, data in elderly patients are lacking. We aimed to assess the safety and efficacy of UST in elderly CD.

Methods: We performed a retrospective cohort study of CD patients classified as elderly (age ≥ 65 years at UST initiation) or nonelderly (<65 years) treated at a large, tertiary referral center. Outcomes assessed were clinical (measured by physician global assessment [PGA]) and steroid-free response, remission, adverse events, and postsurgical complications were compared by age category. Multivariable regression modeling and survival analysis was also performed.

Results: In total, 117 patients (elderly n = 39, nonelderly n = 78) were included in the study. Elderly patients had predominantly moderate disease (87.2%), while nonelderly had a higher proportion of severe disease activity (44.9%) (p = 0.001), though no differences in baseline endoscopic activity, prior biologic use, or steroid or immunomodulator use at baseline existed (p > 0.05 all). While nearly 90% patients in both groups experienced clinical response to UST, compared to nonelderly, elderly patients were less likely to achieve complete clinical remission (28.2% vs. 52.6%, p = 0.01). On regression modeling, age was not associated with clinical outcomes (p > 0.05 all). Mucosal healing was achieved in 26% elderly and 30% nonelderly patients (p = 0.74). There were no significant differences in infusion reactions (2.6% vs. 6.4%, p = 0.77), infection (5.2% vs. 7.7%, p = 0.7), or postsurgical complications (p = 0.99) by age category.

Conclusion: UST is safe and effective in elderly CD. Although limited by sample size and retrospective design, such real-world data can inform biologic positioning in this IBD population.
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http://dx.doi.org/10.1007/s10620-021-07117-9DOI Listing
June 2021

Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Background And Aims: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures.

Methods: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal).

Results: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties.

Conclusions: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
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http://dx.doi.org/10.1016/j.cgh.2021.05.054DOI Listing
June 2021

Mouse Models of Intestinal Fibrosis.

Methods Mol Biol 2021 ;2299:385-403

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Mouse models are essential for investigation of underlying disease mechanisms that drive intestinal fibrosis, as well as assessment of potential therapeutic approaches to either prevent or resolve fibrosis. Here we describe several common mouse models of intestinal inflammation and fibrosis, including chemically driven colitis models, a bacterially triggered colitis model, and spontaneous intestinal inflammation in genetically susceptible mouse strains. Detailed protocols are provided for dextran sodium sulfate (DSS) colitis, 2,4,6-trinitro-benzene sulfonic acid (TNBS) colitis, adherent-invasive Escherichia coli (AIEC)-triggered colitis, the interleukin-10 knockout (IL-10KO) mouse model of spontaneous colitis, and the SAMP/YitFc model of spontaneous ileocolitis.
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http://dx.doi.org/10.1007/978-1-0716-1382-5_26DOI Listing
January 2021

Novel mechanisms and clinical trial endpoints in intestinal fibrosis.

Immunol Rev 2021 Jul 16;302(1):211-227. Epub 2021 May 16.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

The incidence of inflammatory bowel diseases (IBD) worldwide has resulted in a global public health challenge. Intestinal fibrosis leading to stricture formation and bowel obstruction is a frequent complication in Crohn's disease (CD), and the lack of anti-fibrotic therapies makes elucidation of fibrosis mechanisms a priority. Progress has shown that mesenchymal cells, cytokines, microbial products, and mesenteric adipocytes are jointly implicated in the pathogenesis of intestinal fibrosis. This recent information puts prevention or reversal of intestinal strictures within reach through innovative therapies validated by reliable clinical trial endpoints. Here, we review the role of immune and non-immune components of the pathogenesis of intestinal fibrosis, including new cell clusters, cytokine networks, host-microbiome interactions, creeping fat, and their translation for endpoint development in anti-fibrotic clinical trials.
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http://dx.doi.org/10.1111/imr.12974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292184PMC
July 2021

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

Gut 2021 May 5. Epub 2021 May 5.

Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Objective: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion.

Design: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures.

Results: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials.

Conclusion: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.
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http://dx.doi.org/10.1136/gutjnl-2021-324374DOI Listing
May 2021

Systematic review: Sweet syndrome associated with inflammatory bowel disease.

J Crohns Colitis 2021 Apr 23. Epub 2021 Apr 23.

Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio.

Background And Aims: Sweet syndrome (SS) is a dermatologic condition associated with both IBD and azathioprine use. We performed a systematic review to better delineate clinical characteristics and outcomes of SS in IBD patients.

Methods: Peer-reviewed, full-text journal publications from inception to April 2020 in English language and adult subjects with IBD were included. Skin biopsy was required as SS gold-standard diagnosis. Azathioprine-associated SS required recent azathioprine introduction or recurrence of SS after azathioprine re-challenge.

Results: We included 89 publications with 95 patients (mean age of SS diagnosis: 44 years; 59% female; 20 with azathioprine-associated SS and 75 without). SS was diagnosed prior to IBD in 5.3%, at time of IBD diagnosis in 29.5% and after diagnosis in 64.2%. 91% of patients with SS had known colonic involvement and the majority (76%) had active IBD at diagnosis; 22% had additional extra-intestinal manifestations. Successful therapies for SS included corticosteroids (90.5%), anti-TNF-α inhibitor therapy (14.8%) and azathioprine (11.6%). Azathioprine-associated SS was distinct, with 85% male patients, mean age of SS diagnosis of 50 years and a lower likelihood to be prescribed corticosteroids for treatment (75% vs. 94.7% of non-azathioprine-associated SS, p=0.008). All patients with azathioprine-associated SS improved with medication cessation and developed recurrence after re-challenge.

Conclusions: SS may precede or occur with IBD diagnosis in almost one third of cases. Azathioprine and IBD-associated SS present and behave distinctly, especially with regard to gender, age at diagnosis and recurrence risk. Corticosteroids and TNF-α inhibitors have demonstrated efficacy in treating SS in IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjab079DOI Listing
April 2021

Optimal inflammatory bowel disease management during the global coronavirus disease 2019 pandemic.

Curr Opin Gastroenterol 2021 07;37(4):313-319

Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Purpose Of Review: This review aims to summarize the current evidence regarding the risks and implications of coronavirus disease 2019 (COVID-19) in patients with inflammatory bowel disease (IBD) and discuss optimal management of IBD during this pandemic.

Recent Findings: Patients with IBD are not at increased risk of COVID-19 but several risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection) have been identified, such as active IBD, obesity, and corticosteroid use. COVID-19 outcomes are similar among patients with IBD and the overall population. Although biologics have not been shown to increase the risk of severe COVID-19 complications, several risk factors have been associated with negative COVID-19 outcomes in patients with IBD, including older age, obesity, the presence of comorbidities, active disease, and corticosteroid use. IBD therapy should, therefore, be continued with the aim of attaining or maintaining remission, except for corticosteroids, which should be held or reduced to the minimal effective dose. Although it has been recommended that immunosuppressive therapy be held during a case of COVID-19, the half-lives of these drugs and data on the timing of restarting therapy limit the strength of these recommendations. We recommend COVID-19 vaccination for IBD patients whenever available, as benefits to the individual and to society outweigh the risks.

Summary: As our understanding of SARS-CoV-2 and COVID-19 continues to evolve, we are learning more about its impact in patients with IBD and how to better manage patients in this setting. Managing IBD during this pandemic has also highlighted the importance of restructuring services in order to adapt to current and potential future outbreaks. The COVID-19 pandemic has transformed IBD care through the expansion of telemedicine and development of novel approaches to remote monitoring.
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http://dx.doi.org/10.1097/MOG.0000000000000741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285035PMC
July 2021

Ileal Crohn's Disease Exhibits Similar Transmural Fibrosis Irrespective of Phenotype.

Clin Transl Gastroenterol 2021 Apr 13;12(4):e00330. Epub 2021 Apr 13.

Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Portugal.

Introduction: In Crohn's disease (CD), the assessment of transmural inflammation and fibrosis is of utmost importance. This study aimed to quantify these parameters in CD ileal specimens and correlate them with disease progression.

Methods: This is a retrospective unicentric study based on the analysis of archived specimens (n = 103) of primary ileal resection. Data were retrieved from a prospective national inflammatory bowel disease registry. Two pathologists, blinded for CD phenotype and clinical indications for surgery, examined 3 sections per patient and graded inflammation and fibrosis, based on a histopathological score.

Results: Penetrating (B3, n = 74) CD exhibited significantly higher inflammation in diseased areas, compared with stricturing (B2, n = 29) disease (score 3: 96% vs 76%, P = 0.005 in inflamed areas; 78% vs 55%, P = 0.019 in most affected areas). This was also observed for the comparison of B2 CD with B3 CD with (B3s, n = 54) and without associated stricture (B3o, n = 20): B3s vs B2: 81% vs 55%, P = 0.033 in most affected areas; B3o vs B2: 100% vs 76%, P = 0.006 in inflamed areas; 70% vs 55%, P = 0.039 in most affected areas. We could not show differences in fibrosis scores between the subphenotypes. Postoperative new penetrating events occurred only in B3s (n = 6, 11%, P = 0.043) patients. The changing of biologic therapy after surgery correlated with severe inflammation at the proximal ileal margin (55% changed vs 25% not changed, P = 0.035).

Discussion: In our cohort, fibrosis scores and fibromuscular changes were comparable, irrespective of CD phenotype. Inflammation severity was the major differentiator between penetrating and stricturing disease.JOURNAL/cltg/04.03/01720094-202104000-00012/inline-graphic1/v/2021-04-13T161901Z/r/image-tiff.
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http://dx.doi.org/10.14309/ctg.0000000000000330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049162PMC
April 2021

Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homolog in Crohn's Disease Fibrosis.

J Crohns Colitis 2021 Apr 2. Epub 2021 Apr 2.

Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium.

Background And Aims: Intestinal fibrosis is a common complication of Crohn's disease (CD). It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined.

Methods: We performed a pilot proteomic study comparing the proteome of surface epithelium, isolated by laser-capture microdissection, in normal and fibrotic zones of resected ileal CD strictures (13 zones collected in 5 patients). Proteins of interests were validated by immunohistochemistry (IHC) in ileal and colonic samples of stricturing CD (n=44), pure inflammatory CD (n=29) and control (n=40) subjects. The pro-fibrotic role of one selected epithelial protein was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model.

Results: Proteomic study revealed an endoplasmic reticulum (ER) stress proteins increase in the epithelium of CD ileal fibrotic strictures, including Anterior gradient protein 2 homolog (AGR2) and Binding-immunoglobulin protein (BiP). This was confirmed by IHC. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2 intracellular expression and its secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin, led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. By using recombinant protein and blocking agent for AGR2, we demonstrated that the secretion of this protein by epithelial cells can play a role in the myofibroblastic differentiation.

Conclusions: The development of CD fibrotic strictures could involve epithelial ER stress and particularly the secretion of AGR2.
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http://dx.doi.org/10.1093/ecco-jcc/jjab061DOI Listing
April 2021

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

Gastroenterology 2021 Jun 19;160(7):2291-2302. Epub 2021 Feb 19.

Alimentiv Inc (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada; Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.

Background & Aims: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment.

Methods: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting.

Results: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations.

Conclusions: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.
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http://dx.doi.org/10.1053/j.gastro.2021.02.035DOI Listing
June 2021

Development and Validation of a Novel Computed-Tomography Enterography Radiomic Approach for Characterization of Intestinal Fibrosis in Crohn's Disease.

Gastroenterology 2021 Jun 17;160(7):2303-2316.e11. Epub 2021 Feb 17.

Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China. Electronic address:

Background & Aims: No reliable method for evaluating intestinal fibrosis in Crohn's disease (CD) exists; therefore, we developed a computed-tomography enterography (CTE)-based radiomic model (RM) for characterizing intestinal fibrosis in CD.

Methods: This retrospective multicenter study included 167 CD patients with 212 bowel lesions (training, 98 lesions; test, 114 lesions) who underwent preoperative CTE and bowel resection at 1 of the 3 tertiary referral centers from January 2014 through June 2020. Bowel fibrosis was histologically classified as none-mild or moderate-severe. In the training cohort, 1454 radiomic features were extracted from venous-phase CTE and a machine learning-based RM was developed based on the reproducible features using logistic regression. The RM was validated in an independent external test cohort recruited from 3 centers. The diagnostic performance of RM was compared with 2 radiologists' visual interpretation of CTE using receiver operating characteristic (ROC) curve analysis.

Results: In the training cohort, the area under the ROC curve (AUC) of RM for distinguishing moderate-severe from none-mild intestinal fibrosis was 0.888 (95% confidence interval [CI], 0.818-0.957). In the test cohort, the RM showed robust performance across 3 centers with an AUC of 0.816 (95% CI, 0.706-0.926), 0.724 (95% CI, 0.526-0.923), and 0.750 (95% CI, 0.560-0.940), respectively. Moreover, the RM was more accurate than visual interpretations by either radiologist (radiologist 1, AUC = 0.554; radiologist 2, AUC = 0.598; both, P < .001) in the test cohort. Decision curve analysis showed that the RM provided a better net benefit to predicting intestinal fibrosis than the radiologists.

Conclusions: A CTE-based RM allows for accurate characterization of intestinal fibrosis in CD.
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http://dx.doi.org/10.1053/j.gastro.2021.02.027DOI Listing
June 2021

Implications of COVID-19 for patients with pre-existing digestive diseases: an update.

Lancet Gastroenterol Hepatol 2021 04 2;6(4):258-260. Epub 2021 Feb 2.

Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(21)00025-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952087PMC
April 2021

Activated intestinal muscle cells promote preadipocyte migration: a novel mechanism for creeping fat formation in Crohn's disease.

Gut 2021 Jan 19. Epub 2021 Jan 19.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Objective: Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn's disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems.

Design: Tissues from normal, UC, non-strictured and strictured Crohn's disease intestinal specimens were obtained. The muscularis propria matrisome was determined via proteomics. Mesenteric fat explants, primary human preadipocytes and adipocytes were used in multiple ex vivo and in vitro cell migration systems on muscularis propria muscle cell derived or native extracellular matrix. Functional experiments included integrin characterisation via flow cytometry and their inhibition with specific blocking antibodies and chemicals.

Results: Crohn's disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by transforming growth factor-β1. The muscle cell-derived matrix triggered migration of preadipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the preadipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularised intestinal tissue extracellular matrix.

Conclusion: Crohn's disease creeping fat appears to result from the migration of preadipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.
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http://dx.doi.org/10.1136/gutjnl-2020-323719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286985PMC
January 2021

IL-36 in chronic inflammation and fibrosis - bridging the gap?

J Clin Invest 2021 Jan;131(2)

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, -β, and -γ, act primarily as proinflammatory cytokines, and their signaling through the IL-36 receptor (IL-36R) promotes immune cell infiltration and secretion of inflammatory and chemotactic molecules. However, IL-36 signaling also fosters secretion of profibrotic soluble mediators, suggesting a role in fibrotic disorders. IL-36 isoforms and IL-36 have been implicated in inflammatory diseases including psoriasis, arthritis, inflammatory bowel diseases, and allergic rhinitis. Moreover, IL-36 has been connected to fibrotic disorders affecting the kidney, lung, and intestines. This review summarizes the expression, cellular source, and function of IL-36 in inflammation and fibrosis in various organs, and proposes that IL-36 modulation may prove valuable in preventing or treating inflammatory and fibrotic diseases and may reveal a mechanistic link between inflammation and fibrosis.
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http://dx.doi.org/10.1172/JCI144336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810483PMC
January 2021

Patients With Low Drug Levels or Antibodies to a Prior Anti-Tumor Necrosis Factor Are More Likely to Develop Antibodies to a Subsequent Anti-Tumor Necrosis Factor.

Clin Gastroenterol Hepatol 2021 Jan 6. Epub 2021 Jan 6.

Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibodies (ADAb) is used widely to confirm therapeutic exposure, rule out immunogenicity, and optimize treatment of biologics in patients with inflammatory bowel diseases. A recent genome-wide association study found the variant HLA-DQA1∗05 to increase the risk of development of antibodies against infliximab (IFX) and adalimumab (ADM) 2-fold, regardless of concomitant immunomodulator use. However, there is currently limited evidence showing whether patients who develop antibodies to 1 anti-tumor necrosis factor (TNF) are prone to develop antibodies to the subsequent anti-TNF. Our aim was to investigate the risk of subsequent antibody development in cases (with ADAb to prior anti-TNF) versus control subjects (without ADAb to prior anti-TNF) using a large cohort of patients with inflammatory bowel diseases who underwent TDM with a drug-tolerant assay.
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http://dx.doi.org/10.1016/j.cgh.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257758PMC
January 2021

Degree of Creeping Fat Assessed by Computed Tomography Enterography is Associated with Intestinal Fibrotic Stricture in Patients with Crohn's Disease: A Potentially Novel Mesenteric Creeping Fat Index.

J Crohns Colitis 2021 Jul;15(7):1161-1173

Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.

Background And Aims: Emerging evidence points to a link between creeping fat and the pathogenesis of Crohn's disease [CD]. Non-invasive assessment of the severity of creeping fat on cross-sectional imaging modality has seldom been investigated. This study aimed to develop and characterize a novel mesenteric creeping fat index [MCFI] based on computed tomography [CT] in CD patients.

Methods: MCFI was developed based on vascular findings on CT in a retrospective cohort [n = 91] and validated in a prospective cohort [n = 30]. The severity of creeping fat was graded based on the extent to which mesenteric fat extended around the intestinal circumference using the vessels in the fat as a marker. The accuracy of MCFI was assessed by comparing it with the degree of creeping fat observed in surgical specimens. The relationship between MCFI and fibrostenosis was characterized by determining if these correlated. The accuracy of MCFI was compared with other radiographic indices [i.e. visceral to subcutaneous fat area ratio and fibrofatty proliferation score].

Results: In the retrospective cohort, MCFI had moderate accuracy in differentiating moderate-severe from mild fibrostenosis (area under the receiver operating characteristic [ROC] curve [AUC] = 0.799; p = 0.000). ROC analysis in the retrospective cohort identified a threshold MCFI of > 3 which accurately differentiated fibrostenosis severity in the prospective cohort [AUC = 0.756; p = 0.018]. An excellent correlation was shown between MCFI and the extent of fat wrapping in specimens in the prospective cohort [r = 0.840, p = 0.000]. Neither visceral to subcutaneous fat area ratio nor fibrofatty proliferation score correlated well with the degree of intestinal fibrosis.

Conclusions: MCFI can accurately characterize the extent of mesenteric fat wrapping in surgical specimens. It may become another non-invasive measure of CD fibrostenosis.
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http://dx.doi.org/10.1093/ecco-jcc/jjab005DOI Listing
July 2021

Hypoalbuminaemia, Not Biologic Exposure, Is Associated with Postoperative Complications in Crohn's Disease Patients Undergoing Ileocolic Resection.

J Crohns Colitis 2021 Jul;15(7):1142-1151

Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA.

Background: There are limited data on the postoperative outcomes in Crohn's disease patients exposed to preoperative ustekinumab or vedolizumab. We hypothesised that preoperative biologic use in Crohn's disease is not associated with postoperative complications after ileocolic resection.

Methods: Crohn's disease patients who underwent ileocolic resection over 2009-2019 were identified at a large regional health system. Preoperative biologic use within 12 weeks of surgery was categorised as no biologic, anti-tumour necrosis factor, vedolizumab, or ustekinumab. The primary endpoint was 90-day intra-abdominal septic complication. Risk factors included preoperative medical therapies, demographics, disease characteristics, laboratory values, and surgical approach. Regression models assessed the association of biologic use with intra-abdominal septic complication.

Results: A total of 815 Crohn's disease patients who underwent an ileocolic resection were included [62% no biologic, 31.4% anti-tumour necrosis factor, 3.9% vedolizumab, 2.6% ustekinumab]. Primary anastomosis was performed in 85.9% of patients [side-to-side 48.8%, end-to-side 26%, end-to-end 25%] in primarily a stapled [77.2%] manner. Minimally invasive approach was used in 41.4%. The 90-day postoperative intra-abdominal sepsis rate of 810 patients was 12%, abscess rate was 9.6%, and anastomotic leak rate was 3.2%. Multivariable regression modelling controlling for confounding variables demonstrated that preoperative biologic use with anti-tumour necrosis factor [p = 0.21], vedolizumab [p = 0.17], or ustekinumab [p = 0.52] was not significantly associated with intra-abdominal septic complication. Preoperative albumin < 3.5 g/dl was independently associated with intra-abdominal septic complication (odds ratio [OR] 1.76 [1.03, 3.01]).

Conclusions: In Crohn's disease patients undergoing ileocolic resection, preoperative biologics are not associated with 90-day postoperative intra-abdominal septic complication. Preoperative biologic exposure should not delay necessary surgery.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa268DOI Listing
July 2021

Potassium channels in intestinal epithelial cells and their pharmacological modulation: a systematic review.

Am J Physiol Cell Physiol 2021 04 16;320(4):C520-C546. Epub 2020 Dec 16.

Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.

Several potassium channels (KCs) have been described throughout the gastrointestinal tract. Notwithstanding, their contribution to both physiologic and pathophysiologic conditions, as inflammatory bowel disease (IBD), remains underexplored. Therefore, we aim to systematically review, for the first time, the evidence on the characteristics and modulation of KCs in intestinal epithelial cells (IECs). PubMed, Scopus, and Web of Science were searched to identify studies focusing on KCs and their modulation in IECs. The included studies were assessed using a reporting inclusiveness checklist. From the 745 identified records, 73 met the inclusion criteria; their reporting inclusiveness was moderate-high. Some studies described the physiological role of KCs, while others explored their importance in pathological settings. Globally, in IBD animal models, apical K1.1 channels, responsible for luminal secretion, were upregulated. In human colonocytes, basolateral K3.1 channels were downregulated. The pharmacological inhibition of K and K influenced intestinal barrier function, promoting inflammation. Evidence suggests a strong association between KCs expression and secretory mechanisms in human and animal IECs. Further research is warranted to explore the usefulness of KC pharmacological modulation as a therapeutic target.
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http://dx.doi.org/10.1152/ajpcell.00393.2020DOI Listing
April 2021

Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn's Disease: The Path From Bench to Bedside.

Inflamm Bowel Dis 2021 Jun;27(7):971-982

Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.

Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-β/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-β signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs.
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http://dx.doi.org/10.1093/ibd/izaa321DOI Listing
June 2021

Fibrosis: from mechanisms to medicines.

Nature 2020 11 25;587(7835):555-566. Epub 2020 Nov 25.

Inflammation & Immunology Research Unit, Pfizer Worldwide Research, Development & Medical, Cambridge, MA, USA.

Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis.
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http://dx.doi.org/10.1038/s41586-020-2938-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034822PMC
November 2020

Prevention and Treatment of Stricturing Crohn's Disease - Perspectives and Challenges.

Expert Rev Gastroenterol Hepatol 2021 Apr 28;15(4):401-411. Epub 2020 Dec 28.

Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

: Fibrostenosis is a hallmark of Crohn's disease (CD), remains a challenge in today's clinical management of inflammatory bowel disease patients and represents a key event in the disease course necessitating improved preventative strategies and a multidisciplinary approach to diagnosis and management. With the advent of anti-fibrotic therapies and well-defined clinical endpoints for stricturing CD, there is promise to impact the natural history of disease.: This review summarizes current evidence in the natural history of stricturing Crohn's disease, discusses management approaches as well as future perspectives on intestinal fibrosis.: Currently, there are no specific therapies to prevent progression to fibrosis or to treat it after it becomes clinically apparent. In addition to the international effort by the Stenosis Therapy and Anti-Fibrotic Research (STAR) consortium to standardize definitions and propose endpoints in the management of stricturing CD, further research to improve our understanding of mechanisms of intestinal fibrosis will help pave the way for the development of future anti-fibrotic therapies.
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http://dx.doi.org/10.1080/17474124.2021.1854732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026566PMC
April 2021

Novel Functions of the Septin Cytoskeleton: Shaping Up Tissue Inflammation and Fibrosis.

Am J Pathol 2021 01 8;191(1):40-51. Epub 2020 Oct 8.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

Chronic inflammatory diseases cause profound alterations in tissue homeostasis, including unchecked activation of immune and nonimmune cells leading to disease complications such as aberrant tissue repair and fibrosis. Current anti-inflammatory therapies are often insufficient in preventing or reversing these complications. Remodeling of the intracellular cytoskeleton is critical for cell activation in inflamed and fibrotic tissues; however, the cytoskeleton has not been adequately explored as a therapeutic target in inflammation. Septins are GTP-binding proteins that self-assemble into higher order cytoskeletal structures. The septin cytoskeleton exhibits a number of critical cellular functions, including regulation of cell shape and polarity, cytokinesis, cell migration, vesicle trafficking, and receptor signaling. Surprisingly, little is known about the role of the septin cytoskeleton in inflammation. This article reviews emerging evidence implicating different septins in the regulation of host-pathogen interactions, immune cell functions, and tissue fibrosis. Targeting of the septin cytoskeleton as a potential future therapeutic intervention in human inflammatory and fibrotic diseases is also discussed.
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http://dx.doi.org/10.1016/j.ajpath.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786077PMC
January 2021

Emerging treatment options for extraintestinal manifestations in IBD.

Gut 2021 Apr 26;70(4):796-802. Epub 2020 Aug 26.

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland

Extraintestinal manifestations (EIMs) are frequently observed in IBDs and contribute considerably to morbidity and mortality. They have long been considered a difficult to treat entity due to limited therapy options, but the increasing use of anti-tumour necrosis factors has dramatically changed the therapeutic approach to EIM in recent years. Newly emerging therapies such as JAK inhibitors and anti-interleukin 12/23 will further shape the available armamentarium. Clinicians dealing with EIMs in everyday IBD practice may be puzzled by the numerous available biological agents and small molecules, their efficacy for EIMs and their potential off-label indications. Current guidelines on EIMs in IBD do not include treatment algorithms to help practitioners in the treatment decision-making process. Herein, we summarise knowledge on emerging biological treatment options and small molecules for EIMs, highlight current research gaps, provide therapeutic algorithms for EIM management and shed light on future strategies in the context of IBD-related EIMs.
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http://dx.doi.org/10.1136/gutjnl-2020-322129DOI Listing
April 2021

Systematic review with meta-analysis: efficacy of balloon-assisted enteroscopy for dilation of small bowel Crohn's disease strictures.

Aliment Pharmacol Ther 2020 10 19;52(7):1104-1116. Epub 2020 Aug 19.

Cleveland, OH, USA.

Background: Evidence for endoscopic balloon dilation of small intestinal strictures in Crohn's disease (CD) using balloon-assisted enteroscopy is scarce.

Aim: To evaluate endoscopic balloon dilation for the treatment of small intestinal CD strictures using balloon-assisted enteroscopy.

Methods: Citations in Embase, MEDLINE, and Cochrane were systematically reviewed. In a meta-analysis of 18 studies with 463 patients and 1189 endoscopic balloon dilations, technical success was defined as the ability to dilate a stricture. Individual data were also obtained on 218 patients to identify outcome-relevant risk factors.

Results: In the pooled per-study analysis, technical success rate of endoscopic balloon dilation was 94.9%, resulting in short-term clinical efficacy in 82.3% of patients. Major complications occurred in 5.3% of patients. During follow-up, 48.3% of patients reported symptom recurrence, 38.8% were re-dilated and 27.4% proceeded to surgery. On the per-patient-based multivariable analysis, that patients with disease activity in the small intestine had lower short-term clinical efficacy (odds ratio 0.32; 95% confidence interval 0.14-0.73, P = 0.007). Patients with concomitant active disease in the small and/or large intestine had an increased risk to proceed toward surgery (hazard ratio 1.85; 95% confidence interval 1.09-3.13, P = 0.02 and hazard ratio 1.77; 95% confidence interval 1.34-2.34, P < 0.001).

Conclusions: Balloon-assisted enteroscopy for dilatation of CD-associated small intestinal strictures has high short-term technical and clinical efficacy and low complication rates. However, up to two-thirds of patients need re-dilation or surgery.
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http://dx.doi.org/10.1111/apt.16049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052861PMC
October 2020

Mechanical and Material Tendon Properties in Patients With Proximal Patellar Tendinopathy.

Front Physiol 2020 24;11:704. Epub 2020 Jun 24.

Department of Sport and Exercise Science, University of Salzburg, Salzburg, Austria.

Introduction: The effect of chronic patellar tendinopathy on tissue function and integrity is currently unclear and underinvestigated. The aim of this cohort comparison was to examine morphological, material, and mechanical properties of the patellar tendon and to extend earlier findings by measuring the ability to store and return elastic energy in symptomatic tendons.

Methods: Seventeen patients with chronic (>3 months, VISA-P < 80), inferior pole patellar tendinopathy (24 ± 4 years; male = 12, female = 5) were carefully matched to controls (25 ± 3 years) for training status, pattern, and history of loading of the patellar tendon. Individual knee extension force, patellar tendon stiffness, stress, strain, Young's modulus, hysteresis, and energy storage capacity, were obtained with combined dynamometry, ultrasonography, magnetic resonance imaging, and electromyography.

Results: Anthropometric parameters did not differ between groups. VISA-P scores ranged from 28 to 78 points, and symptoms had lasted from 10 to 120 months before testing. Tendon proximal cross-sectional area was 61% larger in the patellar tendinopathy group than in the control group. There were no differences between groups in maximal voluntary isometric knee extension torque ( = 0.216; < -0.31) nor in tensile tendon force produced during isometric ramp contractions ( = 0.185; < -0.34). Similarly, tendon strain ( = 0.634; < 0.12), hysteresis ( = 0.461; < 0.18), and strain energy storage ( = 0.656; < 0.36) did not differ between groups. However, patellar tendon stiffness (-19%; = 0.007; < -0.74), stress (-27%; < 0.002; < -0.90) and Young's modulus (-32%; = 0.001; < -0.94) were significantly lower in tendinopathic patients compared to healthy controls.

Discussion: In this study, we observed lower stiffness in affected tendons. However, despite the substantial structural and histological changes occurring with tendinopathy, the tendon capacity to store and dissipate energy did not differ significantly.
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http://dx.doi.org/10.3389/fphys.2020.00704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358637PMC
June 2020

Quantitative Analysis of Patellar Tendon After Total Knee Arthroplasty Using Echo Intensity: A Nonrandomized Controlled Trial of Alpine Skiing.

J Arthroplasty 2020 10 28;35(10):2858-2864. Epub 2020 May 28.

Department of Sport and Exercise Science, Paris Lodron University of Salzburg, Salzburg, Austria.

Background: Despite the knee extensor weakness, less attention has been paid to the evaluation of patellar tendon after total knee arthroplasty (TKA). We previously observed patellar tendon hypertrophy after TKA. The purpose of this study is to reanalyze these ultrasound data to detect whether brightness mode ultrasound imaging reflects pathological changes of the patellar tendon after TKA.

Methods: Twenty-eight participants with post unilateral TKA were assigned to an intervention group or control group. The intervention group underwent a 12-week skiing program. Patellar tendon mechanical properties were obtained by combining isometric dynamometry, ultrasound imaging, and electromyography in operated knee and nonoperated knee. Luminosity ratio (LR) was measured using echo intensity in a relaxed and maximally loaded phase.

Results: Baseline comparisons revealed significant effects of the surgical side (P < .001) and loading phase (P = .017), but no interaction between leg and phase (P < .149). LR of the operated knee was significantly lower than LR of the nonoperated knee in relaxed (P < .001) and maximally loaded phases (P = .003). In addition, there was a significant correlation between LR of maximum phase and isometric knee extension torque (r = 0.156, P = .038). However, LR was not related to patellar tendon stiffness, Young's modulus, or strain. There was a significant time effect in knee extension torque, but no time effects on LR and tendon force.

Conclusion: Patellar tendon LR is decreased along with degenerative change after TKA. Ultrasound imaging provides a promising metric to acquire in vivo patellar tendon pathological assessment after TKA.
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http://dx.doi.org/10.1016/j.arth.2020.05.052DOI Listing
October 2020
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