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Aljabri R, Al-Saraie S, Alhouti A. Optimizing Biologic Therapy for the Prevention of Post-Operative Recurrence in Crohn's Disease: Current Evidence and Future Perspectives. Biomedicines 2025; 13:1232. [PMID: 40427059 PMCID: PMC12108690 DOI: 10.3390/biomedicines13051232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/05/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Crohn's disease (CD) imposes a substantial burden on patients due to its chronic, relapsing nature, often necessitating surgical intervention. However, surgery is not curative, and post-operative recurrence (POR) remains a major clinical challenge, with up to 80% of patients developing endoscopic recurrence within one year if left untreated. The pathophysiology of POR is multifactorial, involving dysregulated immune responses, gut microbiota alterations, and mucosal healing impairment, highlighting the need for targeted therapeutic strategies. This review aims to explore the current landscape of POR management, focusing on biologic therapies and emerging advanced treatments. Conventional management relies on early prophylactic therapy with anti-TNF agents such as infliximab and adalimumab, which have demonstrated efficacy in reducing endoscopic and clinical recurrence. However, newer biologics, including IL-23 inhibitors (risankizumab) and Janus kinase (JAK) inhibitors (upadacitinib), have shown promise in CD management, though their role in POR remains underexplored. The lack of direct clinical evidence for advanced biologics in POR prevention, combined with inter-individual variability in treatment response, underscores the need for further research. Future directions should focus on optimizing therapeutic strategies through personalized medicine, identifying predictive biomarkers, and conducting robust trials to establish the efficacy of novel agents in POR prevention. A tailored, evidence-driven approach is essential to improving long-term outcomes and minimizing disease recurrence in post-operative CD patients.
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Affiliation(s)
- Reem Aljabri
- Division of Gastroenterology, Department of Internal Medicine, Ministry of Health of Kuwait—Farwaniya Hospital, Sabah Al-Nasser 92426, Kuwait; (S.A.-S.); (A.A.)
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Minordi LM, Sacchetti F, Balzano D, Maresca R, D’Angelo FB, Larosa L, Carano D, Laterza L, Pugliese D, Caprino P, Potenza AE, Scaldaferri F, Sofo L, Sala E. Clinical, Radiological, and Surgical Risk Factors for Endoscopic Anastomotic Recurrence Following Surgery in Crohn's Disease. J Clin Med 2024; 13:6669. [PMID: 39597812 PMCID: PMC11594761 DOI: 10.3390/jcm13226669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/11/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Objective: This study investigated the radiological, clinical, and surgical factors linked to the risk of endoscopic recurrence following ileocolic resection for Crohn's disease. Materials and Methods: We conducted a retrospective analysis of data from all patients who underwent primary ileocecal resection for Crohn's disease in a single colorectal unit between 2004 and 2020. We analyzed the potential risk factors subdivided by the clinical, radiological, and surgical factors associated with morphological recurrence, as detected by endoscopy within 2 years after surgery. Cox regression was employed to ascertain the risk factors associated with such recurrence. Results: In total, 63 patients were included, and 24 (38%) had endoscopic recurrence. The age of the patient at the time of surgery was identified as a significant clinical factor associated with the risk of recurrence (HR: 1.04; p = 0.003), indicating that the probability of recurrence increases by 1% as the surgical age increases each year. The radiological factors associated with an increased risk of recurrence included localization in the distal ileum (HR: 3.526; p = 0.015), the number of pathological small-bowel segments affected by the disease (HR: 1.15; p = 0.004), and the total length of the pathological intestinal segment (HR: 1.002; p = 0.014). The presence of granulomas (HR: 6.003; p = 0.004) and the length of the resected bowel (HR: 1.01; p = 0.003) were surgical factors associated with a higher risk of recurrence. Conclusions: This study delineated several clinical, radiological, and surgical factors that serve as predictors for the endoscopic recurrence of Crohn's disease after surgery.
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Affiliation(s)
- Laura Maria Minordi
- UOC di Radioterapia Oncologica ed Ematologia Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.M.); (F.B.D.); (L.L.); (D.C.); (E.S.)
| | - Franco Sacchetti
- UOC di Chirurgia Addominale, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (D.B.); (P.C.); (A.E.P.); (L.S.)
| | - Domenico Balzano
- UOC di Chirurgia Addominale, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (D.B.); (P.C.); (A.E.P.); (L.S.)
| | - Rossella Maresca
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (R.M.); (L.L.); (D.P.); (F.S.)
| | - Francesca Bice D’Angelo
- UOC di Radioterapia Oncologica ed Ematologia Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.M.); (F.B.D.); (L.L.); (D.C.); (E.S.)
| | - Luigi Larosa
- UOC di Radioterapia Oncologica ed Ematologia Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.M.); (F.B.D.); (L.L.); (D.C.); (E.S.)
| | - Davide Carano
- UOC di Radioterapia Oncologica ed Ematologia Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.M.); (F.B.D.); (L.L.); (D.C.); (E.S.)
| | - Lucrezia Laterza
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (R.M.); (L.L.); (D.P.); (F.S.)
| | - Daniela Pugliese
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (R.M.); (L.L.); (D.P.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Paola Caprino
- UOC di Chirurgia Addominale, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (D.B.); (P.C.); (A.E.P.); (L.S.)
| | - Angelo Eugenio Potenza
- UOC di Chirurgia Addominale, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (D.B.); (P.C.); (A.E.P.); (L.S.)
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (R.M.); (L.L.); (D.P.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Luigi Sofo
- UOC di Chirurgia Addominale, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (D.B.); (P.C.); (A.E.P.); (L.S.)
| | - Evis Sala
- UOC di Radioterapia Oncologica ed Ematologia Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.M.); (F.B.D.); (L.L.); (D.C.); (E.S.)
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The detection rate of granulomas differs between intestinal segments and lesions in Chinese patients with Crohn's disease. Clin Res Hepatol Gastroenterol 2023; 47:102076. [PMID: 36623769 DOI: 10.1016/j.clinre.2023.102076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/20/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023]
Abstract
BACKGROUND Crohn's disease (CD) is characterized by non-caseating intestinal granulomas. However, the reported detection rate of granulomas on endoscopy is low. This study aimed to analyze the differences in the detection rate of granulomas in different intestinal segments and lesions in Chinese patients with CD to improve the detection rate of granulomas in clinical practice. PATIENTS AND METHODS 113 patients with CD were analyzed retrospectively. Patients were divided into two groups: those with (n = 51) and without granulomas (n = 62) on endoscopic biopsies. Clinical information was collected from the medical records, including age; erythrocyte sedimentation rate (ESR); C-reactive protein (CRP), albumin, and hemoglobin (Hb) levels; platelet count; disease course; sex; smoking history; related operation history; Montreal classification; and lesion location, size, and shape. RESULTS The detection rates of granulomas in different lesion shapes were significantly different (P < 0.001), with those of longitudinal ulcers and circular ulcers being higher than those of erosion and irregular ulcers. We also found that the detection rates of granulomas in ascending colon and sigmoid colon were relatively higher than other segments of the intestine, however, the difference was not statistically significant (P = 0.716). Additionally, age, sex, smoking history, Montreal classification, related surgical history, disease course, and serum biochemical indicators (ESR; platelet count; and CRP, albumin, and Hb levels) were not significantly different between the two groups. CONCLUSIONS The detection rate of granulomas in patients with CD is related to the morphology of the intestinal lesions. Meanwhile, lesion location may be correlated with the detection rate of granulomas.
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Rezazadeh Ardabili A, Goudkade D, Wintjens D, Romberg-Camps M, Winkens B, Pierik M, Grabsch HI, Jonkers D. Histopathological Features in Colonic Biopsies at Diagnosis Predict Long-term Disease Course in Patients with Crohn's Disease. J Crohns Colitis 2021; 15:1885-1897. [PMID: 33987670 PMCID: PMC8575048 DOI: 10.1093/ecco-jcc/jjab087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIMS Crohn's disease [CD] is characterised by a heterogeneous disease course. Patient stratification at diagnosis using clinical, serological, or genetic markers does not predict disease course sufficiently to facilitate clinical decision making. The current study aimed to investigate the additive predictive value of histopathological features to discriminate between a long-term mild and severe disease course. METHODS Diagnostic biopsies from treatment-naïve CD patients with mild or severe disease courses in the first 10 years after diagnosis were reviewed by two gastrointestinal pathologists after developing a standardised form comprising 15 histopathological features. Multivariable logistic regression models were built to identify predictive features and compute receiver operating characteristic [ROC] curves. Models were internally validated using bootstrapping to obtain optimism-corrected performance estimates. RESULTS In total, 817 biopsies from 137 patients [64 mild, 73 severe cases] were included. Using clinical baseline characteristics, disease course could only moderately be predicted (area under receiver operating characteristic curve [AUROC]: 0.738 [optimism 0.018], 95% confidence interval [CI] 0.65-0.83, sensitivity 83.6%, specificity 53.1%). When adding histopathological features, in colonic biopsies a combination of [1] basal plasmacytosis, [2] severe lymphocyte infiltration in lamina propria, [3] Paneth cell metaplasia, and [4] absence of ulcers were identified and resulted in significantly better prediction of a severe course (AUROC: 0.883 [optimism 0.033], 95% CI 0.82-0.94, sensitivity 80.4%, specificity 84.2%). CONCLUSIONS In this first study investigating the additive predictive value of histopathological features in biopsies at CD diagnosis, we found that certain features of chronic inflammation in colonic biopsies contributed to prediction of a severe disease course, thereby presenting a novel approach to improving stratification and facilitating clinical decision making.
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Affiliation(s)
- Ashkan Rezazadeh Ardabili
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center+, Maastricht, The Netherlands
- School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
- Corresponding author: Ashkan Rezazadeh Ardabili, MD, Department of Internal Medicine, Division of Gastroenterology and Hepatology, NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Postbox 5800, 6202 AZ, Maastricht, The Netherlands. Tel.: 0031-43-3884203; fax: 0031-43-3875006;
| | - Danny Goudkade
- Department of Pathology, Zuyderland Medical Centre, Geleen, The Netherlands
| | - Dion Wintjens
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center+, Maastricht, The Netherlands
- School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Mariëlle Romberg-Camps
- Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine, Zuyderland Medical Centre, Sittard-Geleen, The Netherlands
| | - Bjorn Winkens
- Department of Methodology and Statistics, Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands
| | - Marie Pierik
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center+, Maastricht, The Netherlands
- School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
- Division of Pathology & Data Analytics, Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, UK
| | - Daisy Jonkers
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center+, Maastricht, The Netherlands
- School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
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Ali M, Ng S, Burgess P. Granulomatous Crohn's disease follows a more aggressive clinical course? SURGICAL PRACTICE 2021. [DOI: 10.1111/1744-1633.12488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Muhammad Ali
- Department of Colorectal and General Surgery Great Western Hospital Swindon UK
| | - Sherwin Ng
- Department of Colorectal and General Surgery Great Western Hospital Swindon UK
| | - Phillip Burgess
- Department of Colorectal and General Surgery Great Western Hospital Swindon UK
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Tandon P, Malhi G, Abdali D, Pogue E, Marshall JK, de Buck van Overstraeten A, Riddell R, Narula N. Active Margins, Plexitis, and Granulomas Increase Postoperative Crohn's Recurrence: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021; 19:451-462. [PMID: 32801016 DOI: 10.1016/j.cgh.2020.08.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Rates of postoperative Crohn's disease recurrence remain high, although the ability to predict this risk of recurrence remains limited. As such, we aimed to determine the association of histologic features at the time of resection with postoperative recurrence. METHODS Electronic databases were searched through February 2020 for studies that reported risk of clinical, endoscopic, or surgical postoperative recurrence in patients with positive resection margins, plexitis, or granulomas in the index specimen. Pooled risk ratios (RRs) with 95% CIs were calculated for this risk in patients with and without these histologic features. RESULTS Twenty-one studies (2481 patients) assessed positive resection margins, 10 studies (808 patients) assessed plexitis, and 19 studies (1777 patients) assessed granulomas. Positive resection margins increased the risk of clinical (RR, 1.26; 95% CI, 1.06-1.49; I2 = 41%) and surgical (RR, 1.87; 95% CI, 1.14-3.08; I2 = 71%) recurrence, with a trend toward endoscopic recurrence (RR, 1.56; 95% CI, 0.79-3.05; I2 = 85%). Granulomas increased the risk of clinical (RR, 1.31; 95% CI, 1.05-1.64; I2 = 36%) and endoscopic (RR, 1.37; 95% CI, 1.00-1.87; I2 = 49%) recurrence, with a trend toward surgical recurrence (RR, 1.58; 95% CI, 0.89-2.80; I2 = 75%). Plexitis increased the risk of endoscopic recurrence (RR, 1.31; 95% CI, 1.00-1.72; I2 = 20%), with a trend toward clinical recurrence (RR, 1.34; 95% CI, 0.95-1.91; I2 = 46%). CONCLUSIONS Positive resection margins, granulomas, and plexitis are predictive of postoperative Crohn's disease recurrence and should be recorded at the time of index resection.
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Affiliation(s)
- Parul Tandon
- Division of Gastroenterology and Hepatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Gurpreet Malhi
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Daniyal Abdali
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Elahn Pogue
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - John K Marshall
- Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | | | - Robert Riddell
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Neeraj Narula
- Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada.
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Hong SW, Yoon H, Shin CM, Park YS, Kim N, Lee DH, Kim JS. Clinical significance of granulomas in Crohn's disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2020; 35:364-373. [PMID: 31522456 DOI: 10.1111/jgh.14849] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 08/18/2019] [Accepted: 08/24/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Epithelioid granuloma is one hallmark used to histologically diagnose Crohn's disease (CD). However, the clinical significance of granulomas in CD is unclear. Therefore, we performed a meta-analysis to compare the clinical features with CD according to the presence of granulomas. METHODS A literature search in PubMed, EMBASE, and Cochrane databases was performed on manuscripts published until October 2018. We included studies that met the following inclusion criteria: (i) patient: patients with CD; (ii) exposure: granulomas on the pathology; (iii) comparator: no granulomas; and (iv) outcomes: disease location, disease behavior, perianal disease, disease activity, use of biologics, and CD-associated hospitalization, surgery. RESULTS Nineteen studies met our inclusion criteria. Granulomas in CD patients were associated with a higher proportion of ileocolonic disease (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.21-1.83), a higher proportion of upper gastrointestinal disease (OR: 2.25, 95% CI: 1.28-3.95), a higher proportion of penetrating behavior (OR: 1.48, 95% CI: 1.09-2.01), a higher prevalence of perianal disease (OR: 2.15, 95% CI: 1.48-3.11), and a higher severity index at presentation (standardized mean difference: 0.20, 95% CI: 0.09-0.32). In addition, the use of biologics was significantly higher in CD patients with granulomas compared with without granulomas (OR: 1.66, 95% CI: 1.07-2.59). The presence of granulomas was significantly associated with CD-associated hospitalization (OR: 3.88, 95% CI: 1.44-10.49), but not with CD-associated surgery. CONCLUSIONS Clinical features in CD patients were significantly different according to the presence of granulomas. It may indicate a more aggressive phenotype of CD.
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Affiliation(s)
- Seung Wook Hong
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea
| | - Nayoung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea
| | - Dong Ho Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Penetrating Crohn Disease Is Not Associated With a Higher Risk of Recurrence After Surgery. Ann Surg 2019; 270:827-834. [DOI: 10.1097/sla.0000000000003531] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Johnson CM, Hartman DJ, Ramos-Rivers C, Rao BB, Bhattacharya A, Regueiro M, Schwartz M, Swoger J, Al Hashash J, Barrie A, Pfanner TP, Dunn M, Koutroubakis IE, Binion DG. Epithelioid Granulomas Associate With Increased Severity and Progression of Crohn's Disease, Based on 6-Year Follow-Up. Clin Gastroenterol Hepatol 2018; 16:900-907.e1. [PMID: 29277619 DOI: 10.1016/j.cgh.2017.12.034] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/11/2017] [Accepted: 12/15/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Epithelioid granulomas are characteristics of a subset of patients with Crohn's disease (CD), but their significance, with regard to disease progression and severity, is unclear. We investigated the relationship between granulomas and CD severity over a 6-year time period in a large cohort of patients. METHODS We performed a retrospective study of patients with CD seen at the Inflammatory Bowel Disease Center at the University of Pittsburgh; data were collected from 2009 through 2014 and patients were assigned to groups with and without histologic evidence of granuloma. Demographic, clinical (including disease activity, quality of life, medication use, and healthcare utilization), and laboratory data were used in association and survival analyses. Differences between groups were evaluated using the Mann-Whitney U-test for continuous variables. RESULTS Of 1466 patients with CD, granulomas were identified in 187 (12.8%). In the subset of patients who underwent surgery, 21.0% had granulomas. The presence of granuloma was associated with increased serum levels of c-reactive protein (odds ratio [OR], 2.9; 95% CI, 2.078-4.208; P < .0001), younger mean age at diagnosis (23.6 ± 11.3 years in patients with granulomas vs 27.9 ± 13.3 years in patients without; P = .0005), higher rates of stricturing or penetrating disease phenotype, higher rates of steroid and narcotic use, and higher healthcare utilization. Among patients that underwent surgery, the presence of granulomas was associated with need for repeat surgery during the 6-year observation period (OR, 2.5; 95% CI, 1.54-4.02; P = .0002). Infliximab use was associated with detection of granuloma in a significantly lower proportion of surgical specimens compared to patients who had not been treated with a biologic agent (OR, 0.22; 95 CI, 0.05-0.97; P = .03). CONCLUSIONS Epithelioid granulomas develop in less than 13% of patients with CD, and are associated with a more aggressive disease phenotype. Patients who have undergone surgery for CD and have granulomas are at increased risk for repeat surgery within 6 years.
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Affiliation(s)
- Christopher M Johnson
- Division of Gastroenterology, Baylor Scott & White Health, Texas A&M Health Science Center, Temple, Texas
| | - Douglas J Hartman
- Department of Anatomic Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Claudia Ramos-Rivers
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Bhavana Bhagya Rao
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Abhik Bhattacharya
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Miguel Regueiro
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Marc Schwartz
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jason Swoger
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jana Al Hashash
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Arthur Barrie
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Timothy P Pfanner
- Division of Gastroenterology, Baylor Scott & White Health, Texas A&M Health Science Center, Temple, Texas
| | - Michael Dunn
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ioannis E Koutroubakis
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David G Binion
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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Rinawi F, Zevit N, Eliakim R, Niv Y, Shamir R, Assa A. Long-Term Outcomes After Primary Bowel Resection in Pediatric-Onset Crohn's Disease. Inflamm Bowel Dis 2017; 24:149-158. [PMID: 29272491 DOI: 10.1093/ibd/izx030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND There is limited evidence on the long-term outcome of intestinal resection in pediatric-onset Crohn's disease (POCD) with no established predictors of adverse outcomes. We aimed to investigate clinical outcomes and predictors for adverse outcome following intestinal resection in POCD. METHODS The medical records of patients with POCD who underwent at least 1 intestinal resection between 1990 and 2014 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, second intestinal resection, and response to nonprophylactic biologic therapy. RESULTS Overall, 121 patients were included. Median follow-up was 6 years (range 1-23.6). One hundred and seven (88%) patients experienced at least 1 postsurgical exacerbation, 52 (43%) were hospitalized, and 17 (14%) underwent second intestinal resection. Of 91 patients who underwent surgery after the year 2000, 37 (41%) were treated with antitumor necrosis factor ɑ (anti-TNFɑ) (nonprophylactic) following intestinal resection. Time to hospitalization and to second intestinal resection were shorter among patients with extraintestinal manifestations (EIMs) (HR 2.7, P = 0.006 and HR = 3.1, P = 0.03, respectively). Time to initiation of biologic treatment was shorter in patients with granulomas (HR 2.1, P = 0.038), whereas being naïve to anti-TNFɑ treatment before surgery was a protective factor for biologic treatment following surgery (HR 0.3, P = 0.005). Undergoing intestinal resection beyond the year 2000 was associated with shorter time to first flare (HR 1.9, P = 0.019) and hospitalization (HR 2.6, P = 0.028). CONCLUSION Long-term risk for flares, hospitalization, or biologic treatment is significant in POCD following bowel resection. EIMs increase the risk for hospitalization and second intestinal resection.
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Affiliation(s)
- Firas Rinawi
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Noam Zevit
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Rami Eliakim
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.,Department of Gastroenterology, Sheba Medical Center -Tel Hashomer, Ramat Gan, Israel
| | - Yaron Niv
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.,Department of Gastroenterology, Rabin Medical Center, Petach Tikva, Israel
| | - Raanan Shamir
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Amit Assa
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
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Rothschild B, Rinawi F, Herman Y, Nir O, Shamir R, Assa A. Prognostic significance of granulomas in children with Crohn's disease. Scand J Gastroenterol 2017; 52:716-721. [PMID: 28346037 DOI: 10.1080/00365521.2017.1304571] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Granulomas have long been considered the histological hallmark of Crohn's disease (CD). Currently, there is considerable dispute with regards to their prognostic implications. We aimed to determine the effect of granulomas on phenotypic features and disease's long-term outcomes in a large cohort of pediatric CD patients. MATERIALS AND METHODS Medical records of pediatric CD patients diagnosed at the Schneider Children's Medical Center were reviewed retrospectively. Patients were categorized into two groups based on the presence or absence of granulomas at diagnosis. Baseline characteristics included anthropometric, clinical, laboratory, radiological and endoscopic data. Outcome measures included flares, hospitalizations, biological therapy and surgery. RESULTS Of 289 CD patients diagnosed between 2001 and 2015, 99 patients (34%) had granulomas. Median age of the entire cohort at diagnosis was 14.2 years (females, 42.6%), with a median follow-up of 8.5 years. Patients with granulomas had a significantly higher percentage (47.5% vs. 23.7%, p = .001) of upper gastrointestinal involvement and ileo-colonic disease (64.9% vs. 49.5%, p = .01). Extraintestinal manifestations were twice as common in patients without granulomas (16.3% vs. 8.1%, p = .05). Patients with granulomas were more likely to be hospitalized (HR =1.43, 95% CI: 1.0-2.0) and to receive biologic therapy (HR = 1.52, 95% CI: 1.1-2.11). Additionally, both of these disease outcomes occurred significantly earlier (p = .013 and p = .027, respectively). In contrast, patients with granulomas did not exhibit increased risk of flares or bowel resection. CONCLUSION Patients with granulomas exhibited a distinct phenotype at diagnosis and demonstrated a more severe disease course.
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Affiliation(s)
- Benjamin Rothschild
- a Institute of Gastroenterology, Nutrition and Liver Disease , Schneider Children's Hospital , Petach-Tikva , Israel
| | - Firas Rinawi
- a Institute of Gastroenterology, Nutrition and Liver Disease , Schneider Children's Hospital , Petach-Tikva , Israel
| | - Yonatan Herman
- a Institute of Gastroenterology, Nutrition and Liver Disease , Schneider Children's Hospital , Petach-Tikva , Israel
| | - Osnat Nir
- b Sackler Faculty of Medicine, Tel-Aviv University , Tel-Aviv , Israel
| | - Raanan Shamir
- a Institute of Gastroenterology, Nutrition and Liver Disease , Schneider Children's Hospital , Petach-Tikva , Israel.,b Sackler Faculty of Medicine, Tel-Aviv University , Tel-Aviv , Israel
| | - Amit Assa
- a Institute of Gastroenterology, Nutrition and Liver Disease , Schneider Children's Hospital , Petach-Tikva , Israel.,b Sackler Faculty of Medicine, Tel-Aviv University , Tel-Aviv , Israel
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12
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Gklavas A, Dellaportas D, Papaconstantinou I. Risk factors for postoperative recurrence of Crohn's disease with emphasis on surgical predictors. Ann Gastroenterol 2017; 30:598-612. [PMID: 29118554 PMCID: PMC5670279 DOI: 10.20524/aog.2017.0195] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 07/10/2017] [Indexed: 12/12/2022] Open
Abstract
Intestinal resection for Crohn’s disease is not curative and postoperative recurrence rates remain high. Early detection of indices associated with recurrence and risk stratification are fundamental for the postoperative management of patients. Early endoscopy at 6-12 months is the “gold standard” procedure, whereas other modalities such as fecal calprotectin and imaging techniques can contribute to the diagnosis of recurrence. The purpose of this review is to summarize current data regarding risk factors correlated with postoperative relapse. Smoking is a well-established, modifiable risk factor. There are sufficient data that correlate penetrating disease, perianal involvement, extensive resections, prior surgery, histological features (plexitis and granulomas), and improper management after resection with high rates for recurrence. The literature provides conflicting data for other possible predictors, such as age, sex, family history of inflammatory bowel disease, location of disease, strictureplasties, blood transfusions, and postoperative complications, necessitating further evidence. On the other hand, surgical factors such as anastomotic configuration, open or laparoscopic approach, and microscopic disease at specimen margins when macroscopic disease is resected, seem not to be related with an increased risk of recurrence. Further recognition of histological features as well as gene-related factors are promising fields for research.
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Affiliation(s)
- Antonios Gklavas
- 2 Department of Surgery, Aretaieion University Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Dionysios Dellaportas
- 2 Department of Surgery, Aretaieion University Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Ioannis Papaconstantinou
- 2 Department of Surgery, Aretaieion University Hospital, University of Athens, School of Medicine, Athens, Greece
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13
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Lemmens B, de Buck van Overstraeten A, Arijs I, Sagaert X, Van Assche G, Vermeire S, Tertychnyy A, Geboes K, Wolthuis A, D'Hoore A, De Hertogh G, Ferrante M. Submucosal Plexitis as a Predictive Factor for Postoperative Endoscopic Recurrence in Patients with Crohn's Disease Undergoing a Resection with Ileocolonic Anastomosis: Results from a Prospective Single-centre Study. J Crohns Colitis 2017; 11:212-220. [PMID: 27466173 DOI: 10.1093/ecco-jcc/jjw135] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 07/09/2016] [Accepted: 07/17/2016] [Indexed: 12/13/2022]
Abstract
AIM Ileocolonoscopy allows early detection of recurrence after surgical resection for Crohn's disease [CD]. Plexitis, defined as presence of inflammatory cells in or around enteric ganglia or nerve bundles, in the proximal surgical margin has been associated with an increased overall recurrence risk. We investigated prospectively whether plexitis can predict endoscopic recurrence [ER] in a consecutive cohort of CD patients undergoing ileocolonic resection. METHODS All CD patients undergoing ileocolonic resection in our institution between October 2009 and December 2012 were eligible for this study. Clinical data were obtained prospectively from the patients' files, and biopsies from the proximal surgical margins were analysed immunohistochemically for inflammation at the myenteric and submucosal plexus [lymphocytes, mast cells, eosinophils]. The degree of plexitis was correlated with the presence of ER at 6 months, defined as a modified Rutgeerts' score of ≥ i2b. Multivariate models were developed and tested to predict posterior probability of ER. RESULTS A total of 74 patients were included. Six months after ileocolonic resection, 50% showed ER. Known risk factors such as penetrating disease, previous resections, and active smoking, showed no relation with ER. On the other hand, submucosal lymphocytic plexitis was associated with ER [p = 0.020]. The predictive value of lymphocytic cell count increased with more extensive biopsy sampling and with application of immunohistochemistry. CONCLUSIONS Submucosal lymphocytic plexitis in the proximal surgical margin was significantly related with a higher risk for ER after ileocolonic resection. These data support development of a postoperative prevention trial with vedolizumab, which may block lymphocytic trafficking in the postoperative bowel.
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Affiliation(s)
- Bart Lemmens
- Translational Cell & Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Anthony de Buck van Overstraeten
- Translational Research in Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Ingrid Arijs
- Translational Research in Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Xavier Sagaert
- Translational Cell & Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Translational Research in Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | | | - Karel Geboes
- Translational Cell & Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Albert Wolthuis
- Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Andre D'Hoore
- Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Translational Cell & Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Translational Research in Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, University Hospitals Leuven, KU Leuven, Leuven, Belgium .,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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14
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Presence of Granulomas in Mesenteric Lymph Nodes Is Associated with Postoperative Recurrence in Crohn's Disease. Inflamm Bowel Dis 2015. [PMID: 26218143 DOI: 10.1097/mib.0000000000000541] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The association between the presence of granulomas in the mesenteric lymph node (MLN) and postoperative recurrent Crohn's disease (CD) is unknown. Our aim was to assess the predictive value of the presence of granulomas in MLN as well as in bowel wall for postoperative recurrence of CD. METHODS Patients with CD who underwent the index ileocolonic resection between 2004 and 2012 were included. Surgical pathology reports were reviewed for the presence and location of granulomas. The status of MLN granulomas was confirmed by re-review of surgical pathology specimen from randomly sampled patients by an expert pathologist. Both univariable and multivariable analyses were performed to assess the risk factors associated with postoperative recurrent CD. RESULTS A total of 194 patients were included. Granulomas were detected in the MLN in 23 patients (11.9%), and in the intestinal wall in 57 (29.4%). On Kaplan-Meier curve, the presence of granulomas in MLN was found to be a risk factor for postoperative endoscopic recurrence (P = 0.015) as well as surgical recurrence (P = 0.035). In contrast, granulomas in the bowel wall, which was not found to be associated with neither endoscopic recurrence (P = 0.94) or surgical recurrence (P = 0.56). On Cox proportional hazards regression analysis, the presence of MLN granulomas was independently associated with an increased risk for both postoperative endoscopic recurrence (hazard ratio [HR] = 1.91; 95% confidence interval [CI], 1.06-3.45; P = 0.031) and surgical recurrence (HR = 3.43; 95% CI, 1.18-9.99; P = 0.023). CONCLUSIONS The presence of granulomas in MLN but not in intestine per se was found to be an independent risk factor for recurrence in CD patients undergoing ileocolonic resection.
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Abstract
BACKGROUND Granulomas are occasionally detected on biopsy specimen of the ileal pouch and their clinical implications are not clear. The aim of this study was to evaluate clinical implications of noncaseating granuloma on histology in patients with ileal pouches. METHODS All eligible patients with confirmed noncaseating granulomas on histology of the biopsy specimens of the pouch body, afferent limb, or cuff in our prospectively maintained Pouch Registry between 2002 and 2014 were evaluated. Demographic and clinical factors were analyzed. The disease course of those patients was evaluated. RESULTS Of 1564 patients in the Registry, 42 met the criteria and were included. The median duration from the pouch construction to the last visit was 9 years (range, 2-28 yr). Twenty-eight patients (66.7%) developed clinical Crohn's disease (CD) of the pouch, whereas 14 (33.3%) were classified as having histologic CD of the pouch. Six patients (21.4%) in the clinical CD of the pouch group and 4 (28.6%) in the histologic CD of the pouch group had granulomas on more than 1 endoscopy. Postoperative biological therapy was administered more in the clinical CD group than in the histologic CD group (39.3% versus 0%, P = 0.007). Pouch-related fistulae and presacral sinus were verified more in clinical CD group than the histologic CD group. However, Kaplan-Meier plot showed comparable pouch survival between clinical CD and histologic CD groups. CONCLUSIONS In our current study, one-third of the patients with noncaseating pouch granulomas did not develop clinical CD of the pouch. With proper medical therapy, long-term pouch outcomes appeared to be similar in those patients with clinical CD or histologic CD of the pouch.
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16
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Abstract
Recurrence of Crohn's disease (CD) after ileal or colonic resection is common. Many studies have tried to identify predictors of postoperative recurrence (POR) in CD. A wide range of histologic features have been identified, but for most of them, the literature provided conflicting data. In last years, several studies have suggested that histologic findings including inflammatory changes within the enteric nervous system of the resection margin may be associated with CD recurrence. Herein, after briefly summarizing pathophysiology of POR, we review all histological features that have been studied so far: granulomas, histologic appearance at the margin of resection, plexitis, lymphatic vessel density in proximal margin of resection, and morphological analysis of Paneth cells. Granulomas and chronic inflammation at the margin of resection do not seem to predict POR in CD. Active disease at the margin of resection, plexitis, lymphatic vessels density, morphological analysis of Paneth cells may predict POR. Most of these histological features await replication in independent studies. Available evidence indicates that histological findings may be taken into account when developing strategies aimed at preventing postoperative CD recurrence.
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17
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De Cruz P, Kamm MA, Prideaux L, Allen PB, Desmond PV. Postoperative recurrent luminal Crohn's disease: a systematic review. Inflamm Bowel Dis 2012; 18:758-77. [PMID: 21830279 DOI: 10.1002/ibd.21825] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 06/15/2011] [Indexed: 12/20/2022]
Abstract
Despite improved immunosuppressive therapy, surgical resection is still often required for uncontrolled inflammatory disease and the stenosing and perforating complications of Crohn's disease. However, surgery is not curative. A majority of patients develop disease recurrence at or above the anastomosis. Subclinical endoscopically identifiable recurrence precedes the development of clinical symptoms; identification and treatment of early mucosal recurrence may therefore prevent clinical recurrence. Therapy to achieve mucosal healing should now be the focus of postoperative therapy. A number of clinical risk factors for the development of earlier postoperative recurrence have been identified, and reasonable evidence is now available regarding the efficacy of drug therapies in preventing recurrence. This evidence now needs to be incorporated into prospective treatment strategies.
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Affiliation(s)
- Peter De Cruz
- Department of Gastroenterology and Medicine, St Vincent's Hospital, Melbourne, Australia
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18
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Denoya P, Canedo J, Berho M, Allende DS, Bennett AE, Rosen L, Hull T, Wexner SD. Granulomas in Crohn's disease: does progression through the bowel layers affect presentation or predict recurrence? Colorectal Dis 2011; 13:1142-7. [PMID: 20860713 DOI: 10.1111/j.1463-1318.2010.02421.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIM The aim of the study was to correlate the presence and pattern of distribution of granulomas in resected specimens to clinical characteristics and outcome in patients undergoing surgery for Crohn's disease. METHOD Patients with Crohn's disease who underwent surgical resection between 2001 and 2007 were identified. Pathology slides were reviewed for the presence, number and location of granulomas in four representative slides from each specimen. RESULTS Two-hundred and seven patients were identified. At a mean follow up of 14 months, 39 patients had a recurrence, 22 (57%) of whom underwent reoperation. Ninety-four (45%) patients had granulomas present in the surgical specimen. Patients with granulomas were younger (P<0.001), had a lower preoperative body mass index (P=0.037), were more likely to be female (P=0.017) and were more likely to have extra-intestinal manifestations (P=0.026) or perianal disease (P=0.012). Sites of disease and procedures performed were similar in both groups. Disease recurrence and reoperative rates were similar in both groups, as were length of stay and morbidity rates. The average number of granulomas present in each sampled pathology slide was 7.2, and there was no correlation between number of granulomas and disease severity. No link was found between the depth of involvement of the granulomas and fistulizing or stricturing disease. CONCLUSION Granulomas were associated with increased extra-intestinal manifestations and perianal disease, a lower body mass index and younger or female patients. There was no correlation between the presence of granulomas and disease progression or recurrence rates during the short follow-up period of this study.
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Affiliation(s)
- P Denoya
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, Florida 33331, USA
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Cunningham MF, Docherty NG, Coffey JC, Burke JP, O'Connell PR. Postsurgical recurrence of ileal Crohn's disease: an update on risk factors and intervention points to a central role for impaired host-microflora homeostasis. World J Surg 2011; 34:1615-26. [PMID: 20195604 DOI: 10.1007/s00268-010-0504-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND A pressing need exists to identify factors that predispose to recurrence after terminal ileal resection for Crohn's disease (CD) and to determine effective prophylactic strategies. This review presents an up-to-date summary of the literature in the field and points to a role for bacterial overproliferation in recurrence. METHODS The literature (Medline, Embase, and the Cochrane Library, 1971-2009) on ileal CD and postoperative recurrence was searched, and 528 relevant articles were identified and reviewed. RESULTS Smoking is a key independent risk factor for recurrence. NOD2/CARD15 polymorphisms and penetrating phenotype are associated with aggressive disease and higher reoperation rates. Age at diagnosis, disease duration, gender, and family history are inconsistent predictors of recurrence. Prophylactic 5-aminosalicylic acid therapy and nitromidazole antibiotics are beneficial. Combination therapies with immunosuppressants are also effective. Anti-TNFalpha-based regimens show benefit but the evidence base is small. Corticosteroid, interleukin-10, and probiotic therapies are not effective. Wider, stapled anastomotic configurations are associated with reduced recurrence rates. Strictureplasty and laparoscopic approaches have similar long-term recurrence rates to open resection techniques. Length of resection and presence of microscopic disease at resection margins do not influence recurrence. A lack of consensus exists regarding whether the presence of granulomas or plexitis affects outcome. CONCLUSIONS Current evidence points to defects in mucosal immunity and intestinal dysbiosis of either innate (NOD2/CARD15) or induced (smoking) origin in postoperative CD recurrence. Prophylactic strategies should aim to limit dysbiosis (antibiotics, side-to-side anastomoses) or prevent downstream chronic inflammatory sequelae (anti-inflammatory, immunosuppressive, and immunomodulatory therapy).
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Affiliation(s)
- Michael F Cunningham
- Surgical Professorial Unit, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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Mazor Y, Karban A, Nesher S, Weiss B, Leshinsky-Silver E, Levine A, Eliakim R. Granulomas in Crohn's disease: are newly discovered genetic variants involved? J Crohns Colitis 2010; 4:438-43. [PMID: 21122541 DOI: 10.1016/j.crohns.2010.02.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 01/25/2010] [Accepted: 02/19/2010] [Indexed: 12/23/2022]
Abstract
BACKGROUND Non-caseating granulomas exist in a substantial portion of patients with Crohn's disease (CD). Several single nucleotide polymorphisms (SNPs) have been identified as a having strong association with CD, including SNPs within the autophagy related 4 homolog A (ATG4A) gene and the neutrophil cytosolic factor 4 (NCF4) gene. We hypothesized a possible association between the presence of granulomas in CD patients and variants in the ATG4A and NCF4 genes. AIMS To investigate whether variants in the NCF4 and ATG4A genes are associated with granuloma formation in a cohort of Israeli patients with CD, exploring demographic and clinical characteristics that differ between granuloma positive and granuloma negative patients. METHODS 307 Israeli patients with CD were studied. Patients with CD who underwent biopsy or resection of the intestine were classified according to presence or absence of granulomas. Using PCR-RFLP we determined the allele frequency in SNP rs4821544 (NCF4 gene) and SNP rs807185 (ATG4A gene) for all patients. RESULTS Granulomas were found in 85 out of 307 CD patients (27%). There were no significant differences between patients with or without granulomas in allele frequency in SNPs rs4821544 and rs807185. CD Patients with granuloma were younger at diagnosis than patients without granuloma (mean age 19 vs. 27, respectively, P<0.0001) and were more likely to undergo surgery (55.3% vs. 34.8%, respectively, P=0.002). CONCLUSIONS No association was found between SNPs rs4821544 and rs807185 and the presence of granulomas in CD patients. Granuloma positive patients were more likely to be younger and to undergo surgery.
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Abstract
PURPOSE This study used meta-analytical techniques to compare the recurrence of granulomatous vs nongranulomatous Crohn disease. METHODS Comparative studies published between 1954 and 2007 of granulomatous vs nongranulomatous Crohn disease were included. Using a random effects model, end points evaluated were the number of recurrences and reoperations, and the time to recurrence and reoperation, of granulomatous vs nongranulomatous Crohn disease. Heterogeneity was assessed and sensitivity analysis was performed to account for bias in patient selection. RESULTS Twenty-one studies (14 nonrandomized retrospective, 7 nonrandomized prospective) reported on 2236 patients with Crohn disease, of whom 1050 (47.0%) had granulomas (granulomatous group) and 1186 (53.0%) had no granulomas (nongranulomatous group). The number of recurrences and reoperations was found to be significantly higher in the granulomatous group compared to the nongranulomatous group (odds ratio 1.37, P = .04; odds ratio 2.38, P < .001; respectively), with significant heterogeneity between studies (P = .06; P < .001; respectively). The time to recurrence and reoperation was significantly shorter in the granulomatous group compared with the nongranulomatous group (hazard ratio 1.63, P = .001; hazard ratio 1.62, P = .002; respectively), with no significant heterogeneity between studies. The number of recurrences and reoperations remained significantly higher in the granulomatous group compared to the nongranulomatous group during sensitivity analysis of higher-quality studies, more recent studies, and studies with a larger group of patients. CONCLUSIONS Granulomatous Crohn disease appears to be associated with a higher number of recurrences and reoperations and a shorter time to recurrence and reoperation compared to nongranulomatous Crohn disease. Because of significant heterogeneity between studies, further studies should be undertaken to confirm these findings.
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Ng SC, Lied GA, Kamm MA, Sandhu F, Guenther T, Arebi N. Predictive value and clinical significance of myenteric plexitis in Crohn's disease. Inflamm Bowel Dis 2009; 15:1499-507. [PMID: 19338051 DOI: 10.1002/ibd.20932] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Recurrence of Crohn's disease (CD) after ileal or colonic resection is common. Myenteric plexitis in the proximal resection margin of an ileocolonic CD resection specimen may indicate ongoing pathology that relates to disease recurrence. We assessed risk factors for myenteric plexitis, the effect of plexitis on clinical recurrence, and whether preoperative medical therapies affect the intensity of plexitis. METHODS Ileocolonic resection specimens from 99 patients with CD were histologically scored for the presence and severity of plexitis. Myenteric plexitis was correlated with immunosuppressive therapy before index surgery. Univariate and multivariate analyses were performed to identify predictive factors for plexitis. RESULTS Myenteric plexitis was present in 43% and 85% of cases in the proximal resection margin and the affected resected segments of CD, respectively. Patients with a previous resection were more likely to have plexitis than those with no previous resection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.21-10.15, P = 0.02), and those with a greater duration of disease were less likely to have plexitis in the proximal resection margin (OR 0.68, 95% CI 0.48-0.96, P = 0.03). Preoperative immunosuppressive therapy was not associated with a lesser incidence of plexitis. Twelve of 40 (30%) patients with plexitis and 9 of 54 (16%) patients without plexitis in the proximal resection margin subsequently developed clinical recurrence (median 10 months; P = 0.17). CONCLUSIONS Previous resections and shorter disease duration are associated with plexitis in proximal resection margin of CD. The prognostic value of plexitis in postoperative disease recurrence and risk stratification remain to be prospectively established.
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Affiliation(s)
- Siew C Ng
- Department of Gastroenterology, St Mark's Hospital, London, UK
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Rubio CA, Orrego A, Nesi G, Finkel Y. Frequency of epithelioid granulomas in colonoscopic biopsy specimens from paediatric and adult patients with Crohn's colitis. J Clin Pathol 2007; 60:1268-72. [PMID: 17293387 PMCID: PMC2095463 DOI: 10.1136/jcp.2006.045336] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2007] [Indexed: 12/28/2022]
Abstract
AIMS To test the assumption that epithelioid granulomas found in colonoscopic biopsy specimens in patients with Crohn's colitis are markers of a different clinical behaviour. METHODS Sections from colonoscopic biopsy specimens from 352 consecutive patients (119 children and 233 adults) were investigated. RESULTS A total of 1117 colonoscopies were performed: 293 in children (mean 2.46 per patient) and 824 in adults (mean 3.53 per patient) (p<0.05). Granulomas at initial colonoscopy were recorded in 67.2% (43/64) of children and 65.9% (27/41) of adults (p>0.6), and at subsequent colonoscopies in 53.8% (64/119) of children and 17.6% (41/233) of adults (p<0.05). Surgical intervention was required in 6.3% (4/64) of the children having previous granuloma, but also in 14.5% (8/55) of those without previous granuloma, the rate for operated adults being 26.8% (11/41) and 24.5% (47/192), respectively (p>0.6). CONCLUSIONS Granulomas in entry and/or in subsequent colonoscopic biopsy specimens in patients with Crohn's colitis did not predict the need for subsequent surgical intervention. The fact that the frequency of granulomas was significantly higher in children than in adults with Crohn's colitis (despite a higher mean number of colonoscopic biopsies in adults), and that granulomas were present in colonoscopic biopsy specimens but not in the subsequent surgical specimens from 50% of the paediatric and 36% of the adult patients strengthen the conviction that granulomas in Crohn's colitis might evolve or regress at different time intervals during the course of the disease. This behaviour would reflect a particular immunological reaction, an epiphenomenon from immature tissues-as in children-when challenged by the so far elusive aetiological agent responsible for Crohn's disease.
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Affiliation(s)
- C A Rubio
- Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
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Cullen G, O'toole A, Keegan D, Sheahan K, Hyland JM, O'donoghue DP. Long-term clinical results of ileocecal resection for Crohn's disease. Inflamm Bowel Dis 2007; 13:1369-73. [PMID: 17600379 DOI: 10.1002/ibd.20220] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The efficacy of biologic agents in Crohn's disease (CD) has led to proposals that they be introduced early in the disease (top-down treatment) with the aim of reducing corticosteroid dependency and surgical resection. However, the long-term use of biologic agents in limited CD may be difficult to justify. The aims were to assess outcomes for ileocecal resection in CD and evaluate its role in the current era. METHODS The study included 139 CD patients who underwent ileocecal resection between 1980 and 2000. Data were retrieved from a prospectively maintained database. Disease recurrence was defined as symptoms in addition to endoscopic or radiological evidence of disease activity. Severe disease recurrence was defined as a need for repeat resection surgery. RESULTS Seventy-two (52%) patients developed disease recurrence. Median (interquartile range) time to recurrence was 7.1 (5-10.6) years. Forty-nine (35%) patients required repeat resection surgery. Median (IQ range) time to repeat surgery was 7.2 (4.9-10.8) years. The presence of granulomas was associated with disease recurrence (P = 0.03) and repeat resection surgery (P = 0.01). CONCLUSIONS Long-term outcomes for ileocecal resection in CD are excellent with 48% of patients remaining symptom-free and only 35% requiring repeat resection surgery at 10 years. This should be borne in mind when considering biologic therapy.
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Affiliation(s)
- Garret Cullen
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland.
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Leong RWL, Lawrance IC, Chow DKL, To KF, Lau JY, Wu J, Leung WK, Chan FKL, Sung JJY. Association of intestinal granulomas with smoking, phenotype, and serology in Chinese patients with Crohn's disease. Am J Gastroenterol 2006; 101:1024-9. [PMID: 16573779 DOI: 10.1111/j.1572-0241.2006.00503.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Crohn's disease (CD) is a heterogenous disease characterized by variable manifestations and outcomes, and increasing in incidence in China. Phenotypic classification has been proposed to assist in subtyping of disease. Non-caseating intestinal granulomas are a hallmark of CD, but whether intestinal granulomas help predict Chinese CD phenotypes or determine severity, is not known. AIMS To determine the association between intestinal granulomas with CD phenotype, severity, risk factors, and serological markers. METHODS This was a single-centre study of consecutive definite Chinese CD cases. Granulomas were diagnosed by an experienced GI pathologist. Correlation with the Vienna Classification and other parameters was performed. RESULTS Eighty Chinese CD patients were recruited, 40 (50%) of whom had intestinal granulomas. Intestinal granulomas were independently associated with the stricturing behavior (OR: 4.71; 95% CI: 1.41-15.72), colonic location of disease (OR: 26.96; 95% CI: 2.68-271.14), but not with age of CD diagnosis. Current or previous smoking protected against the development of granulomas (OR: 0.16; 95% CI: 0.04-0.59). Granulomas were not associated with peri-anal involvement, extra-intestinal manifestations, anti-neutrophil cytoplasmic antibody or anti-Saccharomyces cerevisiae antibody serology, or severity of CD gauged by the requirement of major intestinal surgery or immunomodulating therapy. CONCLUSIONS Intestinal granulomas in the setting of CD may be helpful in determining phenotypic subtypes of CD, but is unhelpful in predicting disease severity. Smoking impairs the formation of granulomas in CD.
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Affiliation(s)
- Rupert W L Leong
- Faculty of Medicine, The University of New South Wales, Department of Gastroenterology, Bankstown-Lidcombe Hospital, Sydney, Australia
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Ferrante M, de Hertogh G, Hlavaty T, D'Haens G, Penninckx F, D'Hoore A, Vermeire S, Rutgeerts P, Geboes K, van Assche G. The value of myenteric plexitis to predict early postoperative Crohn's disease recurrence. Gastroenterology 2006; 130:1595-606. [PMID: 16697723 DOI: 10.1053/j.gastro.2006.02.025] [Citation(s) in RCA: 127] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2005] [Accepted: 02/01/2006] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Early ileocolonoscopy allows detection of recurrence after surgically induced remission of Crohn's disease (CD). Unequivocal histologic markers predicting recurrence have not been identified. We assessed the predictive value of neural lesions for early endoscopic CD recurrence and long-term reintervention risk. METHODS Ileocolonic resection specimens from 59 patients with CD and 21 control patients were histologically scored for typical inflammatory bowel disease lesions, neural hypertrophy, and presence and severity of inflamed ganglia and nerve bundles. Endoscopic recurrence was determined at 3 months in all patients and at 1 year in 32 patients as part of 2 prospective clinical trials. RESULTS Myenteric plexitis of the proximal resection margin was present in 32 patients with CD (54%) in absence of surrounding inflammation. Patients with this feature had a higher endoscopic recurrence (Rutgeerts score >/=2) at 3 months (75% vs 41%; odds ratio, 4.36; 95% confidence interval, 1.44-13.23; P = .008) and at 1 year (93% vs 59%; odds ratio, 9.80; 95% confidence interval, 1.04-92.70; P = .041) and had a trend toward an earlier reintervention (mean, 7.00 vs 5.30 years; P = .174). The severity of myenteric plexitis in the proximal resection margin correlated with the severity of endoscopic recurrence at 3 months (r = 0.334, P = .010) and 1 year (r = 0.560, P = .001). Myenteric plexitis was the only consistent predictor of endoscopic recurrence. CONCLUSIONS The presence of myenteric plexitis in proximal margins of ileocolonic resection specimens is predictive of early endoscopic CD recurrence.
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Affiliation(s)
- Marc Ferrante
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
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Anseline PF, Wlodarczyk J, Murugasut R. Presence of granulomas is associated with recurrence after surgery for Crohn's disease: Experience of a surgical unit. Br J Surg 2005. [DOI: 10.1046/j.1365-2168.1997.02483.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
Although in Crohn’s disease post-operative recurrence is common, the determinants of disease recurrence remain speculative. The aim of this study was to examine factors affecting post-operative recurrence of Crohn’s disease. A Medline-based literature review was carried out. The following factors were investigated: age at onset of disease, sex, family history of Crohn’s disease, smoking, duration of Crohn’s disease before surgery, prophylactic medical treatment (corticosteroids, 5-amino salicylic acid [5-ASA] and immunosuppressants), anatomical site of involvement, indication for surgery (perforating or non-perforating disease), length of resected bowel, anast-omotic technique, presence of granuloma in the specimen, involvement of disease at the resection margin, blood transfusions and post-operative complications. Smoking significantly increases the risk of recurrence (risk is approximately twice as high), especially in women and heavy smokers. Quitting smoking reduces the post-operative recurrence rate. A number of studies have shown a higher risk when the duration of the disease before surgery was short. There were, however, different definitions of ‘short’ among the studies. Prophylactic cortic-osteroids therapy is not effective in reducing the post-operative recurrence. A number of randomized controlled trials offered evidence of the efficacy of 5-ASA (mesalazine) in reducing post-operative recurrence. Recently, the thera-peutic efficacy of immunosuppressive drugs (azathioprine and 6-mercaptopurine) in the prevention of post-operative recurrence has been investigated and several studies have reported that these drugs might help prevent the recurrence. Further clinical trials would be necessary to evaluate the prophylactic efficacy of immunosuppressants. Several studies showed a higher recurrence rate in patients with perforating disease than in those with non-perforating disease. However, evidence for differing recurrence rates in perforating and non-perforating diseases is inconclusive. A number of retrospective studies reported that a stapled functional end-to-end anastomosis was associated with a lower recurrence rate compared with other types of anastomosis. However, prospective randomized studies would be necessary to draw a definite conclusion. Many studies found no difference in the recurrence rates between patients with radical resection and non-radical resection. Therefore, minimal surgery including strictureplasty has been justified in the management of Crohn’s disease. In this review, the following factors do not seem to be predictive of post-operative recurrence: age at onset of disease, sex, family history of Crohn’s disease, anatomical site of disease, length of resected bowel, presence of granuloma in the specimen, blood transfusions and post-operative complications. The most significant factor affecting post-operative recurrence of Crohn’s disease is smoking. Smoking significantly increases the risk of recurrence. A short disease duration before surgery seems, albeit to a very minor degree, to be associated with a higher recurrence rate. 5-ASA has been shown with some degree of confidence to lead to a lower recurrence rate. The prophylactic efficacy of immunosuppressive drugs should be assessed in future. A wider anastomotic technique after resection may reduce the post-operative recurrence rate, though this should be investigated with prospective randomized controlled trials.
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Affiliation(s)
- Takayuki Yamamoto
- Inflammatory Bowel Disease Center and Department of Surgery, Yokkaichi Social Insurance Hospital, 10-8 Hazuyamacho, Yokkaichi, Mie 510-0016, Japan.
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Abstract
AIM: Granuloma is considered the hallmark of microscopic diagnosis in Crohn’s disease (CD), but granulomas can be detected in only 21-60% of CD patients. The aim of this study was to evaluate the frequency of granulomas by multiple endoscopic biopsies in patients with CD and to examine whether group of patients with or without granuloma exhibit a different clinical course.
METHODS: Fifty-six patients with newly diagnosed CD were included in the study. Jejunoscopy, enteroclysis and ileo-colonoscopy were performed in all patients. At least two biopsy specimens from each examined gastrointestinal segment were examined microscopically searching granuloma. The clinical course was followed in all patients, and extraintestinal manifestations as well as details of any immunosuppressive therapy and surgical intervention were noted.
RESULTS: Granuloma was found in 44.6% of the cases (25 patients). Patients with granuloma had higher activity parameters at the time of the biopsies. Extraintestinal manifestations were observed and surgical interventions were performed more often in the granuloma group. The need of immunosuppressive therapy was significantly more frequent in the patients with granuloma. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease.
CONCLUSION: The significantly higher frequency of surgical interventions and immunosuppressive therapy suggests that granuloma formation is associated with a more severe disease course during the first years of CD.
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Affiliation(s)
- Tamas Molnár
- First Department of Medicine, Faculty of Medicine, University of Szeged, H-6720 Szeged, Korányi fasor 8., Hungary.
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Heresbach D, Alexandre JL, Branger B, Bretagne JF, Cruchant E, Dabadie A, Dartois-Hoguin M, Girardot PM, Jouanolle H, Kerneis J, Le Verger JC, Louvain V, Politis J, Richecoeur M, Robaszkiewicz M, Seyrig JA. Frequency and significance of granulomas in a cohort of incident cases of Crohn's disease. Gut 2005; 54:215-22. [PMID: 15647184 PMCID: PMC1774855 DOI: 10.1136/gut.2004.041715] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Epithelioid granulomas is one of the best histological criterion for distinguishing Crohn's disease (CD) from other inflammatory bowel diseases. Few data are available on the time of occurrence of epithelioid granulomas, and the value of epithelioid granulomas in predicting outcome has been determined only in cohorts of prevalent CD cases. Our objective was to evaluate epithelioid granuloma occurrence in incident CD cases and to examine the associations between epithelioid granulomas and outcome. PATIENTS AND METHODS We reviewed the histological reports of endoscopic and surgical specimens in a cohort of 188 consecutive incident CD cases seen in 1994 and 1995, and recorded the occurrence of epithelioid granulomas, isolated giant cells, and microgranulomas. Kaplan-Meier curves were plotted for time from CD diagnosis to immunosuppressive treatment or surgery, and associations between epithelioid granulomas and outcome were evaluated in a multivariate analysis. Follow up was at least five years. RESULTS Granulomas were found in 69 (37%) patients, including 46 (25%) at presentation. Median time from CD diagnosis to epithelioid granuloma detection was 0.16 (0-63) months overall, and 9.59 (0.1-63) months in 23 patients who became epithelioid granuloma positive during follow up. Isolated giant cells were found in 6% of patients and microgranulomas in 12%. Epithelioid granuloma detection increased with the number of endoscopic sampling procedures; sampling site had no influence. By multivariate analysis, epithelioid granulomas were associated with surgical resection but not immunosuppressive therapy. CONCLUSIONS Epithelioid granulomas may separate CD into two pathological subsets and may indicate aggressive disease.
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Affiliation(s)
- D Heresbach
- ABERMAD, Pontchaillou Teaching Hospital, 35033-Rennes Cedex, France.
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Abstract
Crohn's disease (CD) is diagnosed from information obtained clinically, pathologically, and radiologically. One important pathologic finding is a granuloma, which is helpful when a positive diagnosis of CD will affect treatment. Whether the presence of a granuloma has any clinical implication is not clear. We conducted a retrospective study to determine whether a granuloma found on a biopsy sample is associated with disease severity, fistulizing or perianal disease, frequent relapses, and extraintestinal manifestations. Eighty-two patients were identified who had a biopsy or bowel resection for CD between 1990 and 1994 at a tertiary referral center; 21 (25.6%) had a granuloma. This group was compared with a group of 61 patients without a granuloma. Forty-five percent were male (n = 37), mean age at diagnosis was 42.6 years (median, 39.5 years), mean disease duration at presentation was 8.8 years (median, 4.8 years), and mean follow-up duration was 2 years (range, 1 day to 10.2 years). No significant differences were demonstrated between the two groups by the Fisher exact test with regard to fistulizing or perianal disease, oral aphthous ulcers, disease severity, axial or peripheral arthralgia, episcleritis, anterior uveitis, erythema nodosum, or pyoderma gangrenosum.
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Affiliation(s)
- Nizar N Ramzan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona 85259, USA
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32
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Abstract
PURPOSE Previous studies on recurrence and reoperation after colectomy in Crohn's colitis have been based on heterogeneous groups of patients, and divergent findings may be explained by referral biases and small numbers of patients. The aim of this study was to account for recurrence rates, present risk factors for recurrence after primary colectomy, and account for the ultimate risk of having a stoma after colectomy with ileorectal anastomosis in patients with Crohn's colitis. METHODS Data on the primary resection, postoperative recurrence, influence of concomitant risk factors, frequency of stoma operations and proctectomy were evaluated retrospectively using multivariate analysis in a population-based cohort of 833 patients with Crohn's colitis. RESULTS The cumulative 10-year risk of a symptomatic recurrence was 58 percent (95 percent confidence interval, 53-63 percent) and 47 percent (95 percent confidence interval, 42-52 percent), respectively, after colectomy with ileorectal anastomosis and segmental colonic resection. In colectomy with ileostomy, lower rates were found with respectively 24 percent (95 percent confidence interval, 18-30 percent) and 37 percent (95 percent confidence interval, 32-43 percent) after subtotal colectomy and proctocolectomy with ileostomy. The multivariate analysis showed that perianal disease, ileorectal anastomosis, and segmental resection were independent risk factors for postoperative recurrence. In 76 percent of patients with ileorectal anastomosis, a stoma-free function could be retained during a median follow-up of 12.5 years. CONCLUSION Colectomy with ileorectal anastomosis or segmental resection is a feasible option in the surgical treatment of Crohn's colitis, although anastomoses, in addition to perianal disease, carry an increased risk of recurrent disease.
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Affiliation(s)
- O Bernell
- Departments of Surgery and Gastroenterology, Huddinge University Hospital, Sweden
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Bernell O, Lapidus A, Hellers G. Risk factors for surgery and recurrence in 907 patients with primary ileocaecal Crohn's disease. Br J Surg 2000; 87:1697-701. [PMID: 11122187 DOI: 10.1046/j.1365-2168.2000.01589.x] [Citation(s) in RCA: 248] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Previous studies on risk factors for resection and postoperative recurrence in Crohn's disease have given inconclusive results. The aim of this study was to assess the risk for resection and postoperative recurrence in the treatment of ileocaecal Crohn's disease and to define factors affecting the course of the disease. METHODS A population-based cohort of 907 patients with primary ileocaecal Crohn's disease was reviewed retrospectively. RESULTS Resection rates were 61, 77 and 83 per cent at 1, 5 and 10 years respectively after the diagnosis. Relapse rates were 28 and 36 per cent 5 and 10 years after the first resection. A younger age at diagnosis resulted in a low resection rate. The presence of perianal Crohn's disease and long resection segments increased the incidence of recurrence, and resection for a palpable mass and/or abscess decreased the recurrence rate. A decrease in recurrence rate during the study period (1955-1989) was observed. CONCLUSION In ileocaecal Crohn's disease the probability of resection is high and the risk of recurrence moderate. Crohn's disease in childhood carries a lower risk of primary resection. Perianal disease and extensive ileal resection increase the risk of recurrence.
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Affiliation(s)
- O Bernell
- Departments of Surgery and Gastroenterology, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden
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Jeshion WC, Larsen KL, Jawad AF, Piccoli DA, Verma R, Maller ES, Baldassano RN. Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease in children. J Clin Gastroenterol 2000; 30:294-8. [PMID: 10777191 DOI: 10.1097/00004836-200004000-00018] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this study was to evaluate whether these drugs healed pediatric perianal Crohn's disease. Records of pediatric Crohn's patients were retrospectively reviewed for significant perianal disease treated with AZA or 6-MP for > or =6 months. The patient's perianal disease was reviewed and evaluated for fistulas, drainage, induration, and tenderness. In addition, the patients were given a score using the Irvine Perianal Disease Activity Index (PDAI). Patients were retrospectively scored upon initiation of treatment and after six months of therapy. Possible scores ranged from 0-20. Twenty patients met the study criteria. Five patients were considered treatment failures. One patient required a colostomy after 1.5 months of therapy, one developed pancreatitis, and three were noncompliant with therapy. Of the remaining 15 patients who were treated for > or =6 months, 67% had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in fistula closure. The mean Irvine PDAI was 7.67 +/- 2.19 initially and 4.40 +/- 1.72 after six months of therapy. The improvement was statistically significant (p < 0.001). AZA and 6-MP are effective treatments for healing significant perianal Crohn's disease in pediatrics.
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Affiliation(s)
- W C Jeshion
- Division of Gastroenterology and Nutrition, Children Hospital of Philadelphia, Pennsylvania 19104, USA
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Anseline PF, Wlodarczyk J, Murugasu R. Presence of granulomas is associated with recurrence after surgery for Crohn's disease: experience of a surgical unit. Br J Surg 1997. [PMID: 9043461 DOI: 10.1002/bjs.1800840129] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The determinants for recurrence of Crohn's disease remain controversial. Eight factors that might predict recurrence were studied in 130 patients operated on for Crohn's disease over a 24-year period. METHODS Separate survival curves were estimated for each variable. A multivariate analysis was then carried out in which several selected explanatory variables were included simultaneously in a proportional hazards regression model. RESULTS Operation for recurrent disease was necessary in 36 patients. Univariate analysis revealed a highly significant relationship between the presence of granulomas and subsequent recurrence (P = 0.003). There was a trend towards increased recurrence in patients with ileocolonic disease and segmental colectomy (P = 0.11 and P = 0.1 respectively). Age, sex, length of history, indication for operation and affected lines of transection were not associated with recurrence. After multivariate analysis, the association of granulomas with recurrence remained significant (P = 0.03). This association persisted when death was regarded as a treatment failure (P = 0.02). CONCLUSION The presence of granulomas in patients with Crohn's disease is significantly associated with recurrence.
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Affiliation(s)
- P F Anseline
- Department of Surgery, Royal Newcastle Hospital, University of Newcastle, New South Wales, Australia
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Longo WE, Oakley JR, Lavery IC, Church JM, Fazio VW. Outcome of ileorectal anastomosis for Crohn's colitis. Dis Colon Rectum 1992; 35:1066-71. [PMID: 1425051 DOI: 10.1007/bf02252997] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
One hundred thirty-one patients underwent ileorectal anastomosis (IRA) for Crohn's colitis. Preoperatively, 84 patients (63 percent) were found to have mild or moderate proctitis and 47 (37 percent) had rectal sparing. Sixty-eight (52 percent) had associated small bowel disease, and 20 (15 percent) had perianal disease. Sixty-five IRAs were performed at the time of subtotal colectomy, while 56 were done after previous surgery. Anastomotic leaks occurred in four patients. There were no operative deaths. Thirteen patients (10 percent) with protecting stomas never underwent closure. Among the remaining 118 patients with functioning IRAs, 30 (23 percent) required later proctectomy and 16 (13 percent) required proximal diversion, with the mean period with a functioning IRA in these 46 patients being 4.1 years (range, 6.2 months-12.7 years). An additional 13 patients required preanastomotic resection and neo-IRA, and 11 required proximal small bowel resection. The mean duration of function of all 118 IRAs was 9.2 years. At the time of review, after a mean follow-up of 9.5 years, 72 patients (61 percent) retained a functioning IRA, with 44 being free of disease, while 28 were being treated with steroids or antidiarrheal medication. The mean stool frequency was 4.7 per day. In patients with Crohn's colitis, IRA should be considered as an alternative to proctocolectomy if the rectum is not severely diseased and sphincter function is not compromised.
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Affiliation(s)
- W E Longo
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Ohio 44195-5044
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Williams JG, Wong WD, Rothenberger DA, Goldberg SM. Recurrence of Crohn's disease after resection. Br J Surg 1991; 78:10-9. [PMID: 1998847 DOI: 10.1002/bjs.1800780106] [Citation(s) in RCA: 117] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Recurrent Crohn's disease develops in most patients after surgical resection if the patient is followed for sufficient time. This review examines various aspects of recurrent Crohn's disease. It is concluded that Crohn's disease is a diffuse condition of the gastrointestinal tract and that radical resection of Crohn's disease does not prevent recurrence. Assorted factors thought to be associated with recurrence are examined and the relevance of these factors to the surgeon treating Crohn's disease is discussed.
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Affiliation(s)
- J G Williams
- Division of Colon and Rectal Surgery, University of Minnesota, Minneapolis 55455
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39
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Ritchie JK. The results of surgery for large bowel Crohn's disease. Ann R Coll Surg Engl 1990; 72:155-7. [PMID: 2357033 PMCID: PMC2499178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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40
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Kuramoto S, Oohara T, Ihara O, Shimazu R, Kondo Y. Granulomas of the gut in Crohn's disease. A step sectioning study. Dis Colon Rectum 1987; 30:6-11. [PMID: 3803110 DOI: 10.1007/bf02556910] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
To investigate the distribution of granulomas in Crohn's disease, a step sectioning study of the surgically resected intestines was carried out. This study proved that granulomas in Crohn's disease are found in the seemingly uninvolved intestinal mucosa as well as in the affected mucosa. Granulomas in the apparently involved mucosa were close to the mucosal surface (less than 500 microns) and small (80 to 160 microns across), while in the affected mucosa they were farther away from the mucosal surface (more than 500 microns) and larger (more than 160 microns across). We emphasize that these small granulomas, namely microgranulomas, in the apparently uninvolved intestinal mucosa, are of great value in diagnosing Crohn's disease.
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Chardavoyne R, Flint GW, Pollack S, Wise L. Factors affecting recurrence following resection for Crohn's disease. Dis Colon Rectum 1986; 29:495-502. [PMID: 3731965 DOI: 10.1007/bf02562601] [Citation(s) in RCA: 122] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The records of 187 patients with Crohn's disease who underwent resectional surgery were analyzed to evaluate the effect of several clinical and histologic features on the recurrence rate. Recurrence was defined as the need for re-resection. The data were analyzed by the life-table method. Age, sex, age at onset of disease and at time of resection, family history, presence of granuloma, and microscopic involvement at the line of resection did not affect the recurrence rate. The distribution of the disease and duration of symptoms before primary resection did influence the rate of re-resection. Patients with predominantly large bowel disease (N = 56) were found to have a higher rate of re-resection (45 percent) when compared with 32 percent in patients with small bowel involvement (N = 94) and with 35 percent in patients with both small and large bowel involvement (N = 37) (P = 0.04). A detailed review, an analysis of the literature, and a comparison with our results are made.
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Geboes K, van den Oord J, De Wolf-Peeters C, Desmet V, Rutgeerts P, Janssens J, Vantrappen G, Penninckx F, Kerremans R. The cellular composition of granulomas in mesenteric lymph nodes from patients with Crohn's disease. VIRCHOWS ARCHIV. A, PATHOLOGICAL ANATOMY AND HISTOPATHOLOGY 1986; 409:679-92. [PMID: 3092463 DOI: 10.1007/bf00713433] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The immunohistochemical findings in granulomatous lymphadenitis in patients with Crohn's disease are presented and compared with conventional light microscopic findings. The cellular composition of the granulomas in mesenteric lymph nodes was examined with a broad panel of monoclonal and polyclonal antibodies directed to B-cells, T-cells, monocytes/macrophages, dendritic reticulum cells, HLA-DR antigens and the transferrin receptor. The centre of the granulomas contains OKIa+, OKM1+, OKT9+, DRC-, To5- epithelioid cells and giant cells and OKT3+ lymphocytes. In general, the majority of the small lymphocytes within the granulomas expresses the OKT3+, OKT4+ Leu 3a+ phenotype which points toward T-helper cells. Fewer OKT3+ OKT8+ T suppressor/cytotoxic cells are observed. At the periphery of the granulomas a lymphocytic corona composed of BA1+, B1+ B lymphocytes may be present. From these findings it can be concluded that the granulomas in mesenteric lymph nodes from patients with Crohn's disease are composed of centrally located T-lymphocytes and of epithelioid cells which are of monocyte/macrophage origin and have the characteristics of antigen-presenting cells.
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Rutgeerts P, Geboes K, Vantrappen G, Kerremans R, Coenegrachts JL, Coremans G. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery. Gut 1984; 25:665-72. [PMID: 6735250 PMCID: PMC1432363 DOI: 10.1136/gut.25.6.665] [Citation(s) in RCA: 565] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
An endoscopical and histological study was carried out in 114 patients, treated by 'curative' resection of the terminal ileum and part of the colon for Crohn's disease, in order to study the natural history of recurrent Crohn's disease. The recurrence rate of Crohn's disease in patients examined within one year of the operation was 72%. This figure did not differ significantly from that in patients examined one to three years or three to 10 years after surgery (79% and 77% respectively). Recurrence was located in the neoterminal ileum and at the anastomosis in 88% of the patients. Early endoscopic signs of recurrence were small aphthous ulcers in the neoterminal ileum. Ileal biopsies at this stage showed an important inflammatory cell infiltrate of the lamina propria with numerous eosinophils and fusion and blunting of the villi. More advanced lesions observed in patients examined one to three years after surgery, consisted of larger, often serpiginous ulcerations and nodular thickening of folds. In patients examined three to 10 years after the operation, the anastomosis was frequently stenosed and rigid, with large ulcers extending from the stenosis into the colon. Mucosal granulomas may be found in normal appearing mucosa as well as in the obviously inflamed mucosa surrounding the ulcers. These studies suggest that recurrence of Crohn's disease almost always develops in the first year after the operation. Significant endoscopic lesions may be present without clinical symptoms, particularly in the earlier stages of the disease.
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Shorter RG. Idiopathic Inflammation Bowel Disease: is there a role for immunological mechanisms in etiopathogenesis? GASTROENTEROLOGIA JAPONICA 1982; 17:476-88. [PMID: 6757043 DOI: 10.1007/bf02774726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Trnka YM, Glotzer DJ, Kasdon EJ, Goldman H, Steer ML, Goldman LD. The long-term outcome of restorative operation in Crohn's disease: influence of location, prognostic factors and surgical guidelines. Ann Surg 1982; 196:345-55. [PMID: 7114939 PMCID: PMC1352614 DOI: 10.1097/00000658-198209000-00014] [Citation(s) in RCA: 76] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The course of all 113 patients with Crohn's disease whose initial procedure involved an anastomosis operated upon from 1942 to 1972 was followed through 1980. The calculated cumulative 30-year total mortality was 23.4%, 16.7% disease-related. The cumulative recurrence rate was 29% at five years, 52% at ten years, 64% at 15 years and 84% at 25 years, with no important differences between disease locations and types of operation. Sex, age, duration, granulomas, enteral or perirectal fistulas and length of the resection, the disease, and the proximal resection margin had no significant influence on the rates of development of recurrent disease or on functional outcome. By far the most common site of recurrence was the neo-terminal ileum, but in ileocolitis compared with ileitis, recurrence was 5.2 times more likely (p = 0.0001) to involve the adjacent or remote colon as well. Moreover, only 1/63 ileitis patients eventually required ileostomy, whereas 15/47 patients with ileocolitis or colitis ultimately required this procedure (p less than 0.001). The current status of the patients was excellent or good in 64% and unwell or dead related in 24%. Urolithiasis developed in 19%.
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Abstract
In a retrospective survey, patients with Crohn's disease who were HLA B8 were found to have significantly fewer granulomas in rectal biopsies (p less than 0.002) and in resected bowel specimens (p less than 0.02) than non-HLA B8 patients. No statistically significant difference was found between HLA B12 and non-B12 patients. This in vivo evidence of differing immune response capabilities between HLA B8 and non-HLA B8 individuals is compatible with previously reported in vitro studies. Despite these differences, the clinical manifestations and disease course of the two groups of patients was similar, suggesting that neither the presence of HLA B8 nor the development of granuloma directly influence the course of Crohn's disease.
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Auer IO, Ziemer E. Immune status in Crohn's disease. 4. In vitro antibody dependent cell mediated cytotoxicity in peripheral blood. KLINISCHE WOCHENSCHRIFT 1980; 58:779-87. [PMID: 7442085 DOI: 10.1007/bf01478286] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In Crohn's disease (CD) a potential etiopathogenetic role of the antibody dependent cell mediated cytotoxicity (ADCC) has been discussed. By means of a 51Cr release assay with an established human lymphoblastoid cell line as target, the in vitro ADCC activity was studied in the peripheral blood of 34 patients with CD. 11 patients with inflammatory bowel disease other than CD or ulcerative colitis (group D) and 45 sex and age matched healthy people served as controls. In unseparated mononuclear cell suspensions, we found a significantly lower ADCC activity in CD patients and in group D than in normals. Depletion of both phagocytic and plastic adherent cells, i.e. macrophages, resulted in complete normalisation of the ADCC activity in all patients of group D and also two-thirds of the CD patients. However, the remaining one third CD patients still exhibited ADCC activity below 1 standard deviation of normal. Most of these latter CD patients had highly active disease. Thus, this study showes that the general ADCC per se is normal in CD, except for a decrease in patients with high activity of disease. However, the normal general ADCC activity per se is significantly suppressed by phagocytic, plastic adherent cells. In this regard similar results were found in group D.
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Abstract
Analysis of peripheral blood lymphocytes from 44 patients with Crohn's disease showed no difference in the proportions of T- and B-cells from those in 38 healthy controls. Analysis revealed no disturbances in relation to duration or to activity of disease or to drug treatment. Lymphocytes from 18 patients with rheumatoid arthritis also showed normal proportions of T- and B-cells. Lymphocytes taken from gut lymph nodes were studied in five patients with Crohn's disease. On comparison with peripheral blood lymphocytes, significantly decreased proportions of T-cells and significantly increased proportions of B-cells were found in lymph nodes draining areas of diseased bowel. No differences were seen in the proportions of T- and B-cells from lymph nodes taken from apparently healthy bowel of the Crohn's patients and of four control subjects without inflammatory bowel disease, though these were different from those in the peripheral blood in both the Crohn's patients and control subjects.
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