Histological Healing in Inflammatory Bowel Disease: Comparison
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Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Alina Ecaterina Jucan.

Inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn’s disease and ulcerative colitis. In long-standing ulcerative colitis disease activity, histological persistent inflammation has been linked to an increased risk of relapse, and long-term corticosteroid use, even when endoscopic remission is reached. In Crohn’s disease, the discontinuous nature of lesions and transmural inflammation have limited the standardized histological assessment. The current evidence from research proposes that besides clinical and endoscopic healing, the achievement of histological healing constitutes an endpoint to assess disease activity and remission in IBD patients concerning better long-term disease outcomes. Histological alterations may persist even in the absence of endoscopic lesions. For these reasons, new advanced techniques promise to revolutionize the field of IBD by improving the endoscopic and histologic assessment, disease characterization, and ultimately patient care, with an established role in daily practice for objective assessment of lesions. 

  • Crohn’s disease
  • histological healing
  • inflammatory bowel disease

1. Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of chronic inflammatory bowel disease (IBD) characterized by an idiopathic inflammatory disorder affecting the gastrointestinal tract. The etiology and pathogenesis of IBD are still unclear. The most common triggers are dysregulated immune response to the commensal gut flora and host genetic and environmental factors [1].
Recent research suggests that in addition to endoscopic healing, the achievement of histological healing (HH) is associated with better long-term outcomes and could represent a potential main goal in managing IBD. The idea of using histological healing as an endpoint to assess disease activity and remission in IBD patients started with the demonstration that treatment with 5-aminosalicylic acid (5-ASA), corticosteroids, immunomodulators, and then biological agents could induce symptomatic relief and also endoscopic and histologic remission [2]. In patients with UC, it has been shown that microscopic activity, even when endoscopic remission is achieved, is an independent risk factor associated with an increased risk of relapses, long-term corticosteroid use, and complications, suggesting the hypothesis that HH could represent a potential therapeutic target [3]. The focus on CD histology has increased recently, but data are still inconsistent and conflicting. The assessment of HH has several limitations due to the discontinuous nature of lesions. However, recent international consensuses have considered that achieving histological remission is an appropriate and realistic goal in both UC and CD clinical trials [4].
Recently, the concept of “disease clearance” has been proposed and described as a profound and complete state of disease remission, comprising symptomatic remission and a “true” mucosal healing state (clinical, endoscopic, and microscopic remission) [5]. However, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE II consensus) working group does not yet recommend HH as a treatment target and very few available clinical trials have assessed histological findings among primary outcomes [6], with it quite frequently being specified as an additional exploratory result. Instead, STRIDE-II certifies that the most feasible long-term targets for IBD patients are clinical remission, endoscopic healing, restoration of QoL (quality of life), and absence of disability [7].

2. Histological Healing—Current Concept and Clinical Relevance

Researchers searched the published literature by exploring the PubMed, GoogleScholar, EMBASE, and MEDLINE databases utilizing the following keywords: “inflammatory bowel disease”, “IBD”, “ulcerative colitis”, “Crohn’s disease”, “guidelines”, “histological healing”, “surrogate markers”, “diagnostic tools”, and “disease clearance”, in all possible combinations. Researchers extracted information on diagnosis and management and summarized the current knowledge related to the latest challenges in IBD to promote further research that may improve understanding and help develop clinical practice guidelines for better disease progression and control.
Different authors have defined HH as a mucosa with few architectural abnormalities but normally differentiated epithelial cells and no signs of active inflammation or an increased density of lymphocytes and plasma cells [8]. The European Crohn’s and Colitis Organisation (ECCO) guidelines defined HH as a resolution of crypt architectural distortion and inflammatory infiltrate defined by the absence of intraepithelial neutrophils, erosions, and ulceration as the minimum standard to classify a patient as having achieved histological remission of the bowel mucosa [9]. Therefore, a simplified definition of HH can be described as the microscopic normalization of mucosal biopsies defined by the absence of acute inflammation. Furthermore, in the STRIDE-II committee, HH in UC and transmural healing in CD are considered measures of remission depth and not therapeutic goals [7,10][7][10]. However, the STRIDE guidelines’ recommendations focused on daily practice, not clinical trials.
Given the concept that the resolution of intestinal inflammation beyond endoscopic healing could provide clinically relevant advantages or major contributions to patient care, there is increasing interest in assessing histological disease activity. Clinical signs and symptoms combined with endoscopic examination are traditionally used to monitor and assess disease activity status in IBD [11]. HH is achievable in many UC patients and is associated with better disease outcomes than clinical remission and/or endoscopic healing, as revealed by several studies [12]. Evidence indicated that histological remission represents a different target from endoscopic mucosal healing in UC and is associated with lower relapse rates, reduced risk of developing colorectal cancer, and need for surgery or hospitalizations [13,14,15,16,17][13][14][15][16][17]. Also, the role of histology as a predictive factor has been explored in several trials in CD [18]. While in UC patients, histological activity is a stronger predictor of clinical relapse, the role of histological assessment in CD has been explored less. From the registered evidence on CD assessment for patients in clinical remission, HH was associated with a lower risk of relapse or hospitalization, improved clinical outcomes, and decreased need for medication escalation or corticosteroid use [19]. As a particularity, in CD a new target and relevant element of healing is transmural healing, assessed by cross-sectional imaging techniques (ultrasound, contrast-enhanced computed tomography, and magnetic resonance enterography) [20]. Table 1 presents a summary of the studies analyzing the association between histological activity disease and clinical relapse.
Table 1. The association between histological activity and the risk of clinical relapse. A p-value < 0.05 is considered statistically significant; CR—clinical relapse; OR—odds ratio; CI—confidence interval; NQHA—normal or quiescent histological activity; CHA—chronic histological activity; AHA—acute histological activity; NHI—Nancy histopathological index; HR—hazard ratio.
Study Type of Study Disease N Patients Endoscopic Activity Histological Index Outcome
Park et al. [21] Systematic review and meta-analysis UC 1360 patients Endoscopic remission Truelove and Richards index; Riley index; Geboes score.

Histological remission- present in 964 patients (71%).		 52% relative risk reduction in relapse/exacerbation for UC patients with histologic remission compared to histologic activity.
Narang et al. [22] Prospective observational study UC 76 patients in clinical remission for at least 6 months.

46 patients with endoscopic remission included (Mayo score ≤ 1; 46/76, 60.5%), 1 year of follow-up.		 Endoscopic remission Geboes score;

Histological remission in 67.3% (31/46) of patients, while 32.7% (15/46) with histologically active disease.		 87.1% (27/31) of patients with histological remission remained asymptomatic, while 12.9% (4/31) had relapsed. Among histologically active patients, 46.6% (7/15) sustained clinical remission, while 53.3% (8/15) had relapsed.

(87.1% vs. 46.6%, p = 0.006).
Ozaki et al. [23] Prospective study UC 194 patients,

20 months of follow-up.		 Endoscopic remission NHI was significantly higher in MES 1 than in MES 0 [1.11 ± 0.09 vs. 0.41 ± 0.07, p < 0.0001]. 67 patients relapsed during the follow-up period;

risk of relapse (HR- 2.18 [1.16–5.82]; p = 0.03).
Bryant et al. [24] Prospective study UC 91 patients,

6 years of follow-up.		 Endoscopic remission 24% of patients had persistent inflammation. Histological remission predicted lower rates of corticosteroid use and acute severe colitis requiring hospitalization during follow-up (HR 0.42 (0.2 to 0.9), p = 0.02; HR 0.21 (0.1 to 0.7), p = 0.02, respectively).
Bessissow et al. [25] Cohort study UC 75 patients,

12 months of follow-up		 Endoscopic remission Geboes score ≥3.1 in 40% and basal plasmacytosis in 21% of patients. The presence of basal plasmacytosis, predictive of CR; OR = 5.13 (95% CI: 1.32–19.99), p = 0.019.
Calafat et al. [26] Retrospective observational study UC 113 patients underwent dysplasia surveillance colonoscopy between January 2005 and October 2015; follow-up of 12 months was included.

The median time of follow-up—2.5 years.		 Endoscopic remission 62 patients (57%) presented NQHA, 33 (30%) presented CHA, and 22 (20%) presented AHA. Basal plasmacytosis- present in 9 patients (8%), six of them in association with AHA (5%). 9 patients (8%) relapsed within the first year of follow-up and 37 patients (33%) relapsed during the whole follow-up period.

The presence of AHA is a risk factor for clinical relapse.
Christensen et al. [27] Retrospective study CD 101 patients,

follow-up for a median of 21 months.		 63% of patients with endoscopic remission. 55% of patients achieved histologic remission. CR occurred in 42% (n = 42) of patients

Histologic healing was associated with a decreased risk of CR (HR- 2.05; 95% CI, 1.07–3.94; p = 0.031).
Brennan et al. [28] Retrospective cohort study CD 62 patients,

follow-up for at least 6 months.

A total of 103 patients with CD underwent elective colonoscopies during clinical remission.		 55 patients (53%) in endoscopic healing,

48 patients (47%) with active disease.		 A semiqualitative score (0 to 3) was assigned for the histologic characteristics in each of the biopsy samples. At 12 months, the rate of relapse was 25.5% in patients with histologic activity, compared with only 2.4% of

patients without histologic activity at baseline.

The presence of histological activity was associated with higher flare rates (p < 0.05).
In long-standing disease, the persistence of histological inflammation can lead to other complications, such as dysplasia, strictures, fissures and fistulous tracts, perianal manifestations, intermural- or abdominal abscesses, and atrophic mucosal surface. In UC, inflammatory pseudo-polyps may develop as a result of extensive ulcered areas with sparing fields of residual normal mucosa. In CD, ulcerated areas can fuse, and inflammation in the intestines can result in a thickening of the intestinal wall, leading to massed and profound linear ulcers with prominent mucosal edges appearing as patches of cobblestones. Spontaneous bowel perforations to the abdominal cavity are a potentially devastating complication of fissures or fistulas resulting from superimposed ischemia or infection [8]. The risk of colorectal carcinoma in IBD patients is influenced by the chronicity of inflammation during multiple surveillance episodes. A recent meta-analysis conducted by Flores et al. showed that the risk of developing colorectal carcinoma was higher in patients with microscopic activity compared to patients with endoscopic mucosal healing (OR = 2.6 (95% CI, 1.5–4.5; p = 0.01)) [29]. Thus, persistent histologic activity is an independent risk factor for developing colorectal carcinoma, and these patients should be considered more frequently at surveillance intervals. Figure 1 reflects the classical features of the long-standing inflammatory activity of UC and CD diseases represented by gross pathology and microscopic changes.
Figure 1. Macroscopic and microscopic changes after a long-standing activity of ulcerative colitis and Crohn’s disease; the histological features that define chronicity are crypt architectural distortion, crypt atrophy, non-necrotizing granulomas, basal plasmacytosis, basally located lymphoid aggregates, and Paneth cell metaplasia; the presence of neutrophils defines inflammatory activity.
Current drugs and their effect on intestinal inflammation struggle to achieve even endoscopic mucosal healing, which is an earlier target and usually easier to achieve than histological healing. As mentioned above, because patients with histologic persistent inflammation have a higher risk of relapse, the physician might consider optimizing any current medical therapy they are taking. For example, if a patient is taking 5-ASA agents at a low or maintenance dose but has ongoing histologic inflammation, the physician may increase that dose to try to achieve histologic healing [12]. The potency of inducing histologic remission appears to be different depending on the drug; thus, researchers need more evidence to demonstrate that the resolution of microscopic inflammation as a result of modifying therapy or increasing dose is indeed a superior goal [12]. Therefore, if histologic healing is taken as a treatment target, further data are needed to support and extend these findings. Current guidelines do not yet consider histological healing as a therapeutic target, as more evidence-based studies are needed. Therefore, there are currently no international guidelines in force to assist GI physicians on the specific therapeutic changes imposed by the current state of the histological disease activity.
The value of consensus definitions in studies evaluating HH and establishing relevant cut-offs is needed not only to optimize treatment or a standardized measurement of histological activity but also to change the long-term history of the disease to improve patient outcomes. HH has increasingly become a significant target to achieve; therefore, the importance of histologic remission as a therapeutic aim in IBD continues to evolve.

References

  1. Zhang, Y.; Si, X.; Yang, L.; Wang, H.; Sun, Y.; Liu, N. Association between intestinal microbiota and inflammatory bowel disease. Anim. Models Exp. Med. 2022, 5, 311–322.
  2. Fabian, O.; Bajer, L. Histopathological assessment of the microscopic activity in inflammatory bowel diseases: What are we looking for? World J. Gastroenterol. 2022, 28, 5300–5312.
  3. Chateau, T.; Feakins, R.; Marchal-Bressenot, A.; Magro, F.; Danese, S.; Peyrin-Biroulet, L. Histological Remission in Ulcerative Colitis: Under the Microscope Is the Cure. Am. J. Gastroenterol. 2020, 115, 179–189.
  4. Ma, C.; Sedano, R.; Almradi, A.; Vande Casteele, N.; Parker, C.E.; Guizzetti, L.; Schaeffer, D.F.; Riddell, R.H.; Pai, R.K.; Battat, R.; et al. An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials. Gastroenterology 2021, 160, 2291–2302.
  5. Danese, S.; Roda, G.; Peyrin-Biroulet, L. Evolving therapeutic goals in ulcerative colitis: Towards disease clearance. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 1–2.
  6. Colombel, J.F.; D’haens, G.; Lee, W.J.; Petersson, J.; Panaccione, R. Outcomes and Strategies to Support a Treat-to-target Approach in Inflammatory Bowel Disease: A Systematic Review. J. Crohn’s Colitis 2020, 14, 254–266.
  7. Turner, D.; Ricciuto, A.; Lewis, A.; D’Amico, F.; Dhaliwal, J.; Griffiths, A.M.; Bettenworth, D.; Sandborn, W.J.; Sands, B.E.; Reinisch, W.; et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021, 160, 1570–1583.
  8. Kellermann, L.; Riis, L.B. A close view on histopathological changes in inflammatory bowel disease, a narrative review. Dig. Med. Res. 2021, 4, 3.
  9. Magro, F.; Gionchetti, P.; Eliakim, R.; Ardizzone, S.; Armuzzi, A.; Barreiro-de Acosta, M.; Burisch, J.; Gecse, K.B.; Hart, A.L.; Hindryckx, P.; et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 1: Definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders. J. Crohn’s Colitis 2017, 11, 649–670.
  10. Agrawal, M.; Colombel, J.F. Treat-to-Target in Inflammatory Bowel Diseases, What Is the Target and How Do We Treat? Gastrointest. Endosc. Clin. N. Am. 2019, 29, 421–436.
  11. Kim, K.O. Endoscopic activity in inflammatory bowel disease: Clinical significance and application in practice. Clin. Endosc. 2022, 55, 480–488.
  12. Rath, T.; Atreya, R.; Neurath, M.F. Is histological healing a feasible endpoint in ulcerative colitis? Expert Rev. Gastroenterol. Hepatol. 2021, 15, 665–674.
  13. Ponte, A.; Pinho, R.; Fernandes, S.; Rodrigues, A.; Alberto, L.; Silva, J.C.; Silva, J.; Rodrigues, J.; Sousa, M.; Silva, A.P.; et al. Impact of histological and endoscopic remissions on clinical recurrence and recurrence-free time in ulcerative colitis. Inflamm. Bowel Dis. 2017, 23, 2238–2244.
  14. Pai, R.K.; Hartman, D.J.; Rivers, C.R.; Regueiro, M.; Schwartz, M.; Binion, D.G.; Pai, R.K. Complete resolution of mucosal neutrophils associates with improved long-term clinical outcomes of patients with ulcerative colitis. Clin. Gastroenterol. Hepatol. 2020, 18, 2510–2517.e5.
  15. Cushing, K.C.; Tan, W.; Alpers, D.H.; Deshpande, V.; Ananthakrishnan, A.N. Complete histologic normalisation is associated with reduced risk of relapse among patients with ulcerative colitis in complete endoscopic remission. Aliment. Pharmacol. Ther. 2020, 51, 347–355.
  16. Kevans, D.; Kirsch, R.; Dargavel, C.; Kabakchiev, B.; Riddell, R.; Silverberg, M.S. Histological markers of clinical relapse in endoscopically quiescent ulcerative colitis. Inflamm. Bowel Dis. 2020, 26, 1722–1729.
  17. Lobatón, T.; Bessissow, T.; Ruiz-Cerulla, A.; De Hertogh, G.; Bisschops, R.; Guardiola, J.; Van Assche, G.; Vermeire, S.; Ferrante, M. Prognostic value of histological activity in patients with ulcerative colitis in deep remission: A prospective multicenter study. United Eur. Gastroenterol. J. 2018, 6, 765–772.
  18. Pai, R.K.; Jairath, V. What is the role of histopathology in the evaluation of disease activity in Crohn’s disease? Best Pract. Res. Clin. Gastroenterol. 2019, 38–39, 101601.
  19. Hu, A.B.; Tan, W.; Deshpande, V.; Ananthakrishnan, A.N. Ileal or Colonic Histologic Activity Is Not Associated with Clinical Relapse in Patients with Crohn’s Disease in Endoscopic Remission. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2021, 19, 1226–1233.e1.
  20. Villanacci, V.; Baert, F.; Cornillie, F.; De Hertogh, G.; Panés, J. Challenges Faced by Cross-sectional Imaging and Histological Endpoints in Clinical Trials. J. Crohn’s Colitis 2017, 11 (Suppl. S2), S586–S592.
  21. Park, S.; Abdi, T.; Gentry, M.; Laine, L. Histological Disease Activity as a Predictor of Clinical Relapse Among Patients with Ulcerative Colitis: Systematic Review and Meta-Analysis. Am. J. Gastroenterol. 2016, 111, 1692–1701.
  22. Narang, V.; Kaur, R.; Garg, B.; Mahajan, R.; Midha, V.; Sood, N.; Sood, A. Association of endoscopic and histological remission with clinical course in patients of ulcerative colitis. Intest. Res. 2018, 16, 55–61.
  23. Ozaki, R.; Kobayashi, T.; Okabayashi, S.; Nakano, M.; Morinaga, S.; Hara, A.; Ohbu, M.; Matsuoka, K.; Toyonaga, T.; Saito, E.; et al. Histological Risk Factors to Predict Clinical Relapse in Ulcerative Colitis with Endoscopically Normal Mucosa. J. Crohn’s Colitis 2018, 12, 1288–1294.
  24. Bryant, R.V.; Burger, D.C.; Delo, J.; Walsh, A.J.; Thomas, S.; von Herbay, A.; Buchel, O.C.; White, L.; Brain, O.; Keshav, S.; et al. Beyond endoscopic mucosal healing in UC: Histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up. Gut 2016, 65, 408–414.
  25. Bessissow, T.; Lemmens, B.; Ferrante, M.; Bisschops, R.; Van Steen, K.; Geboes, K.; Van Assche, G.; Vermeire, S.; Rutgeerts, P.; De Hertogh, G. Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am. J. Gastroenterol. 2012, 107, 1684–1692.
  26. Calafat, M.; Lobatón, T.; Hernández-Gallego, A.; Mañosa, M.; Torres, P.; Cañete, F.; Cabré, E.; Ojanguren, I.; Domènech, E. Acute histological inflammatory activity is associated with clinical relapse in patients with ulcerative colitis in clinical and endoscopic remission. Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver 2017, 49, 1327–1331.
  27. Christensen, B.; Erlich, J.; Gibson, P.R.; Turner, J.R.; Hart, J.; Rubin, D.T. Histologic Healing Is More Strongly Associated with Clinical Outcomes in Ileal Crohn’s Disease than Endoscopic Healing. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2020, 18, 2518–2525.e1.
  28. Brennan, G.T.; Melton, S.D.; Spechler, S.J.; Feagins, L.A. Clinical Implications of Histologic Abnormalities in Ileocolonic Biopsies of Patients with Crohn’s Disease in Remission. J. Clin. Gastroenterol. 2017, 51, 43–48.
  29. Flores, B.M.; O’Connor, A.; Moss, A.C. Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: A systematic review and meta-analysis. Gastrointest. Endosc. 2017, 86, 1006–1111.e8.
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