(Re)Appraising Remission in Ulcerative Colitis

Abstract

As the therapeutic targets in ulcerative colitis (UC) shift from control of symptoms to mucosal healing and prevention of disease complications like disability, colectomy, and cancer, the definition of remission has evolved. The current definition of clinical remission is variable and is determined by the clinical context in which it is being used. This results in skepticism and uncertainty about the true meaning of the term “clinical remission.” In this review, the authors reexamine the definition of clinical remission and propose a novel approach to define remission in UC.

Introduction

Ulcerative colitis (UC) is a chronic disease with a relapsing-remitting course characterized by contiguous inflammation of the colorectal mucosa.¹ As there is no curative treatment at present, the therapeutic end point of medical management in these patients is to achieve remission.² The concept of “remission” in UC, however, is an abstraction. Remission for a patient may imply freedom from symptoms with minimal adverse effects of the drugs and improvement in quality of life. On the other hand, for a clinician, freedom from symptoms is just one milestone on the way to the ultimate destination of resolution of inflammation. The term clinical remission has been used to describe both these aspects (resolution of symptoms and resolution of inflammation) depending upon the clinical setting (clinical practice, clinical trials and/or guidelines and for the registration of a new molecule).³ The authors in the present review call out attention to inconsistencies in the definition of remission and propose a fresh approach to therapeutic end points in UC.

Differentiating “Clinical Remission” from “Symptomatic Remission”

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) recommendations lay out resolution of rectal bleeding and normalization of bowel habits as the definition of clinical remission.⁴ In the recently published STRIDE 2 recommendations, clinical remission is defined as an absolute improvement in the rectal bleeding and stool frequency (partial Mayo score <3 and no score >1) and is taken as an intermediate treatment target.⁵ Clinical remission, here, incorporates only the patient-reported outcomes (ie, disease related symptoms), implying an analogy between “clinical” and “symptomatic” remission. Contrastingly, clinical remission, when defined as a therapeutic end point in clinical trials, includes either only symptomatic remission or both symptomatic and endoscopic remission. (Table 1). The term “deep remission” has previously been used to represent absence of symptoms and normal mucosal endoscopic appearance through various definitions, though none of these have been standardized.^6–8 To further compound the perplexity, several terminologies with diverse definitions have been used in clinical trials to describe the different end points (Table 2). This leads to confusion in understanding the true context of remission.

The definition of clinical remission in UC at present is not uniform, which makes it difficult to establish a standardized algorithm for evaluating clinical outcomes or providing absolute recommendations. Defining clinical remission based solely on symptomatic recovery, as in STRIDE 2, may just reflect the patient’s perspective of recovery rather than being representative of the true recovery. There is thus a need for consistent scientific phraseology to define clinical remission in a more explicit manner.

Remission in UC: One Step at a Time

The need for distinction between symptomatic improvement and actual disease control in UC is more evident now than ever. Altering the disease course by disease-modifying therapies involves climbing up the staircase and fulfilling an objective “target” at each step. The authors suggest using discrete terms to specify each “target” on the way to the top, such as absence of symptoms (symptomatic remission), normalization of inflammatory biomarkers (biomarker remission), normalization of colonic mucosa on endoscopy (endoscopic remission), histological evidence of normalization of the colonic mucosa and absence of neutrophils in the epithelium or lamina propria (histological remission), and a composite of all the parameters (composite remission; Figure 1)

Step 1: Resolution of Disease Related Symptoms (Symptomatic Remission)

The notion of remission in clinical practice is dominated by relief of symptoms. Diarrhea, rectal bleeding, and abdominal pain are the most common symptoms reported by patients with UC. However, a large proportion of patients, especially those with active rectal disease, also experience bowel urgency or incontinence, tenesmus, and a sense of incomplete evacuation.²⁵ Bowel urgency apart from contributing to patient’s perception of disease burden can also predate increased stool frequency and rectal bleeding.²⁶ Therefore, normalization of bowel habits, resolution (absence) of rectal bleeding, and control of urgency have been proposed as targets to define symptomatic remission.²⁷

A limitation of this definition, however, is that normalization of the symptoms alone does not correlate with patients’ perspective of recovery and remission. They may feel affected by other factors that influence the quality of life (QoL) such as general well-being, work productivity, fatigue, and mood disorders.^28–30 Hence, various patient-reported outcome (PRO) tools such as partial Mayo Score, PRO2, PRO3, the self-administered Simple Clinical Colitis Activity Index (SCCAI), Inflammatory Bowel Disease Questionnaire (IBDQ-32), Inflammatory Bowel Disease Questionnaire—Short Form (IBDQ-9), Short Inflammatory Bowel Disease Questionnaire (Short IBDQ), Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQOL), IBD Disability Index (IBDDI), Social Impact of Chronic Conditions—Inflammatory Bowel Disease (SICC-IBD) questionnaire, and IBD-disk have been developed.^31–39

At the moment, a consistent, reliable, and validated tool that measures all the desired components (clinical symptoms, patient’s disease assessment, QoL, and disease-related disability) while also excluding symptoms attributable to IBS is lacking and needs to be developed and validated across different populations. Until the time such a comprehensive PRO tool is developed, partial Mayo clinic score can be a suitable measure to assess symptoms and define outcomes (symptomatic remission defined as score ≤1).^40,41

Step 2: Normalization of Inflammatory Biomarkers (Biomarker Remission)

Although achievement of symptomatic remission is an important therapeutic target, there may still be ongoing inflammation (evidenced by endoscopic and/or histological disease activity) even with complete abatement of symptoms (ie, symptomatic remission).⁴² Resolution of inflammation and not just symptoms is important, as it is associated with better long-term outcomes.^43,44 Performing repeated endoscopies to assess for endoscopic ± histological mucosal healing not only has limited patient acceptance but also carries the risks innate to the procedure. Alternative surrogate markers allowing noninvasive but accurate assessment of degree of endoscopic ± histological inflammation have therefore been extensively sought.

Biomarkers in blood (like erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], leucine-rich alpha-2 glycoprotein, and β2 microglobulin) or stool (fecal calprotectin [FC], lactoferrin, M2 pyruvate kinase, lysozyme, myeloperoxidase, and neopterin, etc.) have been evaluated for assessment of disease activity.^45–47 C-reactive protein is an important protein that sharply increases when there is acute inflammation, induced by interleukin 6, tumor necrosis factor-α, and interleukin-1β. The half-life of CRP is short (19 hours), and it rises rapidly and falls sharply during acute exacerbations of IBD. However, the correlation of inflammatory disease activity and CRP levels is stronger in Crohn’s disease than UC, the cause of which is unclear.^48,49

Various neutrophil-derived proteins have also been evaluated as markers of intestinal inflammation, especially in UC.⁵⁰ Of these, fecal calprotectin (FC) is the most widely used inflammatory biomarker that relates to both the severity and the extent of inflammation.^51,52 It has been hypothesized that resolution of inflammation will result in reduction in the amount of neutrophil migration into the gut lumen and therefore low FC values. Fecal calprotectin has been demonstrated to have higher sensitivity than CRP for assessment of endoscopically active disease and also has moderate correlation with histological activity.⁵³ Furthermore, high FC levels in patients in symptomatic remission predict future relapse.^54,55 Thus, FC appears to be a reliable marker to monitor treatment response in UC.

The optimal cutoff to define normal FC is not defined, as the cutoff values depend upon the commercial kit, the type of the assay used, and the population on which the test is applied.^56,57 Population-specific cutoffs need to be defined taking into consideration the prevalence of other infective/inflammatory intestinal diseases, such as gastrointestinal infections, non-IBD colitis such as eosinophilic or lymphocytic colitis, celiac disease, and malignancies of stomach and colon.⁵⁸ Various cutoff values of FC have been proposed across correlation studies to predict mucosal healing. In a study by Theede et al, FC values of ≤192 μg/g correlated with endoscopic evidence of mucosal healing, whereas a cutoff of 171 μg/g identified patients with histologic evidence of mucosal healing.⁵⁹ In another study correlating FC values with clinical outcomes in a phase 2 clinical trial, FC values <150 μg/g correlated with Mayo endoscopy subscore of 0.⁶⁰ Walsh et al in their prospective analysis found that FC values <72 μg/g correlated with histological healing (Nancy score ≤1) and ≥187 μg/g indicated endoscopically active disease (Ulcerative Colitis Endoscopic Index of Severity [UCEIS] ≥4).⁶¹ Another retrospective analysis predicted Mayo endoscopy subscore 0/1 and Nancy score ≤1 at a FC level of ≤60 μg/g.⁶² A recent systematic review identified FC cutoff range 60 to 75 μg/g to have the best overall accuracy to predict mucosal healing (defined as Mayo endoscopy subscore of 0) in patients with UC.⁶³ Mosli et al also identified FC ≤50 μg/g to be predictive of mucosal (both endoscopic and histologic) healing.⁶⁴ Based upon the existing literature, FC values <50 to 75 μg/g may suggest endoscopic and/or histological mucosal healing; though a single cutoff value to discriminate between active and inactive UC, using endoscopy as the reference, has not been validated as yet.

Although both CRP and FC concentrations can distinguish between patients with active and inactive inflammation in UC, it must be remembered that CRP does not correlate, and hence cannot be used as a surrogate for histological activity.⁶⁵ Normalization of FC, therefore, is the next step after achievement of symptomatic remission.

Step 3: Endoscopic Mucosal Healing (Endoscopic Mucosal Remission)

The role of endoscopy for assessment of mucosal healing is established. However, doing endoscopy in patients with symptomatic and/or biomarker evidence of disease activity is unlikely to reveal mucosal healing. It may therefore be logical to consider endoscopic assessment once symptomatic and biomarker remissions have been achieved (response guided approach), with the aim to confirm and document endoscopic mucosal healing.

Mayo endoscopy subscore of 0 or 1 is traditionally considered as mucosal healing. In multiple post hoc analyses, patients with a Mayo endoscopy subscore of 1 have been shown to have a higher risk of relapse than those with Mayo endoscopy subscore 0, regardless of the extent of disease.^66–68 Therefore, more recent clinical trials have described Mayo endoscopic subscore of 0 as endoscopic remission. Ulcerative Colitis Endoscopic Index of Severity is another validated, reproducible, and sensitive score constructed using a rigorous methodology.⁶⁹ A UCEIS score of ≤1 denotes endoscopic remission and has been found to be comparable to Mayo endoscopy subscore when performed by expert endoscopists. Achievement of Mayo endoscopy subscore of 0 or UCEIS score of ≤1 corresponds to endoscopic mucosal remission and is a step forward towards disease clearance.

Step 4: Histological Mucosal Healing (Histological Mucosal Remission)

The clinical trials rely primarily on the endoscopic visualization of normal-looking colonic mucosa to mark mucosal healing, though more recently histological improvement/remission have been used as efficacy end points in clinical trials in addition to clinical remission (Table 2). Histologic disease activity persists in 10% to 40% of patients with normal-looking mucosa on endoscopy, indicating that reliance only on the endoscopic appearance may be misleading.^70–73 Patients with endoscopically normal mucosa but histological disease activity have greater rates of relapse, corticosteroid use, hospitalizations, colectomy, and risk for colorectal cancer than those with both endoscopic and histological remissions.^74,75

The histologic features usually studied to assess the disease activity in UC include features of both acute and chronic inflammation such as presence of neutrophils in the surface epithelium, crypt epithelium, and lamina propria (normally neutrophils are not present in the epithelium and lamina propria), basal plasmacytosis, mononuclear cell infiltrate in the lamina propria, erosions, ulcers, crypt architectural distortion and atrophy, and mucin depletion. Based on these parameters, more than 30 histological indices have been described for evaluation of disease activity in UC. Of these, Nancy Index and the Robarts Histopathology Index (RHI) are the most validated (Table 3).⁷⁶ Geboes score, though only partially validated, is widely used and has even been used to define histologic remission in recent clinical trials (Table 2). However, the European Crohn’s and Colitis Organization position article on harmonization of the approach to histopathology in ulcerative colitis recommends either Nancy index or RHI for use in clinical trials.⁶⁵ The cutoff values used to define histological remission for Nancy Index and RHI are 0 and ≤6, respectively.⁷⁷ Histological activity is essentially defined by presence of neutrophils in the epithelium and lamina propria.^65,71,78 Therefore, if this stringent criteria of absence of neutrophils from the epithelium and lamina propria is taken into consideration, RHI≤3 along with subscores of 0 for neutrophils in epithelium and lamina propria would represent histological remission.⁶⁵ Presence of basal plasmacytosis has also been reported to be associated with adverse outcomes, though the evidence is inconsistent. If absence of both basal plasmacytosis and mucosal neutrophils is taken into consideration, RHI ≤1 would define histological remission.⁷⁹ Even though RHI ≤1 is too strict a criteria to be used in clinical trials and clinical practice, it portrays the histological remission in a true sense.

The notion of achieving histological remission is attractive but with serious impediments to practical application. The concerns limiting the implementation of histological remission in clinical practice include the choice of histological scoring indices, the precise site(s) and number(s) of biopsies (in view of patchy progression/regression of disease and uneven distribution of microscopic inflammation between or within sites and even within biopsies), the best timing for histological evaluation, and expertise of the pathologist(s).^76,80–82

Modification of therapy to achieve histological remission in patients with symptomatic, biomarker, and endoscopic remissions is debatable and carries a risk of exhaustion of therapies if treatment escalation is done in patients with endoscopic remission but histologic activity. The long-term disease course and natural history in patients who achieve histological remission is also not known at present.⁸³ Nevertheless, contemporary trials have now started evaluating the histologic end points and are expected to guide treatment decisions more accurately and precisely. Assessment of cumulative histological scores over time, rather than a single histological score, also appears promising for predicting the risk of developments of colorectal cancer.⁸⁴

Composite Remission: The Overall Goal

As discussed, evaluation of disease activity in UC includes clinical symptoms, inflammatory biomarkers, and endoscopic and histologic assessments, analyzed in the same chronological order. A composite of achievement of all these parameters can be referred to as “composite remission.” With ever-evolving understanding of the pathophysiology of UC and the availability of efficacious treatment modalities, achieving “composite remission” in UC is a realistic goal, though only limited supportive data is available at the moment.^75,85,86Achieving “composite remission,” however, is not the end of the journey but is just a bend in the road where we have to make a turn towards sustaining “composite remission.” For sustenance of “composite remission,” continuing maintenance therapy is important, as withdrawal of therapy is associated with higher rates of relapse.^8,87–92 Apart from continuation of the maintenance therapy, it is also important to identify and prevent the potential triggers of relapse to sustain “composite remission.” There is evidence to suggest that patients who achieve and then sustain “composite remission” have improved quality of life, low relapse rates, fewer hospitalizations, fewer colectomies, and lower risk of colorectal cancer.^93–95 Sustained composite remission may therefore be an important step in the direction of altering the disease course and achieving disease clearance. The concept of sustained composite remission may also have potential implications in the de-escalation of the therapy, especially in patients who are in sustained composite remission for a not yet defined period of time. However, data on the effect of de-escalation of therapies in patients in sustained composite remission is deficient and needs to be studied prospectively in longitudinal cohorts.

Towards Disease Clearance: The Future?

Just as the concept of remission in UC has metamorphosed, the concept of disease clearance in UC is evolving. A composite of clinical plus endoscopic and histologic remission has previously been proposed to be referred as disease clearance.⁹⁶ However, UC has been characterized as a progressive disease.⁹⁷ Transcriptional analysis of intestinal mucosa of persons with UC in remission has unravelled some pathways that are permanently dysregulated in UC despite histological recovery.^98,99 The progressive nature of UC is also evidenced by transmural effects on the bowel wall (characterized by hypertrophy of the muscularis mucosa and muscularis propria, submucosal fibrosis, thinning of the muscularis externa, proliferation of the perirectal fat, and widening of the pre-sacral space, etc.). It is also evidenced by damage to the enteric nervous system (eg, hypertrophy and hyperplasia of nerve fibers, increased proliferation of interstitial cells of Cajal, ganglioneuritis, etc.) and bowel dysmotility (due to smooth muscle dysfunction, increased dopamine and noradrenergic inhibitory nerves, etc.).^97,100–105 The rectal compliance has been demonstrated to be reduced even in patients with disease in remission.¹⁰⁶ These observations suggest that we might need to look beyond mucosal healing and consider anatomic, molecular, and functional dimensions of UC to define disease clearance in its true sense. The evidence for normalization of these eccentricities using targeted interventions is not available as yet, and further studies prioritizing these considerations as potential treatment goals are needed. Only time will tell whether these aspects of disease progression in UC can be propagated as the potential end points of therapy. Moving on from the target of composite remission to elimination of the disease will be true disease clearance.

Conclusion

The term “clinical remission” has been defined and interpreted differently in different settings leading to incongruity and confusion in its usage in clinical practice. A reappraisal of definition of remission in UC is thus warranted. We suggest that the term “clinical remission” be replaced and remission in UC be defined according to the parameter being used for assessment. Defining remission based on individual components such as absence of symptoms (symptomatic remission), normalization of inflammatory biomarkers (biomarker remission), and normalization of colonic mucosa on endoscopy (endoscopic remission) and histology (histological remission)—each achieved in a stepwise manner—is likely to reflect the true clinical picture of the patient. This will also, expectedly, bring uniformity across the clinical and research scenarios. Collective achievement of remission in each of the individual components would represent composite remission. Adoption of the proposed changes in the nomenclature of clinical remission, however, requires extensive discussion amongst clinicians and academicians. We hope to start this discussion with this review.

Author Contributions

Conceptualization: A.S.

Methodology: A.S., V.M.

Resources: A.S., R.M.

Investigations: A.S., R.M.

Writing Original Draft: A. Singh, R.M.

Writing Review and Editing: A.S., A.Singh, R.M., V.M., C.B., D.R.

Visualization: A.S., C.B., D.R.

Supervision: A.S., V.M., C.B., D.R.

Approval of Final Manuscript: A.S., R.M., A.Singh, V.M., C.B., D.R.

Financial Support

None

Conflicts of Interest

C.B. has served on advisory boards or consulted to Abbvie Canada, Amgen Canada, Avir Pharmaceutical, Bristol Myers Squibb Canada, Janssen Canada, Pfizer Canada, Roche Canada, Sandoz Canada, Takeda Canada, and consulted to Mylan Pharmaceuticals, and Takeda. He has received unrestricted educational grants from Abbvie Canada, Janssen Canada, Pfizer Canada, and Takeda Canada. He has been on the speaker’s bureau for Takeda Canada, Abbvie Canada, Janssen Canada, Pfizer Canada, and Medtronic Canada.

D.R. has received grant support from Takeda and has served as a consultant for Abbvie, Altrubio, Arena Pharmaceuticals, Bristol-Myers Squibb, Genentech/Roche, Gilead Sciences, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Pfizer, Prometheus Biosciences, Reistone, Takeda, and Techlab Inc. A.S. has received speaker honorarium from Pfizer India.

R.M., A.Singh, and V.M. have no conflicts of Interest to declare.

Data Availability

Data sharing is not applicable to this article, as no new data were created or analyzed in this study.

References