Recent change of paradigms toward precision care in IBD

Patients with IBD follow different disease courses; everyone has a unique and unpredictable phenotype. Some patients can have a very mild disease, but over a 10-year period up to 53% of patients with CD will developed narrowing or penetrating disease and up to 19% of patients with UC will require colectomy. ^103,104 This variability reinforces the idea that a unique approach will be suboptimal for a significant proportion of patients, especially those with aggressive factors. These patients have a “window of opportunity” for effective

treatment that should not be missed because delays may lead to intestinal damage with irreversible consequences.¹⁰⁵

Precision medicine is a relatively new concept in IBD and comprises a model of care in which an individual’s phenotypes and genotypes are characterized so the physician can tailor treatment to the patient and deliver it at the appropriate time.^106,107 Precision medicine can be applied before treatment begins, when biomarkers are used to determine the best treatment for a patient. It can also be applied after treatment start, with tight and

personalized monitoring of disease activity and treatment efficacity to improve QoL and prevent adverse drug events and long-term complications. Finally, precision strategies in this field improve medical adherence and follow-up,notably through developing an

IBD-16 specialized clinic with multidisciplinary care and a telemedicine system. With precision medicine, it may be possible to lower the burden of healthcare costs related to biologic drugs that are a large driver of increased healthcare expenditure.⁵

2.1 Step-up versus top-down strategy

In 2004, D’Haens at al. demonstrated the advantages of starting IBD treatment with a combination of immunomodulators and biological therapy and then de-escalating as appropriate (top-down strategy); there was more beneficial than the standard of care that started with steroids and then stepped up to immunomodulators, followed by biologics if necessary (step-up strategy). The study showed that the top down strategy significantly raised clinical remission rates without steroids. In 2010, the pivotal SONIC trial reported that combining immunomodulator and IFX was more effective than immunomodulator or IFX alone to achieve corticosteroid-free remission (56.8% for combined therapy; 30% for immunomodulators alone; 44% for IFX alone) and mucosal healing (44% for combined therapy; 16,5% for immunomodulators alone; 30% for IFX alone).⁸⁶ In 2015, the REACT study reported that an early treatment combination for CD patients was more effective than conventional management for controlling risk of major adverse outcomes like serious disease-related adverse events, hospitalizations, or surgery (27.7% for combined therapy;

35.1% for conventional management, p = 0.0003).¹⁰⁸

In traditional step-up strategy or accelerated step-up approach, which reactively escalates medications in response to disease flares, undertreatment of more severe patients is unavoidable, and this increases the likelihood of developing complications. But a top-down strategy risks overtreating patients who might have remained stable without complications on milder and less expensive drugs. Though step-up strategy was unaffordable in some healthcare settings, biosimilar drugs have recently been shown to be safe and effective, and are to 40% cheaper, significantly decreasing health care costs. The European Crohn’s and Colitis Organization (ECCO) recommend early top-down strategy for treating selected patients with high-risk factors of complicated disease, since they will benefit most from early diagnosis and treatment that modifies the course of the disease.

2.2 Treat to target and tight monitoring

“Treat to target” and “tight monitoring” recently became the standard of care in IBD follow-up and refer to using predefined outcome measures (clinical, biochemical and/or endoscopic)

17 as goals to optimize therapy. Inspired by evidence in other specialties, notably from the rheumatology literature, the IOIBD group published the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) recommendations with the objective of delineating a

“treat to target” approach to obtain clinical and endoscopic remission in IBD.^58,61,109In parallel, there was growing evidence in the IBD literature that endoscopic healing was associated with improved clinical and long-term outcomes.^110,111 The STRIDE

recommendations include targeting improvement in clinical and endoscopic outcomes and also incorporate patient-reported outcome measures (PROMs). Choosing these measures of improvement and PROMs might improve IBD treatment outcomes more than treatment based on symptom-derived scales. Also mucosal healing was considered the sole target endpoint to reach in recent drugs trials¹¹², all newly designed and recently published clinical trials in IBD have moved toward complex outcomes goals encompassing PROMs,

biochemicals and endoscopic improvements.¹¹³ STRIDE recommends using biomarkers like CRP and fecal calprotectin (FCP) to monitor response but there was no consensus on how to use them until the results of the CALM trial were published. In this study, Colombel et al.

tested the efficacy of tight control management based on 3-monthly biomarkers versus conventional management, which used Crohn’s Disease Activity Index on clinical (CDAI) and endoscopic outcomes in moderate to severe CD.¹¹⁴ CALM demonstrated that a significantly higher number of patients achieved mucosal healing in the “tight control” group than in conventional arm. The same group of authors published in 2019 follow-up data that showed that patients who achieved mucosal healing in the first year of treatment were less likely to have disease progression over a median of 3 years, including less likelihood of hard outcomes like hospitalization and surgery.¹¹⁵ The utility of monitoring based on biomarkers was also highlighted by a recent systematic review showing that two consecutive elevated FCP tests predicted disease relapse within the next 2 to 3 months.¹¹⁶ It is also possible to use monitoring to assess the possibility of de-escalation. Louis E and al. highlighted this in the prospective STORI trial that followed 115 CD patients on combination therapy. Anti-TNF was discontinued in these patients after at least 6 months of corticosteroid-free clinical remission, resultingin frequent relapse. These biomarkers can elevate 4 months before clinical symptoms of relapse appear.¹¹⁷

2.3 Personalized approach to predicting disease course and guiding choice of treatment for individual patients

18 Early detection of IBD patients who may be prone to developing a severe form of the

disease is a most difficult challenge. But there are clinical predictors that may predict an unfavorable disease course and help physicians tailor IBD management (Table 1).

Disease Time frame Predictor of unfavorable course Crohn’s

disease

Within 5 years of diagnosis Age < 40 yo

Need for steroids in first flare Perianal disease

Upper gastrointestinal lesions Ileocolonic lesions

Within 10 years of diagnosis Age < 40 yo

Upper gastrointestinal lesions Stricturing and penetrating behavior Terminal ileal lesions

Ulcerative colitis

Within 5 years of diagnosis Younger age Female gender Within 10 years of diagnosis Younger age

Female gender

Fewer systemic symptoms Extensive colitis

Non-smoking status

Table 1: Clinical parameters that predict unfavorable inflammatory bowel disease course (adapted from Borg-Bartolo, et al. F1000Res. 2020 ¹¹⁸)

In CD, early onset diagnosis, extensive disease, deep ulcerations, upper gastrointestinal involvement, smoking, and penetrating phenotypes (strictures and fistulae), or steroids use at diagnosis are associated with poorer prognosis.In UC, early onset diagnosis and

extensive colitis are poor prognostic factors. The presence of extraintestinal manifestations, especially primary sclerosing cholangitis and non-smoking status, predict risk of pouchitis after ileal pouch anal anastomosis.119,120,121 These clinical criteria are helpful but not sufficient to permit accurate prediction of disease severity in individuals.

The paradigm has shifted from a reliance on clinical predictors toward using biomarkers to identify patients at risk of complicated disease and to tailoring treatment algorithms based on disease course. For example, positivity of Anti-Saccharomyces Cerevisiae Antibodies

(ASCA) or newly discovered antibodies like CBir1, Anti-OmpC antibody or anti-I2 in CD

19 correlate to a higher risk of penetrating disease.^122,123 If treatment failure can be predicted, patients’ therapy can be switched early, increasing the likelihood and cost-effectiveness of recapturing response. The thiopurine methyltransferase (TPMT) genotype is now the most accurate at predicting adverse events from azathioprine. Low and intermediate TPMT activity significantly increase risk of adverse events like myelosuppression in patients receiving thiopurines for IBD. For biologic treatments, multiple factors are associated with higher clearance of the drug, including high body weight, low albumin level, low hemoglobin, and high inflammatory burden reflected by biomarkers. ¹²⁴ A recent multicenter, prospective, observational cohort study called PANTS for “Personalized Anti-TNF Therapy in Crohn’s Disease Study” reported that, in 1610 patients, low drug concentration level at Week 14 was associated with PNR and non-remission at Week 54. Obesity at baseline (for adalimumab) and smoking (for infliximab) were associated with non-remission at Week 54 and

immunogenicity.¹²⁵ Even if these biomarkers indicate a risk of a complicated disease evolution, their role in everyday clinical care is not yet well-defined and no study has identified adequate predictors for IBD treatment response that physicians can use in clinics to treat patients with precision medicine.

Some endoscopic findings can predict the course of the disease and help physicians choose among treatments, e.g., deep ulcerations are predictors of worse CD outcomes.¹²⁶ Multiple markers can be combined to predict the course of disease. The Inflammatory Bowel South-Eastern Norway (IBSEN) cohort described four factors associated with higher risk of colectomy in UC patients: i) extent of disease; ii) age (<40 years); iii) need for systemic steroids; iv) CRP (⩾30 mg/l); and, erythrocyte sedimentation rate (⩾30 mm/h) at diagnosis.¹⁰⁴

IBD prognosis is very unpredictable and improved techniques for identifying specific predictors of disease evolution would be welcome. In clinical practice, there is currently no available markers potentially used as predictors for better drug selection before initiating the therapy. Ongoing head-to-head trials are comparing different biologics and their results may improve our algorithms for treating IBD.¹⁰⁰ Today, the choice of adequate treatment is based on assessing multiple factors like disease activity, size and location of mucosal lesions, anatomic distribution and load of inflammation (local or systemic), prior hospitalizations or surgery, postoperative complications, and presence of extraintestinal manifestations and previous treatment response. Other essential considerations include the impact of the disease on the patient’s QoL and treatment preference.

20 2.4. Defining personalized targets for treatment and follow-up strategy once

treatment has begun:

Patients and physician may define remission differently; the first takes a subjective

approach, but the second benefits from added objective measures. For many years, patients were defined as “in remission” if they had few or no IBD symptoms. Earlier studies were based only on subjective parameters and analyzed predictive factors of therapeutic response by comparing responders to non-responders after therapy start. Later studies of IBD patient management included objective parameters. The goal of IBD treatment is now a composite of clinical remission, biochemical remission with a normalized C-reactive protein (CRP) and fecal calprotectin (FCP), and endoscopic remission or mucosal healing (visual healing of the intestinal mucosa).⁶¹ Clinical, biochemical and endoscopic monitoring of response/remission under treatment should be incorporated into the follow-up process for patients with IBD.

2.4.1 Clinical criteria for remission

Patients are focused on the goal of clinical remission. There are CD and UC disease activity indices like the Crohn’s Disease Activity Index (CDAI) and the pMayo score. ¹²⁷ But

symptoms correlate poorly with endoscopy, especially in CD, where IBD symptoms and other conditions not related to inflammation overlap, e.g., irritable bowel syndrome, bile salt diarrhea, steatorrhea, bacterial overgrowth, and scarring tissue. The correlation between clinical remission and endoscopic findings may be closer in UC. ¹²⁸ Often, assessments based only on symptoms while patient started treatment are insufficiently precise for decision making.

2.4.2 Biologic criteria for remission

The response rate to IFX seems significantly higher after induction treatment in patients with a higher level of CRP (>5 mg/l) than for patients with a normal value before treatment (76%

vs 46%; p = 0.004). ¹²⁹ Early normalization of CRP reportedly correlate with sustained long-term response, without need for therapeutic adjustment (p < 0.001).^130,131 FCP is also an interesting measure for IBD follow-up in clinics. Biochemical remission monitored by FCP correlates strongly with mucosal healing; sensitivity and specificity are about 80%.¹³² Normalizing FCP to a value less than 100 µg/g after induction therapy with anti-TNFa is more likely to result in sustained clinical remission after 12 months than if the post-induction level remains elevated (88% versus 38%; p < 0.0001).¹³³ When patients are in remission, an increase in FCAL levels can predict a relapse.^134,117

21 Biological parameters are useful tools in managing IBD, but abnormalities in any one of them should not, by themselves, indicate the need to change therapies.

2.4.3 Endoscopic criteria for remission

The target of endoscopic healing is sometimes difficult to reach. Endoscopic remission in CD has been defined using different thresholds for the simple endoscopic score for CD (SES-CD) or the CD Endoscopic Index of Severity (CDEIS) score; remission may also be defined as complete absence of ulceration, which may or not consider aphthae. A less strict

measure of endoscopic healing is required for endoscopic response, for which the standard is a 50% reduction of the baseline SES-CD score.¹³⁵ In UC, endoscopic remission is defined in most studies as a Mayo score of 0 (no lesion) or 1 (mild erythema and friability). But a recent study evaluating relapse risk based on the degree of mucosal healing showed that patients whose endoscopic Mayo score was 1 were at higher risk of relapse (36.6%) than those whose score was 0 (9.4%; p < 0.001).¹⁰⁶ The highest rate of endoscopic remission is now obtained with biologic treatments.136,137,138 Histologic healing seems to be of major prognostic importance and may become in a near future an additional target to reach. Some authors demonstrated that UC patients had a significantly higher rate of relapse if they had microscopic inflammation that with patients who had no infiltration¹⁰⁹ but more research is required to determine the precise role of histologic remission in IBD patients.

Post-operatively, both elevation of FCP and early endoscopic anastomotic recurrence are associated with increased risk of recurrence and indicate a need to adapt treatment quickly.

2.5 Personalizing monitoring response to therapy with pharmacogenetics, therapeutic drug monitoring, and pharmacokinetics

Therapeutic drug monitoring (TDM) is the measurement of drug levels (trough or peak) and detection of anti-drug antibody concentrations (ADA). There is growing evidence that this tool has a pivotal role in daily clinical practice, helping physicians personalize and optimize care of IBD patients. Of patients with IBD, 30% are primary non-responders (PNR) to biologic treatment, and up to 50% of those who initially respond to a drug are secondary non-responders (SLR) in whom the treatment loses efficacy.^139,140 PNR and SLR can be due to either pharmacokinetic (PK) or pharmacodynamic (PD) problems. PK problems are associated with inadequate drug exposure, often because the patient develops ADA, but PD issues are typically associated with inflammatory process unrelated to the targeted

22 immunoinflammatory pathway. ¹⁴¹ To optimize the use of treatments, pharmacokinetic measurements of anti-TNFa are frequently used to manage IBD in the induction and maintenance phases.

2.5.1 TDM to assess drug response

Many studies suggested that serum concentrations of IFX and ADA significantly correlate with mucosal healing in patients with IBD. ¹⁴² Multiple pivotal trials demonstrated that infliximab, adalimumab, golimumab, and certolizumab pegol concentrations were higher in patients who achieved clinical and endoscopic remission than in non-responders.The target cutoffs varied between studies, drugs, and timing of dosage (induction or maintenance period). ¹⁴¹ The utility of this tool is less clear for non-anti-TNFa biologics, but some studies have found a correlation between low serum concentrations of vedolizumab and

ustekinumab and lower patient response rates. ¹⁴³

2.5.2 TDM to optimize patient losing response (reactive strategy)

About 37% of patients treated with IFX lose clinical remission over time, as do 18.2% treated with adalimumab; a recent meta-analysis reported annual risk at about 13% for IFX and 24.4% for adalimumab.^98,144 TDM helps manage PNR and SLR by revealing the underlying mechanism of non-response, so physicians can decide whether to optimize the current drug (by increasing dose, shortening the interval of administration or associate a concomitant immunomodulatory drug) or switch to another therapeutic class. This “reactive“ strategy is more cost-effective than empiric dose escalation.^99,145 Several algorithms are available to help clinicians make the best therapeutic decision based on the patient’s PK/PD.^146,147 In summary, patients with a low drug concentration, and who do not have ADA can benefit from increasing the dose, but patients with low drug concentration and high ADA levels should be switched to another TNFa antagonist against which they have no ADA yet;

patients with a high drug concentration and no ADA should be switched to another therapeutic class because their disease is not mainly driven along this inflammatory pathway. Experts recommend reactive TDM for all agents, both for PNR and SLR patients.¹⁴¹

23 Figure 2. Algorithm for using reactive therapeutic drug to monitor IBD patients for secondary loss of response to TNF antagonists. Published in Ma C et al. Curr Treat Options

Gastroenterol. 2019. ¹⁴⁸

2.5.3 TDM to prevent patients from losing response (proactive strategy)

Preliminary data suggest that patients with clinical response/remission can also benefit from implementing TDM strategy before they become symptomatic (proactive strategy).¹⁴¹ The primary objective is to avoid loss of response by maintaining optimal anti-TNF

concentrations, reducing risk of adverse events and possibly costs by implementing a de-escalation strategy in patients with supratherapeutic drug concentrations.

Three important studies evaluated the role of routine proactive TDM. TAXIT and TAILORIX, two randomized control trials, compared anti-TNF dosing based on proactive TDM with dosing based on clinical features. TAXIT found a reduced relapse rate in the proactive TDM group, and modest cost savings. TAILORIX found no significant benefit of systematic proactive TDM overdosing, based on clinical features, but its study design prevented

researchers from drawing firm conclusions. In a recent retrospective study, Papamichael and al. compared patients with IBD who were proactively monitored for drugs (titrated to a target concentration) to those who were reactively monitored (titration performed after loss of response) and found proactive monitoring was associated with better clinical outcomes (greater drug durability, less surgery or hospitalization, and lower risk of immunogenicity to IFX).¹⁴⁹ In 2019, The first prospective randomized controlled trial of proactive TDM was published: the PAILOT study (Paediatric Crohn’s disease Adalimumab-Level-based

24 Optimisation Treatment) achieved its primary end point of sustained corticosteroid-free clinical remission.¹⁵⁰ PAILOT included 78 biological-naïve children with CD who responded to adalimumab induction therapy and were then randomized to either proactive dose optimization or reactive testing. The proportion of patients with corticosteroid-free clinical remission was significantly higher in the proactive group (82%; n=31) than in the reactive TDM group (48%; n=19; p=002), providing more evidence that proactive TDM is more useful than standard dosing and reactive TDM.

A recent consensus among experts is that it is appropriate to order drug/antibody concentration testing at least once a year and at the end of induction for maintenance patients on any anti-TNFa.¹⁴¹

2.5.4 TDM to monitor drug de-escalation or withdrawal

Anti-TNFa TDM was also associated with reduced costs especially when de-escalating IFX dose in patients with IBD. ^151,152 When patients reach clinical and endoscopic remission, proactive TDM can help reduce the amount of the drug in people with supratherapeutic drug levels, which is necessary for their safety and lowers costs. ¹⁵³ TAXIT proved this strategy effective: drug de-escalation was implemented in CD patients with clinical remission and high IFX TL (>7 µg/ml) by reducing their dose or extending the interval between two infusions; 93% of patients (72 patients) were in normal range after their dose was reduced and clinical outcome was unchanged. Using pharmacokinetic parameters may also be

Anti-TNFa TDM was also associated with reduced costs especially when de-escalating IFX dose in patients with IBD. ^151,152 When patients reach clinical and endoscopic remission, proactive TDM can help reduce the amount of the drug in people with supratherapeutic drug levels, which is necessary for their safety and lowers costs. ¹⁵³ TAXIT proved this strategy effective: drug de-escalation was implemented in CD patients with clinical remission and high IFX TL (>7 µg/ml) by reducing their dose or extending the interval between two infusions; 93% of patients (72 patients) were in normal range after their dose was reduced and clinical outcome was unchanged. Using pharmacokinetic parameters may also be