A Real-World Prospective Cohort Study of Patients With Newly Diagnosed Crohn’s Disease Treated by a Multidisciplinary Team: 1-Year Outcomes

Abstract Background Real-world data on outcomes of patients with newly diagnosed Crohn’s disease (ndCD) is limited. We aimed to assess the achievement of corticosteroid-free clinical remission (CS-free CR) and other therapeutic targets 1 year after diagnosis in a cohort of patients with ndCD treated by a multidisciplinary team (MDT). Methods A prospective observational cohort study was conducted on consecutive treatment-naïve adults with ndCD. Patients received management at the treating physician’s discretion, along with a tailored nutritional plan provided by an inflammatory bowel disease (IBD)-oriented dietitian. Patients were guided and educated by an IBD nurse, with flexible communication access to the IBD team. Therapeutic targets were assessed at 1 year. Multivariable logistic regression was used to evaluate predictors of CS-free CR. Results Seventy-six patients (50% female) with a median age of 27 (22–39) years were eligible. Over 75% of patients were assessed by IBD-oriented dietitians and the IBD nurse. Within a median of 4.3 (2.5–6.7) months from diagnosis 60.5% initiated biologics (96% anti- tumor necrosis factor). Dietary intervention was applied to 77.6% of the cohort, either monotherapy (33.9%) or add-on (66.1%). At 1 year, 64.5% of patients achieved sustained CS-free CR, 56.6% biochemical remission, 55.8% endoscopic response, 44.2% endoscopic remission, 30.8% deep remission, and in 39.5% there was an improvement in health-related quality of life (HRQoL). Predictors for CS-free CR were uncomplicated phenotype (B1/P0), lower body mass index, and lower patient-reported outcome 2 scores at diagnosis. Conclusions In a real-world setting at a tertiary medical center, a cohort of ndCD patients treated by an MDT resulted in favorable 1-year outcomes. Over 60% achieved CS-free CR, along with significant improvements in biomarkers and HRQoL.


Introduction
Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) that often has a progressive course.Clinical presentation and treatment response are heterogeneous.Despite the advancement of new therapies and medical strategies, over 50% of patients will develop complications that may lead to surgery over time, [1][2][3] and up to 50% of patients experience at least 1 extraintestinal manifestation. 4 Moreover, CD significantly impairs daily life and psychological well-being and may lead to permanent disability. 52][13] The real-world application of such strategies in synchronization requires a multidisciplinary team (MDT) approach. 14However, data on the actual impact of MDT application on patient outcomes are scarce.
We have established a structured MDT approach for all patients in our IBD center.Focusing on patients with CD, we recruited and prospectively observed an inception cohort of patients with newly diagnosed CD (ndCD) who are treated and cared for according to current standards 15 based on the treating physician's discretion.A structured MDT approach is applied, and comprehensive clinical and exploratory data are collected.
We hereby aimed to assess the rates of the recommended therapeutic targets at 1 year after diagnosis (based on the STRIDE-II consensuses 7 ), specifically looking at sustained corticosteroid-free clinical remission (CS-free CR) and evaluating the possible benefits of our MDT approach.

Study Design and Participants
This prospective observational longitudinal study was conducted in a tertiary IBD center (Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel).Our IBD center is part of Clalit Health Services (the largest health maintenance organization [HMO] in Israel, a public health service) that provides care for patients from the affiliated community clinics in our catchment area and hospital-based patients, allowing a heterogeneous population of patients with ndCD.We screened all consecutive adults (aged ≥ 18 years old) with established ndCD (within the 6 months before enrollment) and those with suspected CD.Patients were eligible to this inception cohort only if CD diagnosis was confirmed according to accepted clinical, endoscopic, and imaging criteria, 16 see Supplementary Methods for detailed inclusion criteria.Recruitment occurred between 2018 and 2021.
Participants in this inception cohort were managed and followed according to the discretion of the treating physician, based on current standards. 15Cases were discussed during weekly MDT meetings, including IBD-oriented gastroenterologists, a dedicated radiology expert, a surgical team, an IBD-oriented registered dietitians (in Israel it is required to complete a specific training program in gastroenterology and IBD), an IBD registered nurse, coordinators, and additional experts as relevant to the discussed case(s).Furthermore, patients received guidance from (1) IBDoriented dietitians who set a nutritional plan based on physician recommendations, symptoms, clinical disease activity, and phenotype, and (2) an IBD nurse who provided personally tailored guidance, information on the disease and medications, and assistance in reaching the therapeutic goals.Patients communicated with the IBD team via email, messages, or phone calls between clinic visits.Finally, each patient underwent scheduled semiannual study visits for comprehensive data collection (see Supplementary Figure 1-study scheme).
For prediction analysis, we included only patients who were naïve to corticosteroids, immunosuppression, or biologic therapy at recruitment and completed 1 year of follow-up under our care.The end of follow-up was determined by the clinic visit at the 1-year period, defined as the latest visit between 9 and 18 months from diagnosis.To assess trends and dynamics of clinical and biomarker status, we captured data at an interim time point, the middle follow-up period for each participant.

Data Collection and Processing
Data were collected via a dedicated case report form.Clinical characteristics, blood, and stool samples for fecal calprotectin (FC) were collected at baseline and in each study visit.Anti-Saccharomyces cerevisiae antibodies (ASCA) IgG and 7 CD-associated polymorphisms that are associated with susceptibility and prognosis were assessed 17 (Supplementary details on susceptible genes variation are presented in Supplementary Table 1).Disease activity was determined by the Crohn's disease activity index (CDAI) and patientreported outcome 2 (PRO-2).Health-related quality of life (HRQoL) was assessed by the short inflammatory bowel disease questionnaire (SIBDQ). 7

Outcomes
We evaluated therapeutic targets according to STRIDE-II recommendations 7 at 1 year after diagnosis.The primary outcome was the 1-year rate of sustained CS-free CR, defined as a combination of CR based on CDAI < 150 without any CS therapy, active perianal disease, treatment escalation, or hospitalization for more than 3 months preceding the analysis-a stringent outcome.Secondary outcomes were: PRO-2 symptom remission-defined as a mean daily score of abdominal pain ≤ 1 and stool frequency ≤ 3; biochemical remission-defined as a combination of C-reactive protein (CRP) < 1 mg/dL and FC < 150 µg/g; endoscopic response-defined as >50% decrease in simple endoscopic score for CD (SES-CD); endoscopic remission-defined as SES-CD < 3; deep remission-defined as a composite of clinical, biochemical, and endoscopic remission and improvement in HRQoL based on the overall change in the SIBDQ, defined as an increase of 9 points.

Statistical Analysis
Categorical variables were expressed as the frequency or percentage.Continuous variables were evaluated for normal distribution and expressed as the mean and SD or median and interquartile range (IQR).Comparison of categorical variables was performed using the Chi-square test or Fisher's exact test, and continuous variables were compared using the Mann-Whitney U test.We used the nonparametric Wilcoxon rank test to compare paired samples.For analysis of predictors, we utilized a multivariable logistic regression using a backward stepwise method for variable selection (P-value > .1 on the Wald test was used for variable removal).All reported P-values are 2-sided, P-values < .05were considered significant.Data were analyzed using SPSS (IBM SPSS Statistics, version 28.0,IBM Corp., Armonk, NY, 2021) and R Foundation for Statistical Computing (version 3.3.3,Vienna, Austria) were used for analysis.

Ethical Consideration
Local and national ethics committees approved the protocols: Rabin Medical Center IRB approval no.0298-17; IRB approval no. for genetics analysis 0299-17.Written informed consent was obtained from all participants.
Lastly, only 21% (16/76) of our real-world cohort would have been eligible to participate in a registration randomized clinical trial (RCT) if the latest inclusion criteria had been

MDT Management
Overall, 77.6% of patients (59/76) received dietary therapy (either monotherapy-20 patients, or add-on-39 patients) after being assessed by the IBD-oriented dietitian.Intervention strategies are depicted in Figure 3.Following determination of the treatment strategy by the treating physician, 82.9% of patients (63/76) received guidance from an IBD specialist nurse.The nurse met with each of these patients at least once after enrollment to discuss their condition, provide education, and tailor a monitoring and follow-up plan.Most of these patients (90%) maintained real-time contact with the nurse by multiple interactions: repeated frontal visits for guidance (on average 5.3 frontal visits per patient per year), and also phone calls, text messages, or emails as needed (on average 15.7 interactions [any type] per patient per year).Notably, there was a trend toward more IBD nurse interactions with patients with severe characteristics (a complex perianal disease, deep ulcers, extensive small bowel involvement, narrowing or penetrating disease) (P = .13).For a detailed number of the different interactions with the MDT, see Supplementary Table 2.

Complications and Safety
Within a median of 3 months (IQR: 2.8-11.1),14.5% of patients (11/76) were hospitalized (disease exacerbation, n = 4; small bowel obstruction, n = 3; perianal abscess, n = 4).Of these, 1 patient had a small bowel obstruction and 4 patients with perianal disease underwent surgery.There were no major treatment adverse events; there was 1 event of mild pancreatitis attributed to 6-mercaptopurine that resolved after drug discontinuation, and 1 minor corneal infection unrelated to the IBD medications.Inception Cohort of New Crohn's Disease

Predictors for CS-Free CR at 1-Year
Finally, we assessed whether clinical or biological markers were associated with CS-free CR at 1 year.In univariable analysis, male sex, nonsmoking, lower body mass index (BMI), lower PRO-2 score, and uncomplicated phenotype (B1/P0) at diagnosis were associated with the likelihood of reaching sustained CS-free CR at 1 year (Table 2).Neither ASCA serology nor the genetic variants that are associated with CD course were found to be related with sustained CS-free CR at 1 year.

Discussion
In this real-world inception cohort of patients with ndCD (allcomers) who were treated and cared for by an MDT in a tertiary center with state-of-the-art management strategies, we showed favorable 1-year outcomes based on the prespecified therapeutic targets.Specifically, sustained CS-free CR reflecting a practical, yet stringent definition that includes no active perianal disease, sustained therapy, and no hospitalization > 3 months was demonstrated in >60% of patients, with similar results between patients with baseline mildmoderate versus moderate-severe disease.Furthermore, we found that a substantial proportion of this cohort achieved all other therapeutic targets such as significant improvement in biomarkers, endoscopic healing, and improved quality of life.In a subset of patients with an uncomplicated phenotype (B1/P0), further improved results were demonstrated, reaching 73% sustained CS-free CR at 1 year.Finally, we showed that uncomplicated phenotype, lower BMI, and lower PRO-2 score at diagnosis could predict the likelihood of reaching sustained CS-free CR at 1 year.
To the best of our knowledge, this is the first study reporting real-world data on outcomes of consecutive, treatment-naïve patients with ndCD treated by an MDT while following contemporary strategies of early intervention, top-down, and tight monitoring.We elected to assess sustained CS-free CR, a strict definition for CR that emulates the desired outcome of interest, especially from the patients' perspective.
9][20][21][22][23] Moreover, most of these trials consider a relatively limited outcome like CDAI < 150 while assessing a specific facet of IBD care-such as drug efficacy, the timing of intervention, or specific management strategies.Finally, almost all RCTs had rigorous inclusion criteria excluding a large proportion of patients with CD, 24,25 which is also demonstrated in our real-world cohort in which almost two-thirds of trialineligible patients (38/60) were actually recommended for advanced therapy.
The favorable results in our study may be partially explained by the characteristics of the study population, patients with early CD, naïve to biologics.Another factor is the rapidity of intervention, about 70% were recommended an advanced treatment strategy to control their disease, of whom 85% started biological therapy within 4 months from diagnosis, similar to contemporary trends observed in the administrative data recently published from the Israeli epi-IIRN. 26dditionally, a potential explanation might be the high rate of anti-TNF therapy in this cohort; however, it should be underscored that we had very high rates of compliance and adherence, which might be associated with our structured MDT (>75% assessed and cared for by the IBD-oriented dietitians and the IBD nurse).It is also not unlikely that the close contact of these patients with our ancillary team members who provided guidance, education, and accessibility impacted response and remission rates.We and others have already shown that an MDT approach and improved accessibility to medical consults benefit decision-making, patients' quality of care, and rates of hospitalizations [27][28][29][30] ; however, our current results suggest that the MDT approach possibly improves disease outcomes.
We showed that clinical markers of mild disease (uncomplicated phenotype and PRO-2 score) at diagnosis could predict sustained CS-free CR at 1 year.Serology and genetic variants were not associated with outcomes, probably owing to the small sample size and short follow-up period.Nonetheless, smoking, and higher BMI at diagnosis were inversely associated with sustained CS-free CR at 1 year (for each unit increase in BMI, the odds of achieving a favorable outcome would decrease by 1.15 times, or 15%), reflecting the impact of environmental factors on the disease course.This is in line with the recent report by Lopes and colleagues, who demonstrated that adherence to a healthy lifestyle (including nonsmoking and a normal BMI) could prevent CD. 31 Finally, such aspects of lifestyle can be communicated to patients with ndCD and further addressed by the MDT approach.
This study is not without limitations, it is single-center design, the decision-making process was nonstructured, the cohort is relatively small, and only patients who had assessments at baseline and 1 year were included, all possibly introducing bias.The lack of a control group is another important limitation, especially when attempting to assess the impact of MDT specifically on patient outcomes.In fact, a rigorous RCT evaluation of MDT intervention in patients with IBD is less feasible in practice since the MDT approach in our center has already been incorporated into standard care.
Additionally, the prevalence of anti-TNF therapy was notably high, approximating 60%.This could have been Inception Cohort of New Crohn's Disease a contributory factor in achieving favorable outcomes.Nonetheless, we posit that this elevated rate of an early advanced therapeutic approach for patients with ndCD aligns with the exigencies of clinical practice in Israel 26,32 and also the STRIDE-II recommendations. 7Moreover, while the utilization rate of anti-TNF therapy may undergo adjustments in certain places due to the introduction of novel pharmacologic agents for the treatment of CD, it will be still pertinent in jurisdictions where economic considerations necessitate the prioritization of biosimilar medications over cost-prohibitive newer therapies. 33inally, there was no 1 specific intervention in this cohort study, but rather a real-world practice utilizing multiple options, mostly tailored, taken together with a specialized MDT.This may appear as a methodological flaw that can imped external validity and generalizability of our findings.However, facing the complexity of CD, this representation of the results is an actual strength.Our study reflects the real-world practice, where we must address the complexities encountered daily, where clinicians manage a diverse patient population and where a universal, curative approach remains elusive.
In conclusion, in this inception cohort of patients with ndCD treated and cared for by an MDT in a real-world setting at a tertiary medical center, there were favorable 1-year outcomes.This cohort represents a mix of patients with ndCD as typically seen in the community and other referral centers with outcomes improved compared to previous reports. 34,35t is most likely that the early introduction of effective therapy was the main determinant that impacted therapeutic targets but it is also plausible that the systematic MDT approach, which allowed attention to the multiple facets of CD patients' care, also had a contributory effect.Therefore, we advocate for the ubiquitous implementation of an MDT approach across all IBD centers/units and in settings where access to a proficient MDT is limited, telemedicine or remote consultations from specialized MDT units that can serve as an effective alternative.This MDT model may allow access to high-quality healthcare and potentially catalyze transformative changes in healthcare delivery systems, thereby enhancing patient care outcomes.

Figure 4 .
Figure 4. Therapeutic targets.(A) Treatment targets at 1 year after diagnosis: proportion of patients with sustained corticosteroid-free clinical remission (CS-free CR), biochemical remission, endoscopic response, endoscopic remission, and deep remission; endoscopic data were available for 52 patients at 1 year.(B) Alterations in PRO-2 (patient-reported outcome 2), CRP (C-reactive protein), fecal calprotectin, and SIBDQ (short IBD questionnaire) through time-diagnosis to 1 year; the SIBDQ data were available for 73 patients; data represented as median and IQR.* 1-year-latest visit between 9 and 18 months from diagnosis; ** interval time-middle of follow-up period.