This is a longitudinal, prospective study involving all pediatric CD patients aged 9–17 years and 364 days, recruited from a single Pediatric Gastroenterology Unit Reference Center in an outpatient setting (convenience sample). The follow-up period spanned 18 months, with data collection carried out between 2 January 2021, and 28 February 2023. Participants completed surveys at baseline and 6-month intervals during their scheduled appointment (Figure 1). Patients were stratified into two groups based on pediatric Crohn's disease activity index (PCDAI)—PCDAI (24, 25): remission group PCDAI <10 (G1) and active disease group PCDAI >10 (G2) at each survey interval. Informed assent (for patients under 16 years) and consent (for patients over 16 years and caregivers of patients under 16 years) were obtained before enrollment. Patients who did not sign the written assent/consent, those with limitations in verbal or written comprehension of Portuguese, hospitalized patients, and recently diagnosed patients (<1 month) were excluded.

All data were collected by the same investigator who also performed the clinical assessment (Figure 2) at baseline and during the scheduled appointments (every 6 months). All pediatric patients completed the questionnaires in the waiting room before the medical appointment or during treatment infusions. Clinical and demographic data were collected from patients' records and supplemented with a brief questionnaire covering academic data and extracurricular/social activities. Different types of data were collected during the study assessment periods (Figure 1) and included the following.

Descriptive statistics were used to summarize the demographic and clinical characteristics of the participants. Paired sample t-tests were used to assess differences between PROMIS measures at individual time points, while the Friedman test was applied to evaluate changes in clinical assessments and disease self-perception over time. Longitudinal changes in PROMIS measures were evaluated using linear mixed models (LMMs), which accounted for repeated measures and included fixed effects for time, sex, age, educational level, and treatment type, with random intercepts for each subject. LMM was selected to account for the nested structure of repeated measures within participants, enabling the analysis of temporal changes while controlling for individual variability.

This study was designed to explore temporal trends in PROMIS measures rather than conduct sensitivity analyses or directly assess associations with disease activity. This reflects the observational nature of the study and the constraints of the available sample size. While no direct statistical tests of association between PROMIS measures and disease activity markers were performed, model coefficients were compared to assess common directional trends. The minimally important difference (MID) threshold of 3 was used to determine clinically significant changes in PROMIS scores.

The study included 31 participants, of whom 58% were female (n = 18), with a mean age of 15.3 (±2.0). Three patients were lost to follow-up during the study. The mean age at CD diagnosis was 12.7 (±3.4) years, and the mean disease duration was 2.7 years (±2.7). Complete demographic and clinical data are presented in Table 1.

At baseline, 70.9% (n = 22) of participants were considered to be in remission according to the physician assessment (Table 2), with a mean PCDAI of 7.5 (±9.8). With regard to biochemical remission, although serological markers were within normal ([mean Hb o13 (±1.3) g/dL, CRP 0.6 (±1.7) mg/dL, ESR 21 (±19.8), and Ferritin (±1,189.7) µg/dL)], the mean FC of 803.7 (±1,189.7) µg/g indicated active disease, with 32% (n = 10) presenting FC < 250 µg/g. Imaging revealed inactive disease in 41.9% (n = 13) of participants.

Most participants (80.6%, n = 25) perceived their health condition as “better or the same” compared with the previous 6 months, with a mean IMPACT-III score of 73.2 (±13.1). During follow-up, clinical stability was observed in most patients, with mean PCDAI scores remaining in the inactive range despite persistently elevated FC values. Treatment intensification with biological agents was required in 54.8% (n = 17) of participants, but none required hospitalization.

PROMIS scores exhibited distinct temporal trends over the study period (Table 2, Figure 3). Global Health showed significant improvements at T2 and T3, while Pain Interference and Fatigue consistently decreased, stabilizing in later time points. Depression and Anxiety showed early improvement during the study period but fluctuated at T3. PROMIS Physical Activity peaked at T2, while Life Satisfaction peaked at T1, showing the highest reported levels early in the study.

A bivariate analysis revealed significant differences in pain interference scores between T0 and T1 (p = 0.040) and in physical activity scores between T2 and T3 (p = 0.030). LMM analyses identified statistically and clinically meaningful changes (exceeding the MID threshold of 3) in several PROMIS measures (Table 3): •

Global Health improved significantly at T2 (β = −3.230, p < 0.05) and T3 (β = −5.695, p < 0.01).

These findings highlight temporal trends in PROMIS measures, consistent with the study's aim to explore their longitudinal changes.

No statistically significant changes were found in laboratory measures between individual time points (Table 4). However, hematocrit increased significantly at T3, and platelet count decreased significantly at T2 and T3. PCDAI scores showed a significant reduction by T3 (p < 0.05), indicating overall clinical improvement over the study period (Figure 3).

Some overlapping trends were observed between PROMIS scores and clinical measures. For example, pain interference scores appeared to decrease alongside reductions in PCDAI scores, and improvements in Global Health and Life Satisfaction coincided with increases in hematocrit. However, no direct statistical tests were performed to assess these associations. While these findings are exploratory, they suggest that PROMIS scores may capture aspects of patient health that complement traditional clinical markers.

PROMIS measures, such as Global Health, Life Satisfaction, and Pain Interference, showed trends aligning with patient-reported outcomes, including IMPACT-III scores and self-perception of disease stability. Patients reporting stable or improved disease perception at baseline exhibited concurrent improvements in PROMIS scores over time. However, patients reporting worsening disease perception showed more variable PROMIS trends.

Both IMPACT-III scores and PROMIS measures demonstrated positive trends during the study period. Depression, Anxiety, Pain Interference, and Fatigue followed expected decreasing trends as patients reported improved wellbeing. These findings reflect an overall pattern of improved patient-reported outcomes but remain exploratory, as causal relationships cannot be established within this study.

Table 5 summarizes physician clinical assessments and patient self-perception of disease over time. No statistically significant differences were observed in physician clinical assessment scores between time points. However, multinomial regression models indicated that patients with a “Moderate” disease score were significantly less likely to achieve remission at T2 and T3 compared with T0 (p < 0.001). Patients with a “Mild” disease score showed no significant change in remission likelihood over time.

Bivariate analysis of self-perception revealed significant differences between T1 and T2 (p = 0.01) and between T1 and T3 (p = 0.03). Patients perceiving their disease as stable (“feeling the same” or “better”) at baseline were more likely to report improvement at later time points. These trends align with broader improvements in PROMIS measures, although causal relationships were not tested.

PROMIS measures, particularly Global Health, Pain Interference, and Fatigue, showed significant improvements over the study period, reflecting better physical and emotional health among participants. These trends coincided with overall clinical stability, as indicated by PCDAI scores, platelet counts, and hematocrit levels. While trends in PROMIS measures, such as Pain Interference and Global Health, appeared to align with changes in the PCDAI and hematocrit, these findings are observational and require further statistical validation to confirm their significance. However, PROMIS measures also varied independently of objective clinical markers, such as fecal calprotectin (FC), emphasizing the unique insights that PROMIS instruments provide into patient-perceived health and QOL. This finding aligns with previous studies that underscore the independence of PROs from traditional clinical markers in pediatric IBD (9, 34).

Some PROMIS domains, including Depression and Anxiety, exhibited fluctuations rather than consistent trends, highlighting the complex interplay between physical symptoms, psychological wellbeing, and external factors and the multifaceted nature of pediatric IBD, underscoring the importance of integrating psychosocial dimensions into disease management (35–37). PROMIS measures, particularly those addressing emotional health, provide valuable insights into how physical symptoms interact with psychological and social wellbeing. These findings emphasize the complex nature of managing pediatric CD and the necessity of considering both physical and psychosocial dimensions of health in clinical practice.

Our findings align with earlier longitudinal research, such as Arvanits et al., which suggested that PROMIS measures respond to changes in disease activity over time. More recently, two longitudinal studies using a web-based cohort of pediatric IBD patients (19, 20) evaluated PROMIS pediatric measures, including domains of pain interference, anxiety, depression, fatigue, and peer relationships. These studies demonstrated significant associations between PROMIS scores and disease activity, documenting clinically meaningful changes in PROs related to clinical markers and QOL. While our study similarly observed trends in PROMIS measures consistent with clinical improvement, the lack of direct statistical testing of these associations limits our ability to draw definitive conclusions.

Interestingly, we found limited changes in IMPACT-III scores compared with PROMIS measures. IMPACT-III, as a disease-specific HRQOL instrument, focuses primarily on IBD-related QOL, whereas PROMIS captures a broader range of physical, emotional, and social health domains. This distinction may explain the discrepancies observed and highlight the advantage of PROMIS instruments for holistic health assessment in pediatric CD patients.

The timing of this study, coinciding with the COVID-19 pandemic, likely influenced PROMIS scores. At baseline, PROMIS measures reflected the negative impact of pandemic-related restrictions on physical and emotional wellbeing. As restrictions eased and access to healthcare improved, PROMIS scores also improved, particularly in domains such as Global Health and Life Satisfaction. Previous studies have documented the pandemic's impact on IBD patients, reporting heightened stress levels and reduced HRQOL during periods of limited healthcare access (38). Our findings are consistent with these observations and underscore the importance of contextual factors in interpreting PROs.

PROMIS pediatric instruments demonstrated value in capturing dimensions of health that extend beyond traditional clinical markers, offering a more comprehensive perspective on patient wellbeing. This is particularly relevant in pediatric IBD, where symptoms often poorly correlate with inflammation or complications (9, 34). The independence of PROMIS measures from objective markers underscores their potential as complementary tools for monitoring patient health in clinical settings.

Additionally, the alignment of PROMIS trends with patient-reported self-perception of disease further supports their utility. Participants reporting the notion of stable (“feeling the same”) or improved disease (“feeling better”) perception exhibited corresponding improvements in PROMIS scores, particularly in domains such as Global Health, Life Satisfaction, and Pain Interference. PROMIS trends, particularly in domains such as Global Health and Life Satisfaction, appeared to align with patient-reported perceptions of disease stability. However, these findings are exploratory, as no direct statistical associations were tested. These findings highlight the importance of integrating patient perspectives into disease management and clinical decision-making.

The longitudinal design of this study, combined with standardized disease assessment and repeated measures using LMM, enhances the robustness of our findings. By capturing temporal changes in PROMIS scores over an 18-month follow-up period, this study contributes to the growing body of evidence supporting the use of PROs in pediatric CD.

However, the study has several limitations. The relatively small sample size limits the generalizability of our findings, and the exclusion of recently diagnosed or hospitalized patients reduces the applicability of our results to broader pediatric IBD populations. Furthermore, while PROMIS measures demonstrated trends aligning with clinical improvement, sensitivity analyses or statistical tests testing associations between PROMIS responsiveness and clinical markers were not performed, emphasizing the exploratory nature of these findings and restricting our ability to fully evaluate the responsiveness of these measures. Future studies with larger and more diverse cohorts are needed to address these limitations and validate the clinical utility of PROMIS instruments in pediatric CD.