Persistent disease burden despite advanced therapies in inflammatory bowel disease: a real-world patient-reported survey from Greece

Abstract

Objectives

Despite therapeutic advances, inflammatory bowel disease (IBD) remains a lifelong debilitating disorder with substantial burden. The study aimed to investigate disease burden and unmet needs in IBD patients receiving advanced therapies in Greece.

Methods

Between October 2023 and January 2024, adult CD and UC patients who were members of Hellenic Society of Crohn’s disease’s and Ulcerative Colitis’ patients (HELLESCC) and receiving advanced therapies completed a structured self-reported questionnaire. The survey collected data on sociodemographic characteristics, smoking status, comorbidities, disease activity, disease characteristics, current medications, and patient-reported outcomes (PROs; Short Inflammatory Bowel Disease Questionnaire [SIBDQ], Work Productivity and Activity Impairment [WPAI], Patient Health Questionnaire-9 [PHQ-9], treatment satisfaction and adherence). Both univariate and multivariate logistic regression analyses were performed to determine associated factors.

Results

Among 287 patients with IBD (201 with CD, 86 with UC) receiving advanced therapies, 57.1% had active disease. Overall, 76.4% reported impaired QoL, 30.3% work productivity loss, and 38.4% activity impairment, while nearly half exhibited moderate-to-severe depressive symptoms. Notably, 39.1% expressed dissatisfaction with their advanced therapy, while 10.9% reported reduced adherence. No significant differences were observed between CD and UC patients across PROs, except for adherence. Higher disease activity was consistently associated with worse QoL, greater work impairment, increased depressive symptoms, and lower treatment satisfaction.

Conclusion

Despite advanced therapies, IBD burden remains substantial among Greek patients. A considerable proportion experience poor QoL, increased work impairment, significant depressive symptoms, and persistent disease activity. Marked treatment dissatisfaction, reported by four out of ten patients, highlights an unmet need for more effective management strategies.

1. Introduction

Inflammatory bowel disease (IBD), mainly represented by Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic debilitating disorder characterized by immune-mediated inflammation of the gastrointestinal tract (1). Both CD and UC follow a progressive clinical course, defined by alternating periods of relapse and remission, and present a broad spectrum of extraintestinal, systemic manifestations in addition to intestinal damage (2, 3).

Over recent decades, the therapeutic landscape for IBD has evolved considerably (4). The advent of biologic therapies, such as anti-tumor necrosis factor (TNF), anti-integrin and anti-interleukin (IL)-12/23 agents, along with newer small-molecule drugs including Janus Kinase (JAK) inhibitors and Sphingosine-1-Phosphate (S1P) receptor modulators, has enabled more targeted treatment approaches and improved clinical outcomes (5). However, clinical effectiveness remains modest with persistent significant unmet needs, including a “therapeutic ceiling” in treatment response, high rates of disease relapse and treatment-related toxicity (5). This is also reflected in real-world evidence demonstrating suboptimal persistence with biologic therapies, often driven by dissatisfaction with treatment response or adverse events (6). Notably, fewer than half of IBD patients remain on their initial biologic therapy after one year (48.48% in CD and 44.78% in UC) (6). As a result, many patients continue to experience a considerable disease burden, characterized by ongoing symptoms, increased pain and fatigue, and impaired health-related quality of life (HRQoL) (5, 7).

Growing recognition that objective measures of disease activity may not adequately reflect the multifaceted nature of IBD has led to the increasing integration of patient-reported outcomes (PROs) into disease assessment (8–10). Consequently, PROs are now recognized as essential endpoints in both clinical trials and clinical practice of IBD (8, 9, 11). Validated questionnaires commonly used to quantify these outcomes include the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) for disease-specific quality of life (QoL) (12–16), the Work Productivity and Activity Impairment (WPAI) questionnaire for work-related outcomes (17–19), and the Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms (20, 21).

Global real-world evidence incorporating PROs highlight that despite advanced therapies, IBD is characterized by persistent symptoms, flares, and diminished QoL (7, 22–24). Consistent with this, data from Greece indicate that IBD patients continue to experience impaired QoL, work impairment, depression, and ongoing disease activity (25, 26). Although UC patients report improved satisfaction with physician care and disease management, communication gaps persist, particularly around QoL and psychosocial concerns (27), while CD patients appear to face greater limitations in daily and social functioning (28). However, Greek data remain limited, particularly in the context of patients receiving advanced therapies, and may not fully capture the multidimensional burden of IBD in this treatment setting.

In this context, the present study aimed to evaluate the ongoing burden and unmet medical needs of IBD in patients who receive advanced therapies in Greece. For this purpose, a structured questionnaire employing a comprehensive set of validated PRO instruments was distributed to members of the Greek national IBD patients’ association. Associations between demographic and disease-related factors, and PROs were also investigated.

2. Materials and methods

2.1. Study design and population

From October 2023 to January 2024, a cross-sectional survey was conducted in collaboration with Hellenic Society of Crohn’s disease and Ulcerative Colitis’ patients (HELLESCC) (25, 26). Eligible participants were adults (age≥18 years) diagnosed with UC or CD, members of this Greek patient association. The questionnaire was distributed as a link via email or phone. Recruitment was conducted by HELLESCC staff without collecting participants’ personal data. Prior to participation, all participants were informed about the purpose of the study and were asked to provide their consent. Survey participation was entirely voluntary, and participants had the right to withdraw at any time. All collected data were kept anonymous and handled confidentially.

2.2. Questionnaire and variables

The questionnaire was developed in Greek (25, 26). Collected variables included sociodemographic characteristics, smoking habits, history of comorbidities, disease characteristics, disease activity, current medications, and PROs (SIBDQ, WPAI, PHQ-9, treatment satisfaction, and treatment adherence). Disease activity in UC was evaluated using the Simple Clinical Colitis Activity Index (SCCAI) index score (29) and classes were defined as follows: remission (0–2), mild (3–5), moderate (6–11) and severe (>11) (30, 31). For CD, disease activity was measured with the Harvey-Bradshaw Index (HBI), defining remission (0-4), mild (5-7), moderate (8-16) and severe (>16) (32). All available prescription medications at the time of survey were recorded. These included advanced therapies, such as tumor necrosis factor inhibitors (TNFi), an integrin α4 inhibitor, an interleukin-12/23 inhibitor (IL-12/23i), and Janus kinase inhibitors (JAKi) as well as non-advanced therapies such as 5-aminosalicylic acids (5-ASAs), corticosteroids, immunosuppressants and antibiotics.

The questionnaire included validated measures to evaluate the following PROs: QoL (SIBDQ), work productivity (WPAI) and psychological burden (PHQ-9) (25, 26). The SIBDQ scores range from 10 to 70 (16, 33), with QoL impairment classified as mild, moderate or severe for SIBDQ scores of 60-70, 45–59 and 10-44, respectively (15, 16, 34). The SIBDQ scores below 60 were considered indicative of moderate-to-severe QoL impairment and scores of 60 or higher were categorized as normal QoL. The WPAI scores (0-100%) measure absenteeism (work time missed), presenteeism (impairment at work), work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment (17, 35). Similar to previous studies, WPAI scores were categorized as mild (0-19%), moderate (20-49%), and severe (≥50%) (25, 26). PHQ-9 scores range from 0 to 27, with increasing values showing greater depressive symptom severity. The threshold score of 10 or above corresponds to moderate-to-severe depressive symptoms, potentially indicative of clinically relevant depression. Severity categories were defined as follows: 0-4 = minimal or none; 5-9 = mild; 10-14 = moderate; 15-19 = moderately severe; 20-27 = severe) (21, 36, 37).

Treatment satisfaction was evaluated with a study-specific, 5-point Likert scale question capturing participants’ level of satisfaction with their current treatment (not at all; little; quite; a lot; very much satisfied) (25, 26). Participants reporting lower satisfaction or dissatisfaction, defined as responses of “not at all,” “little,” or “quite satisfied”, were also asked to specify the reasons underlying their dissatisfaction. A study-specific, 5-point Likert scale question was also used to assess treatment adherence (I follow my treatment regularly; there are few times I forget to/I do not take my treatment; sometimes I forget to/I do not take my treatment; many times, I forget to/I do not take my treatment; I never take my treatment), and among participants reporting suboptimal adherence, further data were collected on factors contributing to non-adherence (25, 26).

2.3. Statistical analysis

Categorical variables were summarized using frequencies (n) and percentages (%), while continuous variables using means and standard deviations (SD). Sociodemographic and clinical variables, and PROs (SIBDQ, WPAI-UC, PHQ-9, treatment satisfaction and treatment adherence) were described by disease type (CD or UC). The association of disease type with sociodemographic and clinical factors was investigated with the Pearson’s χ2 test for categorical variables and with the Mann-Whitney test for continuous variables. The mean or proportional differences between CD and UC groups and their corresponding 95% confidence intervals (CIs) were also calculated. CIs enhance clinical interpretation by providing a plausible range of values in the actual units of measurement, along with the direction and strength of the effect (38). It is important to note that the outcome comparisons are cross-sectional and should not be interpreted as differences in response to treatment. Relationships between PROs and disease activity were quantified using the Spearman’s correlation coefficient (SCC). Sociodemographic and clinical factors associated with PROs were analyzed at both bivariate and multivariate levels using logistic regression. Factors with a p-value < 0.15 in bivariate analyses were included in a multivariate logistic regression model with stepwise selection. Effect sizes are presented as odds ratios (OR) with 95% CIs. Statistical significance was defined as p < 0.05. Data cleaning, data manipulation and data analysis were conducted using the statistical software IBM SPSS Statistics 29.0.

3. Results

3.1. Participants characteristics

The questionnaire was sent to 1.334 patients and returned by 472 [participation rate: 35.4%] (Supplementary Figure 1). A total of 287 patients were receiving advanced therapies and constituted the study population (51 patients who were not receiving any IBD-related drug therapy and 134 patients who were not receiving advanced therapy were excluded from the analysis). The mean age [± SD] was 41.8 [10.4], 57.8% were female, and most participants (54.9%) were in paid employment. The mean age of diagnosis was 30.5 [10.7] and the mean disease duration was 11.3 [7.4]. The mean time from symptom onset to diagnosis was 14.4 months [18.2]. During the last 12 months, the mean number [SD] of gastroenterologist visits was 4.3 [8.3] and 17.7% of patients had at least one hospitalization. A total of 131 patients (65.2%) had at least one comorbidity (Table 1), with arthritis (38.9%) and depression (29%) being the most frequently reported (Supplementary Table 1).

Table 1.

Characteristics of the study population.

Characteristics	Total (n= 287)	CD (n=201)	UC (n=86)	Difference (95% CI)a	p-valueb
Age, years
Mean [SD]	41.8 (10.4)	41.8 (10.1)	41.9 (11.2)	-0.1 (-2.7-2.5)	0.939
Gender, n (%)	n=287	n=201	n=86
Male	121 (42.2%)	81 (40.3%)	40 (46.5)	-6.2% (-18.6% - 6.2%)	0.199
BMI, n (%)	n=287	n=201	n=86
Underweight (<18.5)	10 (3.5%)	9 (4.5%)	1 (1.2%)	3.3% (-1.7% - 7%)	0.380
Normal (18.5–25)	104 (36.2%)	71 (35.3%)	33 (38.4%)	-3% (-15.3% - 8.0%)
Overweight (25–30)	116 (40.4%)	84 (41%)	32 (37.2%)	4.6% (-7.8% - 16.6%)
Obese (≥30)	57 (19.9%)	37 (18.4%)	20 (23.3%)	-4.8% (-15.5% - 5.3%)
Residence, n (%)	n=287	n=201	n=86
Urban area (>10.000 residents)	243 (84.7%)	172 (85.6%)	71 (82.6%)	3.0% (-6.0%, 12.8%)	0.592
Family status, n (%)	n=206	n=141	n=65
Married	107 (51.9%)	71 (50.4%)	36 (55.4%)	-5% (-19.3% - 9.6%)	0.55
Socioeconomic status, n (%)	n=206	n=141	n=65
In paid employment§	113 (54.9%)	76 (53.9%)	37 (56.9%)	-3.0% (-17.3% -11.5%)	0.764
Education level, n (%)	n=206	n=141	n=65
Bachelor degree or more	115 (55.8%)	73 (51.8%)	42 (64.6%)	-12.8% (-26.5% - 1.7%)	0.057
Smoker, n (%)	n=287	n=201	n=86
Current smoker	101 (35.2%)	83 (41.3%)	18 (20.9%)	20.4% (8.8% - 30.7%)	0.001
Age at diagnosis, years	n=287	n=201	n=86
Age at diagnosis, Mean [SD]	30.5 (10.7)	30.5 (10.5)	30.4 (11.6)	-0.1 (-2.7-2.5)	0.939
Disease duration, years	n=287	n=201	n=86
Disease duration, Mean [SD]	11.3 (7.4)	11.3 (7.6)	11.5 (6.9)	-0.2 (-2.1-1.7)	0.824
Time from symptoms’ onset to diagnosis, months	n=287	n=201	n=86
Time from onset, Mean [SD]	14.4 (18.2)	15.6 (19.0)	11.5 (16.1)	4.1 (-0.5, 8.7)	0.082
Surgery during the last 12 months	n=203	n=139	n=64
Surgery, n (%)	61 (30.0%)	56 (40.3%)	5 (7.8%)	32.5% (20.7% - 42.0%)	<0.001
Gastroenterologist visits in the past 12 months	n=203	n=139	n=64
Number of visits, Mean [SD]	4.3 (8.3)	3.5 (3.7)	5.8 (13.7)	-2.3 (-5.8, 1.2)	0.189
Hospitalization in the past 12 months, n (%)	n=203	n=139	n=64
Hospitalization	36 (17.7%)	24 (17.3%)	12 (18.8%)	-1.5% (-13.4% - 9.5%)	0.844
Comorbidities, n (%)	n=201	n=138	n=63
One or more	131 (65.2%)	91 (65.9%)	40 (63.5%)	2.4% (-11.5% - 16.8%)	0.752
Disease Activity*, n (%)	n=287	HBI (n=201)	SCCAI (n=86)
Remission	123 (42.9%)	87 (43.3%)	36 (41.9%)	1.4% (-11.1% - 13.7%)
Mild	77 (26.8%)	51 (25.4%)	26 (30.2%)	-4.9% (-16.4% - 6.3%)
Moderate to Severe	87 (30.3%)	63 (30.3%)	24 (27.9%)	3.4% (-8.3% - 14.5%)	0.673
Moderate	83 (28.9%)	60 (29.9%)	23 (26.7%)	3.1% (-8.5% - 14.0%)
Severe	4 (1.4%)	3 (1.4%)	1 (1.2%)	--
Ongoing treatment
Biological agents, n (%)	n=287	n=201	n=86
TNF inhibitors	191 (66.6%)	145 (72.1%)	46 (53.5%)	18.6% (6.4% - 30.6%)	0.002
Integrin α4 inhibitor	29 (10.1%)	11 (5.5%)	18 (20.9%)	-15.5% [-24.9% - -6.5%)	<0.001
Interleukin-12/23 inhibitor	56 (19.5%)	43 (21.4%)	13 (15.1%)	6.3% (-3.7% - 15.3%)	0.219
JAK inhibitors	11 (3.8%)	2 (1%)	9 (10.5%)	-9.5% (-16.7% - -3.1%)	<0.001
Non-biologic agents, n (%)	n=287	n=201	n=86
5-ASA	65 (22.6%)	14 (7%)	51 (59.3%)	-52.3% (-62.5% - -40.8%)	<0.001
Corticosteroids	28 (9.7%)	15 (7.5%)	13 (15.1%)	-7.7% (-16.5% - 0.5%)	0.045
Immunosuppressants	56 (19.5%)	36 (17.9%)	20 (23.3%)	-5.3% (-16.0% - 4.7%)	0.295
Antibiotics	11 (3.8%)	8 (4%)	3 (3.5%)	0.5% (-6.1% - 4.8%)	0.842

5-ASA, 5-aminosalicylic acid; BMI, body mass index; CD, Crohn’s disease; JAK, Janus kinase; SD, standard deviation; TNF, tumor necrosis factor; UC, ulcerative colitis.

*SCCAI [remission: <2; mild: 3 to 5; moderate: 6 to 11; severe: >11], HBI [remission: 0-4; mild: 5-7; moderate: 8-16; severe:>16].

^§Full- or part-time employment or self-employed.

^aUnadjusted mean difference (95% CI) between groups for continuous variables and difference in percentage points (95% CI) between groups for categorical variables.

^bPearson’s χ² test or Mann-Whitney test.

At the time of assessment, 42.9% of patients treated with advanced therapies were in remission, 26.8% had mild disease and 30.3% had moderate-to-severe disease. Overall, 66.6% were treated with TNF inhibitors, 19.5% with IL-12/23 inhibitors, 10.1% with integrin α4 inhibitor, and 3.8% with Janus kinase inhibitors (Table 1). A proportion of patients were also receiving non-advanced therapy like 5-ASAs (22.6%), corticosteroids (9.7%), immunosuppressants (19.5%) and antibiotics (3.8%).

Notably, a significantly higher proportion of CD patients had undergone surgery in the preceding 12 months compared to UC patients (40.3% vs 7.8%, p <0.001). In addition, current smoking was more prevalent among CD patients than among UC patients (41.3% vs. 20.9%, p = 0.001) (Table 1).

3.2. Patient-reported outcomes

The mean SIBDQ score was estimated at 46.0 ± 15.1, with the majority of participants (76.4%) reporting moderately to severely impaired QoL (Table 2). No statistically significant differences were observed between the CD and UC cohorts.

Table 2.

Patient-reported outcomes in the study population.

PROs	Total	CD (n=201)	UC (n=86)	Difference (95% CI)a	p-valueb
Quality of life
SIBDQ	n=220	n=148	n=72
Mean [SD]	46.0 (15.1)	45.4 (15.4)	47.4 (14.5)	-2.0 (-6.3-2.2)	0.351
Moderate to severe impact [<60], n (%)	168 (76.4%)	113 (76.3%)	55 (76.4%)	-0.1 (-11.6% - 12.3%)	0.995
Productivity loss
WPAI
Absenteeism	n=116	n=77	n=39
Mean [SD]	12% (24.9%)	11.8% (23.6%)	12.4% (25.1%)	-0.4% (-10% - 10%)	0.911
Moderate to severe impact [≥20%], n (%)	23 (19.8%)	15 (19.5%)	8 (20.5%)	-1.0% (-17.2% - 13.8%)	0.895
Presenteeism	n=110	n=74	n=36
Mean [SD]	22.9% (26.2%)	22.4% (25.1%)	23.9% (28.5%)	-1.4% (-12.0% - 9.1%)	0.786
Moderate to severe impact [≥20%], n (%)	53 (48.2%)	28 (51.4%)	15 (41.7%)	9.7% (-10.1%, 28.5%)	0.34
Work productivity loss	n=116	n=77	n=39
Mean [SD]	30.3% (32.7%)	29.4% (31.4%)	32.2% (35.5%)	-2.7% (-15.5% - 10.0%)	0.671
Moderate to severe impact [≥20%], n (%)	60 (51.7%)	42 (54.5%)	18 (46.2%)	8.4% (-10.7% - 16.9)	0.393
Activity impairment	n=212	n=145	n=67
Mean [SD]	38.4% (32.3%)	37.9% (32.0%)	39.4% (31.2%)	-1.4% (-10.9% - 7.9%)	0.758
Moderate to severe impact [≥20%], n (%)	143 (67.5%)	99 (68.3%)	44 (65.7%)	2.6% (-10.7% - 16.3%)	0.707
Psychological burden
PHQ-9	n=212	n=145	n=67
Mean [SD]	10.2 (7.7)	10.1 (7.7)	10.4 (7.9)	-0.3 (-2.5-2)	0.815
Moderate to severe impact [≥10], n (%)	102 (48.1%)	68 (46.9%)	34 (50.7%)	-3.8% (-18.1%, 10.5%)	0.602
Treatment satisfaction	n=271	n=188	n=83
Yes, n (%) ¥	165 (60.9%)	110 (58.5%)	55 (66.3%)	-7.8% (-19.7%, 4.8%)	0.142
Treatment adherence	n=266	n=188	n=83
Yes, n (%) §	237 (89.1%)	174 (95.1%)	63 (75.9%)	19.2% (9.6%, 29.0%)	<0.001

CD, Crohn’s disease; PHQ-9, Patient Health Questionnaire-9; PROs, Patient-Reported Outcomes; SD, standard deviation; SIBDQ, Short Inflammatory Bowel Disease Questionnaire; UC, ulcerative colitis.

^¥Responses for “a lot/very much satisfied”.

^§Responses for “I follow my treatment regularly”.

^aUnadjusted mean difference (95% CI) between groups for continuous variables and difference in percentage points (95% CI) between groups for categorical variables.

^bPearson’s χ2 test or Mann-Whitney test.

Regarding the productivity loss, the mean absenteeism was 12% ± 24.9%, presenteeism 22.9% ± 26.2%, work productivity loss 30.3% ± 32.7%, and activity impairment 38.4% ± 32.3% with comparable values between the two cohorts (Table 2). Moderate-to-severe absenteeism, presenteeism, work productivity and activity impairment were reported by 19.8%, 48.2%, 51.7%, 67.5% patients, respectively (Table 2).

The mean PHQ-9 score was 10.2 ± 7.7, exceeding the threshold (≥10) for moderate-to-severe depression (Table 2). Notably, nearly half of the patients (48.1%) presented with moderate-to-severe depressive symptoms.

Importantly, 39.1% of the participants reported being “not at all,” “little” or only “quite” satisfied with their advanced therapy (Table 2, Supplementary Table 2). “Increasing fatigue” was the most frequently reported reason for dissatisfaction (20.5%), followed by “recurrent flares” (15.3%) and “frequent bowel movements” (14.9%) (Supplementary Table 2). Overall, 10.9% of the population was non-adherent to treatment, with a significantly higher proportion among UC patients compared with CD patients (24.1% vs. 4.9%, p <0.001) (Table 2, Supplementary Table 3). The most commonly reported reason for non-adherence was patients’ perception that their symptoms were under control (Supplementary Table 3).

3.3. Univariate and multivariate analysis

Univariate and multivariate logistic regressions were conducted to identify factors associated with moderately to severely impaired QoL [SIBDQ < 60], moderate to severe overall work impairment [WPAI ≥ 20%], moderate to severe depressive symptoms [PHQ-9 ≥ 10], as well as treatment satisfaction and adherence (Tables 3–5, Supplementary Tables 4, 5).

Table 3.

Factors associated with moderately to severely [SIBDQ <60] impaired QoL: univariate and multivariate logistic regressions analyses.

SIBDQ	Univariate analysis		Multivariate analysis
	OR [95% CI]	p-value	OR [95% CI]	p-value
Gender
Male	Ref		Ref
Female	3.68 [1.91-7.08]	<0.001	2.218 (1.140-4.314)	0.049
Age
<50 years	Ref
50 years or more	1.131 (0.554 – 2.309)	0.735
Employment status
In paid employment	Ref		Ref
Other	3.286 (1.596 – 6.768)	0.001	2.442 (1.168-5.103)	0.046
BMI
Underweight and normal	Ref
Overweight and obese	1.143 (0.612 -2.135)	0.675
Smoking status
Never smoker	Ref		Ref
Former smoker	1.174 (0.559 - 2.465)	0.671	0.881 (0.389 - 1.998)	0.8
Current smoker	2.037 (0.939 - 4.421)	0.072	1.304 (0.564 - 3.018)	0.603
Disease activity
Inactive*	Ref		Ref
Active**	15.171 (6.405 - 35.934)	<0.001	10.751 (4.976-23.231)	<0.001
Age at diagnosis
0–30 years	Ref		Ref
>30 years	1.827 (0.950 - 3.514)	0.071	0.907 (0.420 – 1.956)	0.835
Disease duration
<10 years	Ref
>10years	0.852 (0.456 – 1.592)	0.615
Surgery
No	Ref
Yes	1.254 (0.610 – 2.576)	0.538
Disease
CD	Ref
UC	1.002 (0.516 -1.945)	0.995
Comorbidities
None	Ref		Ref
One or more	3.111 (1.601-6.046)	<0.001	1.664 (0.846 – 3.275)	0.216

CLI, confidence interval; BMI, body mass index; N/A, not applicable; OR, odds ratio; ref, reference value; SIBDQ, Short Inflammatory Bowel Disease Questionnaire.

*Patients in remission.

**Patients with mild, moderate or severe disease activity.

Table 5.

Factors associated with PHQ-9: univariate and multivariate logistic regressions analyses.

PHQ-9	Univariate analysis		Multivariate analysis
	OR [95% CI]	p-value	OR [95% CI]	p-value
Gender
Male	Ref		Ref
Female	4.02 (1.94 -8.34)	<0.001	2.204 (1.256 – 3.868)	0.021
Age
<50 years	Ref
50 years or more	0.878 (0.480 – 1.603)	0.671
Employment status
In paid employment	Ref		Ref
Other	1.781 (1.023-3.101)	0.041	1.210 (0.695 – 2.106)	0.572
BMI
Underweight and normal	Ref
Overweight and obese	1.139 (0.663 – 1.960)	0.637
Smoking status
Never	Ref		Ref
Former smoker	1.393 (0.706 – 2.749)	0.339	1.661 (0.832 – 3.318)	0.228
Current smoker	1.832 (0.953 – 3.519)	0.069	1.699 (0.882 – 3.272)	0.184
Disease activity
Inactive*	Ref		Ref
Active**	6.750 (3.640 – 12.516)	<0.001	6.343 (3.595 – 11.193)	<0.001
Age at diagnosis
0–30 years	Ref
>30 years	1.098 (0.637 – 1.893)	0.735
Disease duration
<10 years	Ref
>10 years	0.899 (0.524 - 1.542)	0.699
Surgery
No	Ref
Yes	0.794 (0.435 – 1.451)	0.454
Disease
CD	Ref
UC	1.167 (0.654 – 2.083)	0.602
Comorbidities
No	Ref		Ref
One or more	3.125 (1.686 – 5.794)	<0.001	1.871 (1.032 – 3.391)	0.083

BMI, body mass index; CI, confidence interval; OR, odds ratio; ref, reference value; PHQ-9, Patient Health Questionnaire.

*Patients in remission.

**Patients with mild, moderate or severe disease activity.

In multivariate analysis, the risk of moderately to severely impaired QoL was significantly higher among women (OR: 2.21, [95%CI: 1.14-4.31], p= 0.049) and among patients not in paid employment (2.44, [1.16–5.10], p= 0.046). Patients with active disease had nearly eleven times higher odds of impaired QoL (10.75, [4.97–23.23], p < 0.001) and almost nine times higher odds of moderate to severe overall work impairment (8.7, [4.02–18.79], p < 0.001) compared to those in remission (Tables 3, 4). Multivariate analysis further demonstrated that both sex and disease severity were independently associated with depression. Specifically, female sex (2.2, [1.25–3.86], p = 0.02) and active disease (6.34, [3.59–11.19], p < 0.001) were identified as factors significantly associated with higher odds of moderate to severe depressive symptoms (Table 5).

Table 4.

Factors associated with moderate to severe overall work impairment (WPAI ≥20%): univariate and multivariate logistic regressions analyses.

WPAI	Univariate analysis		Multivariate analysis
	OR [95% CI]	p-value	OR [95% CI]	p-value
Gender
Male	Ref		Ref
Female	2.52 (1.19 – 5.33)	0.016	2.190 (1.045 – 4.588)	0.081
Age
<50 years	Ref
50 years or more	1.01 (0.42 – 2.46)	0.975
Employment status
Paid employment	Ref
Other	3.00 (0.30 – 29.76)	0.348
BMI
Underweight and normal	Ref
Overweight and obese	1.13 (0.54 – 2.36)	0.746
Smoking status
Never	Ref		Ref
Former smoker	0.956 (0.385 – 2.373)	0.922	0.907 (0.368 – 2.233)	0.858
Current smoker	2.248 (0.924 – 5.472)	0.074	1.90 (0.764 – 4.725)	0.247
Disease activity
Inactive*	Ref		Ref
Active**	9.096 (3.911 – 21.153)	<0.001	8.700 (4.028 – 18.791)	<0.001
Age at diagnosis
0–30 years	Ref		Ref
>30 years	2.455 (1.114 – 5.410)	0.026	1.050 (0.455 – 2.425)	0.923
Disease duration
<10 years	Ref		Ref
>10 years	0.480 (0.227 – 1.017)	0.055	0.577 (0.269 – 1.240)	0.237
Surgery
No	Ref
Yes	1.746 (0.764 – 3.990)	0.186
Disease
CD	Ref
UC	0.714 (0.330 -1.547)	0.384
Comorbidities
No	Ref
One or more	1.327 (0.622 – 2.830)	0.464

BMI, body mass index; CI, confidence interval; OR, odds ratio; ref, reference value; WPAI, Work Productivity and Activity Impairment.

*Patients in remission.

**Patients with mild, moderate or severe disease activity.

Regarding treatment satisfaction, patients with active disease were significantly less likely to report being satisfied with their treatment compared with those in remission (0.28, [0.16–0.49], p < 0.001) (Supplementary Table 4). Notably, multivariate analysis also indicated that UC patients had significantly lower odds of adhering to treatment compared to CD patients (0.24, [0.10–0.54], p = 0.004) (Supplementary Table 5).

3.4. Correlations between PROs and disease activity

All the SCCs demonstrated statistically significant (P<0.01) associations between PROs and disease activity (Figure 1).

Figure 1.

Spearman’s correlation coefficient (SCC) for patient-reported outcomes and disease activity for all patients receiving biologic therapy. PHQ-9, Patient Health Questionnaire-9; SIBDQ, Short Inflammatory Bowel Disease Questionnaire; WPAI, Work Productivity and Activity Impairment Questionnaire. **Correlation is significant at the 0.01 level (2-tailed). *Correlation is significant at the 0.05 level (2-tailed).

QoL was strongly and inversely associated with psychological burden (SCC: -0.820) and with activity impairment (-0.813), representing two of the strongest correlations observed in the analysis. QoL also demonstrated consistent negative correlations with all WPAI domains, including work productivity loss (-0.774), presenteeism (-0.739) and absenteeism (-0.623) (Figure 1).

Disease activity showed a strong negative correlation with QoL (-0.759) (Figure 1). In parallel, disease activity was positively correlated with all WPAI domains, including work productivity loss (0.711), activity impairment (0.708), presenteeism (0.659), and absenteeism (0.618) (Figure 1). A moderate positive association was also observed between disease activity and psychological burden (0.567).

Within the WPAI domains, the strongest correlation was observed between presenteeism and work productivity loss (0.968) (Figure 1). Work productivity loss was also strongly associated with absenteeism (0.731) and activity impairment (0.776), while a strong correlation was additionally observed between activity impairment and presenteeism (0.772).

Psychological burden demonstrated consistent positive correlations with all WPAI domains, with the strongest associations observed for activity impairment (0.692), work productivity loss (0.657), and presenteeism (0.641) (Figure 1).

Correlations between treatment satisfaction and other outcomes were generally moderate to weak. Moderate correlations were observed with presenteeism (0.503), work productivity loss (0.471), and activity impairment (0.443). Treatment satisfaction was also moderately correlated with disease activity (0.459) and inversely correlated with QoL (-0.480). Weaker correlations were identified with absenteeism (0.348) and psychological burden (0.326). No significant correlations were observed between treatment adherence and other PROs or disease activity, except for a weak association with psychological burden (0.141).

4. Discussion

Despite major advances in IBD management, particularly the broad use of biologic therapies, a substantial disease burden persists that extends beyond gastrointestinal symptoms and negatively affects QoL, work productivity and mental well-being. In this context, PROs have become integral to contemporary IBD research and clinical practice, serving as key endpoints in clinical trials and essential tools for capturing the broader patient-perceived impact of disease in real-world settings (39, 40). Accordingly, the present study aimed to assess the multidimensional impact of IBD among patients receiving advanced therapies and to identify unmet medical needs in a Greek real-world setting, where available evidence remains limited.

At the time of assessment, all participants were receiving advanced therapies, with TNF inhibitors being the most commonly used treatment (66.6%). Despite biologic therapy, disease control remained suboptimal, with only 42.9% of patients in remission, while 26.8% had mild disease and 30.3% had moderate-to-severe disease activity. These findings align with real-world and meta-analytic evidence indicating that remission is achieved in approximately 40-60% of patients receiving biologics, leaving a considerable proportion with ongoing disease activity (41). This persistent clinical burden was further reflected in impaired PROs across multiple domains.

The mean SIBDQ score of 46.0 indicated impaired QoL among both CD and UC patients receiving advanced therapies, with more than three-quarters reporting moderate-to-severe impairment. These findings are consistent with previous data from Greece showing that individuals with IBD experience substantially lower health-related QoL compared with the general population, even while receiving treatment (42). Multivariate analysis further demonstrated an inverse association between disease activity and QoL, in line with previous evidence (42, 43). Importantly, patients not engaged in paid employment and women were more likely to report moderately to severely impaired QoL, consistent with existing literature (44).

A substantial work-related burden was also observed. Moderate-to-severe absenteeism, presenteeism, work productivity and activity impairment were reported by 19.8%, 48.2%, 51.7%, 67.5% patients, respectively. Considering that 54.9% of participants were in paid employment, these findings highlight the ongoing socioeconomic impact of IBD, even in the era of advanced targeted therapies. Our results are consistent with a systematic review and meta-analysis showing that work productivity impairment remains a significant and ongoing challenge in IBD, across diverse clinical populations (19). Likewise, a Greek survey demonstrated that IBD interfered with working capacity in 40% of patients, while 57% required time off work (45). Multivariate analysis further demonstrated that active disease was independently associated with greater work impairment, consistent with prior evidence identifying disease activity as a key factor associated with poor work outcomes in patients with IBD (19, 42).

Psychological distress also represented a major component of disease burden. Based on the PHQ-9 scores, nearly half of patients were associated with moderate-to-severe depressive symptoms. These findings are consistent with previous evidence demonstrating high rates of depression and anxiety among individuals with IBD, particularly during periods of active disease (46). A Greek cross-sectional study similarly highlighted the broad psychosocial impact of IBD and emphasized the importance of multidisciplinary care, including mental health support (47). In line with previous studies, multivariate analysis showed that female sex and active disease were independently associated with a higher likelihood of depressive symptoms in IBD (43, 48).

Treatment dissatisfaction was reported by 39.1% of participants, with worsening fatigue identified as the main reason. This finding is consistent with a recent meta-analysis showing modest fatigue reduction while on biological treatment (49), indicating that fatigue remains a significant challenge in IBD despite the availability of advanced therapies (50). Furthermore, multivariate analysis showed that patients with active disease were less likely to report treatment satisfaction, in line with previous evidence linking persistent symptoms, such as pain, discomfort, fatigue and low energy, to lower satisfaction levels (8).

Overall non-adherence in our cohort was relatively low (10.9%), consistent with evidence suggesting that patients receiving advanced therapies demonstrate higher adherence rates (51). However, non-adherence was markedly higher among patients with UC compared with those with CD (24.1% vs. 4.9%), which was also confirmed by the multivariate analysis. A recent meta-analysis including over 40,000 patients with IBD reported higher adherence to biologic therapies among patients with CD compared to UC, supporting the observed difference in our cohort (52).

The observed correlations between PROs and disease activity highlight the following interconnections: (i) poorer QoL was associated with greater work productivity loss and activity impairment, and higher levels of depression; (ii) higher disease activity was associated with decreased QoL, lower work productivity, and activity impairment, and increased levels of depression; (iii) patients experiencing greater productivity loss and activity impairment were more likely to report depressive symptoms. These findings are consistent with previous studies demonstrating strong relationships between disease activity, impaired QoL, work productivity loss, and psychological distress in IBD populations (42, 43, 53, 54).

Multimorbidity also contributed to the overall disease burden. In our cohort, 41.3% of patients reported at least two comorbidities, with arthritis being the most common. This finding reflects the systemic inflammatory nature of IBD and the significant impact of extraintestinal manifestations on patient outcomes (55, 56).

Overall, no meaningful differences were identified between UC and CD patients receiving advanced therapies across key patient-reported outcomes, including QoL, work-related burden, psychological distress and treatment dissatisfaction. These findings suggest that the broader lived experience of patients undergoing advanced therapies is largely comparable between the two conditions, an observation consistent with previously published evidence (14, 57, 58).

This study has several strengths. It comprehensively assessed multiple PRO domains among patients receiving advanced therapies in a Greek real-world setting, providing insights into the persistent burden of IBD beyond clinical disease activity. The use of both validated and study-specific tools, allowed for a broad and nuanced assessment of QoL, work productivity, psychological well-being, treatment satisfaction, and adherence. Overall, this study underscores the importance of systematically incorporating PRO assessment into routine clinical practice and therapeutic decision-making to support improved health outcomes and more patient-centered care.

Several limitations should also be acknowledged. The cross-sectional design of the study precludes causal inference; therefore, the observed relationships between disease activity and PROs should be interpreted as associations rather than evidence of causal effects, while the possibility of reverse causation or bidirectional relationships cannot be excluded. In addition, the recruitment of participants through the HELLESCC patient association may introduce selection bias. Nevertheless, it should be stressed that HELLESCC represents the official national patient association in Greece and is a member of the European Federation of Crohn’s & Ulcerative Colitis Associations (EFCCA), supporting the broader relevance of the study cohort. In addition, reliance on self-reported information may be subject to recall or reporting bias, while objective markers of disease activity were not included. An additional limitation of the study is that detailed treatment history, including previous biologic exposure, number of prior treatment lines, and treatment failures, was not captured in the study questionnaire. Consequently, the potential influence of prior treatment exposure and treatment refractoriness on disease burden and PROs could not be explored. Finally, treatment satisfaction and adherence were assessed using study-specific questionnaires, which may affect measurement reliability; yet there are no “one-way” tools at present (36, 37, 59) and, despite their limitations, these effectively captured patient experiences.

5. Conclusion

In conclusion, this real-world, patient-reported survey demonstrates that a substantial and multidimensional burden persists among Greek patients with UC and CD despite treatment with advanced therapies. Impaired QoL, marked work and activity limitations, and a high prevalence of depressive symptoms highlight the profound impact of IBD beyond clinical disease activity. At the same time, the considerable proportion of patients reporting dissatisfaction with treatment points to a persistent gap between therapeutic targets and outcomes that matter most to patients.

Taken together, these findings reinforce the need to move beyond a solely disease-activity–focused model of care toward a more integrated, patient-centered approach that systematically incorporates patient-reported outcomes into routine clinical practice. Addressing the complex and interrelated physical, psychological, and functional consequences of IBD will require coordinated multidisciplinary management and stronger patient–physician partnerships in therapeutic decision-making. Importantly, the results also have broader health system implications, underscoring the need for policies that recognize the full societal and economic burden of IBD, support access to comprehensive care, and embed patient perspectives in clinical pathways and resource planning. Such efforts are essential to ensure that advances in therapy translate into meaningful improvements in long-term outcomes and QoL for individuals living with IBD in Greece.

Funding Statement

The author(s) declared financial support was received for this work and/or its publication. This work was supported by the Hellenic Society of Crohn’s Disease and Ulcerative Colitis Patients (HELLESCC).

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the Hellenic Society of Crohn’s Disease and Ulcerative Colitis Patients (reference ID: #IBD-27/09/2023). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their informed consent to participate in this study.

Author contributions

CT: Conceptualization, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. V-RV: Conceptualization, Data curation, Validation, Visualization, Writing – original draft, Writing – review & editing. GM: Data curation, Formal analysis, Methodology, Validation, Writing – original draft, Writing – review & editing. AA: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. GG: Conceptualization, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing.

Conflict of interest

Author V-RV is the president of HELLESCC. Authors GG and CT are owners of Health Through Evidence.

The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2026.1866461/full#supplementary-material