Deficits in geriatric assessment associate with disease activity and burden in older patients with inflammatory bowel disease

in (instrumental) activities of daily living, physical capacity (handgrip strength, gait speed), and mental (depressive symptoms, cognitive impairment) and social domain (life-partner) were assessed. De ﬁ cits in geriatric assessment were de ﬁ ned as ‡ 2 abnormal domains; 2 – 3 moderate de ﬁ cits and 4 – 5 severe de ﬁ cits. Clinical (Harvey Bradshaw Index > 4/partial Mayo Score > 2) and biochemical (C-reactive protein ‡ 10 mg/L and/or fecal calprotectin ‡ 250 m g/g) disease activity and disease burden (short In ﬂ ammatory Bowel Disease Questionnaire) were assessed. RESULTS: Somatic domain (51.6%) and activities of daily living (43.0%) were most frequently impaired. A total of 160 (39.5%) patients had moderate de ﬁ cits in their geriatric assessment; 32 (7.9%) severe. Clinical and biochemical disease activity associated with de ﬁ cits (clinical: adjusted odds ratio, 2.191; 95% con ﬁ dence interval, 1.284 – 3.743; P [ .004; biochemical: adjusted odds ratio, 3.358; 95% con ﬁ dence interval, 1.936 – 5.825; P < .001). De ﬁ cits in geriatric assessment independently associate with lower health-related quality of life. CONCLUSION: De ﬁ cits in geriatric assessment are highly prevalent in older patients with IBD. Patients with active disease are more prone to de ﬁ cits, and de ﬁ cits associate with lower health-related quality of life, indicating higher disease burden. Prospective data validating impact of frailty and geriatric assessment on outcomes are warranted to further improve treatment strategies.


BACKGROUND & AIMS:
We aimed to perform geriatric assessment in older patients with inflammatory bowel disease (IBD) to evaluate which IBD characteristics associate with deficits in geriatric assessment and the impact of deficits on disease burden (health-related quality of life).

METHODS:
A prospective multicenter cohort study including 405 consecutive outpatient patients with IBD aged ‡65 years.Somatic domain (comorbidity, polypharmacy, malnutrition), impairments I nflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated disease characterized by a relapsing and remitting course. 1 The incidence and prevalence of IBD in older patients is rising; it has been estimated that in the next decade, older patients with IBD will represent more than one-third of all patients with IBD. 2 Older patients form a challenging patient population due to heterogeneity in somatic, functional, mental, and social abilities compared with younger patients. 3These geriatric domains are measured by a geriatric assessment and then integrated into an overall level of frailty.Research on geriatric impairments in older patients is gaining attention.In older patients with cancer, for example, frailty is associated with poor functioning and high symptom burden during and following treatment, independent of disease-related factors. 4Also, in adult patients with liver cirrhosis, physical frailty is associated with waitlist mortality, regardless of ascites or hepatic encephalopathy. 5More recently, Kochar et al found frailty to be associated with infections in adult patients with IBD receiving immunosuppressive medication, 6 and with mortality in all patients with IBD. 7 However, until now, no evidence is available on the prevalence of deficits in geriatric assessment in older patients with IBD, and no prospective studies have been performed on their impact on adverse health outcomes or quality of life. 8herefore, we aimed to assess the prevalence of deficits in geriatric assessment in older patients with IBD and to evaluate which IBD disease characteristics associate with these deficits.Furthermore, we will evaluate the impact of deficits in geriatric assessment on healthrelated quality of life (HRQoL).

Study Design and Population
This study reports the baseline data of a prospective multicenter cohort study performed in the outpatient departments and infusion centers of 6 hospitals in the Netherlands.In the Leiden University Medical Centre (LUMC, Leiden), patients were included from November 2016 to February 2020; in the Haga Teaching Hospital (HagaZiekenhuis, The Hague), patients were included from December 2017 to July 2018; in the Haaglanden Medical Centre (The Hague), patients were included from March 2019 to February 2020; in the Maastricht University Medical Centre (Maastricht), patients were included from April 2019 to May 2019; in the Alrijne Hospital (Alrijne, Leiden, and Leiderdorp), patients were included from November 2019 to February 2020; and in the Groene Hart Ziekenhuis (Gouda), patients were included from October 2019 to February 2020.

Data Collection
Study data were collected face-to-face, and a geriatric assessment (see below) was performed by trained medical students.Assessments approximately took between 15 and 45 minutes per patient.Demographic and IBD characteristics included age, sex, weight, height, disease type, disease duration, and disease behavior and location according to the Montreal classification 10 (maximum extent at inclusion), current and previous IBD medications, and prior IBD-related surgery.Educational level was noted; high educational level was defined as higher vocational or university.Previous hospitalizations (both all-cause and IBD-related) occurring 3 years prior to the inclusion date were noted.All patient characteristics were verified using the electronical medical record.Clinical disease activity was measured through the Harvey Bradshaw Index (HBI) for patients with CD 11 and partial Mayo score (pMS) 12 for patients with UC or IBD-U.Active disease was defined by a HBI of >4 or a pMS >2.Laboratory values (hemoglobin and C-reactive protein [CRP]) and fecal calprotectin (FCP) were extracted from the electronical medical record if tests were performed within 3 months of baseline.Blood hemoglobin levels were divided by the lower limit of normal: 7.5 mmol/L for female patients and 8.5 mmol/L for male patients.Biochemical disease activity was defined by either a CRP !10 mg/L or FCP !250 mg/ g.To further specify biochemical disease activity, elevated FCP levels were reported separately as well.Endoscopic data were used if endoscopy was performed within 6 months of baseline.IBD-related disability was measured with the IBD Disability Index. 13HRQoL was assessed using the short Inflammatory Bowel Disease Questionnaire (sIBDQ) 14 (low score equals low HRQoL).

Geriatric Assessment
The purpose of a geriatric assessment is to systematically explore geriatric domains as a reflection of patients' health: the somatic, functional, mental, and social domains. 15In this study, the functional domain was further specified in activities of daily living and physical capacity, resulting in an overall 5 different domains.A domain was deemed abnormal when 1 or more components of a domain were abnormal.To compare patients with deficits in geriatric assessment with patients without deficits, we divided our population into those with no deficits, moderate deficits, and severe deficits.Moderate deficits were defined as 2 or 3 impaired domains, and severe deficits were defined as 4 or 5 impaired domains.
The somatic domain comprises the presence of multiple comorbidities (Charlson Comorbidity Index), 16 !3points abnormal, age not included), polypharmacy (!5 non-IBD medications 17 ), or malnutrition (Mini Nutritional Assessment), 18 11 points abnormal).Activities of daily living (ADL) comprises Katz Index of Independence in Activities of Daily Living 19 (!1 points abnormal) and Lawton Instrumental Activities of Daily Living 20 (!1 points abnormal, corrected for sex).Physical capacity comprises hand grip strength 21 (stratified by sex and body mass index) 22 and 4-meter gait speed 23 (stratified by sex and height). 22The mental domain comprises depression (Geriatric Depression Scale, 24 !6 points abnormal) and cognitive function (Six-Item Cognitive Impairment Test, 25 !8 points abnormal).Social domain was considered impaired when patients did not have a life-partner. 26,27A detailed description of the geriatric assessment performed is presented in the Supplementary Methods.

Statistical Analyses
Data analyses were performed using IBM SPSS Statistics for Windows, version 25.Continuous variables are presented as mean with standard deviation or as median with interquartile range (IQR) and compared using an independent t test or Mann Whitney U test.Categorical variables are presented as numbers and percentages and compared using a c 2 test.Logistic regression was performed to assess factors associated with geriatric deficits.Linear regression was used to evaluate the association between the number of impaired geriatric domains, IBD disease activity, and HRQoL (measured by sIBDQ).A sensitivity analysis was added using the siBDQ while excluding 3 questions regarding 'fatigue,' 'depression,' and 'relaxing,' as these questions are less IBDspecific.All regression analyses were performed as What You Need to Know Background Current evidence points towards an association between retrospectively assessed frailty and negative health outcomes in inflammatory bowel disease (IBD).However, there is a large need for prospective evidence on frailty and geriatric assessment in older patients with IBD.

Findings
In a cohort of 405 older patients with IBD, a geriatric assessment including 5 geriatric domains was performed.Of these 405 patients, 39.5% had a moderate number of deficits (2-3 domains) in their geriatric assessment, and 7.9% severe (4-5 domains).The presence of deficits (!2 domains) was associated with IBD disease activity and with a higher disease burden.

Implications for patient care
Prevalence of deficits in geriatric domains is high in older patients with IBD, especially in patients with active disease.A multidisciplinary approach towards geriatric impaired older patients with IBD could improve symptom burden and reduce negative health outcomes.complete case analyses.Potential confounders were agreed upon beforehand (age, sex, IBD type [CD vs UC/ IBD-U], educational level).As no data were available on prevalence of geriatric deficits in older patients with IBD, no sample size calculation was performed.We aimed to include as many patients as possible.A P-value of <.05 was considered statistically significant.

Ethical Considerations
The study protocol was declared not subjective to the medical research involving human subjects act by the Committee on Research Involving Human Subjects at the LUMC and was approved in all participating centers.All patients provided written informed consent.

Results
Overall, 547 patients were approached for participation.Of these, 405 were included (Figure 1).The overall median age was 70 years (IQR, 67-74 years) at baseline; 191 patients (47.0%) were diagnosed with CD.Eightyfive patients (21.7%) had clinical disease activity, 93 patients (26.7%) had biochemical disease activity (elevated CRP or FCP), and 68 patients (29.7%) had an elevated FCP (Table 1).Biochemical disease activity was available in 348 patients, FCP in 229 patients, and endoscopic disease activity in 141 patients.Patients included in a referral hospital (LUMC or Maastricht University Medical Centre) did not differ significantly from patients included in a general hospital regarding disease activity or deficits in geriatric domains.
The results of the geriatric assessment are presented in Table 2. To visualize the number of impaired geriatric domains, we plotted the number of patients against the number of impaired geriatric domains per patient (Figure 2).One hundred ninety-two patients (47.4%) had geriatric deficits, 160 patients had moderate deficits (2-3 deficits), and 32 patients had severe deficits (4-5 deficits).Several differences were noted between these patients, as displayed in Table 1.

Disease Activity
Active disease, when assessed by clinical indices, was more often present in patients with geriatric deficits ).An elevated FCP was also more often present in patients with geriatric deficits (Table 1).

Factors Associated With Deficits in Geriatric Assessment
A multivariate analysis was performed to assess factors associated with deficits in geriatric assessment (Table 3).IBD disease activity, as assessed using clinical disease indices, biochemical disease indices, or elevated FCP, was independently associated with the presence of deficits.Also, being female and having a previous all- cause hospitalization was associated with the presence of deficits.

Impact of Deficits in Geriatric Assessment on Health-Related Quality of Life
Both clinical and biochemical disease activity and the number of deficits in geriatric assessment were associated with a lower HRQoL (Supplementary Figure 3; Supplementary Table 1).Elevated FCP and endoscopic disease activity did not associate with HRQoL (Supplementary Figure 4; Supplementary Table 1).Both clinical disease activity and the number of deficits in geriatric assessment were also independently associated with a lower HRQoL (Table 4).The association between deficits in geriatric assessment and HRQoL did not change when clinical disease activity was replaced by biochemical disease activity or by elevated FCP alone.After excluding the questions regarding fatigue, depression, and relaxing from the sIBDQ, the number of deficits in geriatric assessment remained associated with a lower HRQoL.Four out of 5 geriatric domains impacted HRQoL independent of clinical disease activity: mental domain (B, À6.810; 95% confidence interval [CI], À8.847 to À4.772; P ¼.000), somatic domain (B, À3.182; 95% CI, À4.653 to À1.711; P ¼.000), ADL (B, À2.787; 95% CI, À4.363 to À1.210; P ¼.001), and physical capacity (B, À2.544; 95% CI, À4.401 to À0.686; P ¼.007).

Discussion
In this study, we provide the first prospective data on geriatric assessment in older patients with IBD.Almost 50% had 2 or more deficits in geriatric assessment.Active IBD was associated with the presence of deficits in geriatric assessment, and additionally, the number of deficits was independently associated with a lower HRQoL, demonstrating a higher IBD symptom burden in patients with geriatric deficits.
Older patients form a challenging patient population due to heterogeneity in geriatric domains.Impairments in geriatric assessment reflect the overall level of frailty. 28Recently published studies provide evidence for an association between the presence of frailty and negative health outcomes. 6,7,29However, in these retrospective studies, frailty is measured by International Classification of Diseases codes, and, whereas malnutrition 6,7 and comorbid conditions 29 are the defining domains in those studies, other geriatric domains are not well-represented.Frailty is defined as a state of increased vulnerability to poor resolution of homeostasis following a stressor 28 and comprises a spectrum that is best measured by a comprehensive geriatric assessment. 15The most frequently abnormal domains in our study were the somatic domain, especially polypharmacy, and ADL.In total, almost one-half of all assessed patients with IBD had 2 or   29 By using a geriatric assessment, we not only detected already established diagnoses, but also discovered new deficits.This finding further stresses the importance of prospective research on frailty in older patients with IBD by using a geriatric assessment.Disease activity, both clinical and biochemical (CRP and/or FCP), was independently associated with geriatric deficits.Although CRP corresponds with disease activity and is therefore frequently used as an inflammatory marker during IBD treatment, 30 it is linked to many diseases and correlates with frailty, poor physical activity, and cognitive decline. 31For this reason, we performed the analyses on biochemical disease activity separately for FCP alone and found an association between elevated FCP and geriatric deficits.The association between IBD disease activity and geriatric deficits could be explained by several mechanisms.Patients with polypharmacy or malnutrition have a higher chance of developing an IBD flare. 17,32The association between depression and disease activity has been established before, 33 but a link between IBD disease activity and cognitive function has also been described previously. 34Also, mechanisms related to inflammation contribute to muscle wasting. 35In addition, as ADL comprises stool incontinence, disease activity, including frequent bowel movements, could easily cause impairments in ADL.The association between active inflammation and frailty in older patients has also been confirmed in rheumatoid arthritis. 36atients with older-onset IBD had more deficits in geriatric assessment, mainly in physical capacity and cognition.It could be hypothesized that the recent inflammatory state in patients with older-onset IBD contributes to triggering or exaggerating underlying geriatric deficits.
Furthermore, we found that female sex was predictive of deficits in geriatric assessment.This has also been found in earlier studies 22,29 and could be due to a higher symptom reporting or poorer perceived health and greater vulnerability to frailty via extrinsic effects on sarcopenia. 22,37,38e found an independent association between an increasing number of deficits in geriatric assessment and a decreasing HRQoL.This finding suggests that geriatric impaired and therefore frail older patients with IBD experience a higher disease burden, independent of present disease activity.In patients with cancer, this association has also been found. 4ne of the strengths of this study is that we included patients with IBD in tertiary, peripheral, and teaching hospitals.However, as we aimed to conduct a study with as little study burden as possible, biochemical and endoscopic data of patients were extracted from the electronical medical record and not performed for study purposes.Therefore, no firm conclusions can be drawn on the association between endoscopic disease activity and outcomes of interest due to lower data availability.However, because of this low study burden, we created a low barrier for patients to participate and therefore generated a representative cohort.

Conclusions
In conclusion, our findings underline the importance of assessing the presence of frailty in older patients with IBD, as the prevalence of geriatric deficits we found is high.Patients with active disease were more prone to geriatric deficits, and patients with geriatric deficits had a higher IBD symptom burden.Prospective data validating the influence of frailty and geriatric deficits on negative health outcomes are warranted.As the population ages, we should strive to work towards a multidisciplinary evaluation of older patients with IBD to aim for the best possible treatment goals, while accounting for biological age-based risk factors.

Table 2 .
Geriatric Characteristics of Older Patients With Inflammatory Bowel Disease Nutritional status defined as 'at risk of malnutrition' (Mini Nutritional Assessment 8-11) or 'malnutrition' Mini Nutritional Assessment 7. d Impaired in ADL defined as Katz Index of Independence in Activities of Daily Living !1. e Impaired in IADL defined as Lawton Instrumental Activities of Daily Living !1, corrected for sex.Depressive symptoms defined as Geriatric Depression Scale-15 !6.
NOTE: Valid percentages are reported; missing data: nutritional status, 2; handgrip strength, 18; gait speed, 7; cognition, 1, depressive symptoms, 1; partner, 3. ADL, Katz Index of Independence in Activities of Daily Living; IADL, Lawton Instrumental Activities of Daily Living; IBD, inflammatory bowel disease.aComorbidity defined by Charlson Comorbidity Index !3. b Polypharmacy defined as !5 non-IBD medications.cf Low handgrip strength corrected for sex and body mass index (Fried criteria).gLow gait speed in m/s corrected for sex and height (Fried criteria).hCognitive impairment defined as 6-Cognitive Impairment Test !8.i

Table 3 .
Univariable and Multivariable Logistic Regression Analyses on Factors Associated With Deficits in Geriatric Assessment a in Older Patients With Inflammatory Bowel Disease a Deficits in geriatric assessment: !2 deficits in geriatric assessment.b High educational level: higher vocational or university level.c Biochemical disease activity, CRP !10 mg/L and/or FCP !250 mg/g.

Table 4 .
Multivariable Regression Analysis of the Association Between Number of Deficits in Geriatric Assessment and the Short Inflammatory Bowel Disease Questionnaire in Older Patients With Inflammatory Bowel Disease