Abstract
Background
Fatigue is a disabling symptom in patients with inflammatory bowel disease (IBD). Its prevalence, mechanism, and impact remain poorly understood. We determined changes in fatigue status over time and identified predictors of incident or resolving fatigue.
Methods
This was a prospective study nested within the IBD Partners cohort. Participants prospectively completed the Multidimensional Fatigue Inventory and the Functional Assessment of Chronic Illness Therapy-Fatigue at baseline, 6 months, and 12 months. A Functional Assessment of Chronic Illness Therapy-Fatigue score ≤43 defined significant fatigue. Multivariable regression models using baseline covariates were used to identify risk factors for incident fatigue at 6 months and to predict the resolution of fatigue.
Results
A total of 2429 patients (1605 with Crohn disease, 824 with ulcerative colitis) completed a baseline assessment, and 1057 completed a second assessment at 6 months. Persistent fatigue (at baseline and at 6 months) was the most common pattern, affecting two-thirds (65.8%) of patients. One-sixth (15.7%) of patients had fatigue at 1 timepoint, whereas fewer than one-fifth (18.5%) of patients never reported fatigue. Among patients not fatigued at baseline, 26% developed fatigue at 6 months. The strongest predictor of incident fatigue was sleep disturbance at baseline (odds ratio, 2.91; 95% confidence interval, 1.48–5.72). In contrast, only 12.3% of those with fatigue at baseline had symptom resolution by month 6. Resolution was more likely in patients with a diagnosis of ulcerative colitis, quiescent disease, and an absence of significant psychological comorbidity.
Conclusions
Fatigue is common in patients with IBD. However, only a few fatigued patients experience symptom resolution at 6 or 12 months, suggesting the need for novel interventions to ameliorate its impact.
Keywords: Crohn disease, fatigue, ulcerative colitis
INTRODUCTION
Inflammatory bowel diseases (IBD; includes Crohn disease [CD] and ulcerative colitis [UC]) affect an estimated 7 million individuals worldwide. They are primarily recognized for their direct impact on the gastrointestinal tract, manifesting subjectively as abdominal pain, diarrhea, and rectal bleeding and leading to irreversible bowel damage and intestinal dysfunction. The protracted, relapsing-remitting inflammation exerts a significant negative impact on the health-related quality of life of affected patients.1, 2 However, many patients with IBD frequently experience a range of nongastrointestinal symptoms that exert an equivalent if not more dominant effect on quality of life than gastrointestinal symptoms. Of these, one of the most common is fatigue.
Fatigue is a disabling symptom affecting an estimated 80% of patients with IBD who have active inflammation3 and up to 50% of those in remission.4 The pathophysiology of this symptom remains poorly understood. Consequently, there are few pharmacologic5, 6 or nonpharmacologic7, 8 treatment options. Few studies have attempted to longitudinally track fatigue in patients with IBD.9, 10 Most studies of fatigue have been cross-sectional and consequently have only been able to identify the prevalence of this symptom rather than its incidence or resolution. In addition, whether factors identified cross-sectionally to be in association are truly predictive and lead to fatigue or merely cluster together cannot be inferred from such study designs. The incidence of fatigue in patients with IBD, risk factors for its development, and its longitudinal course have not been examined in a robust manner.
The aims of this prospective study of a large cohort of patients with IBD were the following: (1) to identify the incidence of fatigue in patients with IBD who are not fatigued at baseline and to define risk factors for its occurrence, (2) to describe the longitudinal trajectory of fatigue including identifying determinants aiding its resolution, and (3) to determine the prevalence and risk factors for persistent fatigue.
METHODS
Study Cohort
This prospective study was nested within the Crohn’s & Colitis Foundation IBD Partners cohort, a validated internet-based cohort of patients with IBD. Details of this cohort have been previously published.11, 12 Briefly, patients with a self-reported diagnosis of CD, UC, or indeterminate colitis who were age 18 years or older were approached for participation through mailing lists from the Crohn’s & Colitis Foundation, social media platforms, and during educational meetings.12 All participants completed a baseline questionnaire including demographics, disease characteristics, and past and current IBD treatment history. Review of medical records of a subset of patients confirmed a high accuracy of self-reported diagnosis and disease type.13 In addition to the core survey, optional modules were included with baseline or subsequent follow-up questionnaires. For the purpose of this study, all participants were offered a fatigue-specific module assessing fatigue using validated questionnaires as detailed in the section below. Interested participants were invited to complete a follow-up survey at 6 months and at 12 months where, in addition to reassessing fatigue status, change in disease activity, treatment, and patient-reported outcomes were ascertained.
Assessment of Fatigue
Our main variable of interest was fatigue. The primary questionnaire used to define fatigue was the validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score.14 For our study, based on prior literature, a FACIT-F score of ≤43 defined significant fatigue.15 The FACIT-F was initially developed for use in patients with cancer but has been validated for its ability to define fatigue in patients with IBD. In prior studies, a score of ≤43 on the FACIT-F scale performed best in defining anemia-related fatigue in patients with cancer.15 We used the Multidimensional Fatigue Inventory (MFI)16 to ascertain fatigue in 5 distinct domains: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. High MFI scores suggest more fatigue symptoms. Prior research has shown a strong correlation between the MFI and FACIT-F scores.9
Other Variables
Sleep disturbance, anxiety, and depressive symptoms were assessed using the 8-question National Institutes of Health Patient-Reported Outcomes Measurement Information System short-form questionnaires.17, 18 Continuous scores were translated to a t-score. We defined significantly disturbed sleep, depressive, or anxiety symptoms as a t-score >50. Participants provided information about current and past therapeutic agents (5-aminosalicylates, corticosteroids, immunomodulators, and biologics), surgery, and hospitalizations.19 Disease activity measures were obtained using the Simple Clinical Colitis Activity Index20 for UC and the short Crohn’s disease activity index21 for CD. A Simple Clinical Colitis Activity Index score ≤2 or a short Crohn’s disease activity index score <150 indicated clinical remission.22 Scores above these thresholds indicated active disease.
Outcomes
First, we classified participants into 3 distinct patterns of fatigue: (1) persistent fatigue, defined as meeting the threshold for significant fatigue both at baseline and at 6 months; (2) episodic fatigue, defined as fatigue at any one but not both timepoints; and (3) never fatigue, defined as not meeting the definition of fatigue at either timepoint. Using baseline characteristics, we next examined the predictors of developing new-onset fatigue at 6 months (incident fatigue) in those who were nonfatigued at baseline and resolution of fatigue at follow-up in those who were initially fatigued (resolved fatigue).
Statistical Analysis
Statistical analysis was carried out using Stata 15.2 (StataCorp, College Station, TX). Continuous variables were expressed using means and standard deviations and compared using the t test or the Mann-Whitney U test when appropriate. Categorical variables were reported as proportions and compared using the χ 2 test with the Fisher exact modification when required. First, baseline covariates that predicted fatigue at follow-up in patients who were nonfatigued at enrollment were defined by univariate linear regression analysis with demographic, disease characteristics, and psychosocial parameters. Multivariable models were created, including factors significant in the univariate analysis at P < 0.05. A forward-stepwise approach was performed for the multivariable analysis, retaining variables as being independently significant at a 2-sided P value < 0.05. Similar analysis was performed for the inverse—resolved fatigue—in those who were fatigued at baseline but not at follow-up. We also compared patients in the persistent fatigue group (at all 3 timepoints) with those who had more transient fatigue or who were never fatigued. Paired t tests were used to compare longitudinal changes in fatigue, sleep, depression, and anxiety scores. The correlations between the FACIT-F and MFI domain scores were assessed using Spearman correlation coefficients. The study was approved by the Institutional Review Board of Partners Healthcare (Mass General Brigham), Boston, Massachusetts, and the University of North Carolina at Chapel Hill, North Carolina.
RESULTS
Study Population
A total of 2427 unique patients (1606 with CD, 821 with UC) completed the baseline fatigue assessment, among whom 994 completed a second assessment at 6 months and 450 patients completed a third survey at 12 months. Three-quarters of the participants (75%) were women, with a mean age of 47 years. The mean disease duration of IBD was 18 years. Compared to those who did not complete the survey, participants who completed the survey were more likely to be female (75% vs 68%; P < 0.001) and younger (age 47 years vs 51 years; P < 0.001) and have a shorter duration of IBD (18 years vs 21 years; P < 0.001).
The mean FACIT-F score at baseline was 33.8 (±11.8). Three-quarters of the participants (74%) met the criteria for fatigue (FACIT-F score ≤43). Among patients with fatigue at baseline, fewer than half had symptomatically active disease (31%). The MFI questionnaire scores, consisting of 5 different fatigue domains, were all significantly different with higher MFI scores for participants with fatigue than for those without fatigue symptoms at baseline, supporting the global impact of fatigue (general: 14.9 vs 8.5; physical: 11.2 vs 5.5; reduced activity: 10.7 vs 8.6; reduced motivation: 11.5 vs 6.7; and mental fatigue: 9.8 vs 5.4; all P < 0.001). The FACIT-F scores showed a strong correlation with the 5 general domains (all P < 0.001), in particular the MFI general domain (rho, –0.82; P < 0.001).
Longitudinal Patterns of Fatigue
We identified 3 distinct patterns of fatigue. Persistent fatigue defined as fatigue at both baseline and follow-up was the most common, affecting nearly two-thirds of the cohort (n = 695; 65.8%). Episodic fatigue (at one but not both timepoints) affected 15.7% (n = 166) of participants, whereas 196 (18.5%) reported no fatigue at either timepoint (Table 1). On multivariable analysis, compared with those who were never fatigued, patients who reported persistent or episodic fatigue were more likely to be female (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.19-2.85), have CD (OR, 2.49; 95% CI, 1.62-3.83), have active disease at baseline (OR, 6.90; 95% CI, 4.01-11.87), be younger (OR, 0.98; 95% CI, 0.97-0.99), and have a prior diagnosis of anxiety (OR, 4.60; 95% CI, 1.62-13.09) or a sleep disorder (OR, 7.38; 95% CI, 1.71-31.89). Patients who reported fatigue also had a higher body mass index than those who reported no fatigue (26.6 vs 24.9; P = 0.003). Neither narcotic medications (P = 0.226) nor steroid therapy (P = 0.766) were associated with fatigue on multivariable analysis.
TABLE 1.
Baseline Characteristics of the Study Cohort, Stratified by Fatigue Category
| Characteristic | Persistent Fatigue (n = 695) | Episodic Fatigue (n = 166) | Never Fatigue (n = 196) | P |
|---|---|---|---|---|
| Female, n (%) | 552 (79.4) | 117 (70.5) | 129 (65.8) | <0.001 |
| Age, y, mean (SD) | 46.3 ± 13.7 | 48.3 ± 14.3 | 51.0 ± 14.1 | <0.001 |
| IBD type | <0.001 | |||
| CD, n(%) | 501 (72.1) | 106 (63.9) | 111 (56.6) | — |
| Ulcerative colitis, n (%) | 194 (27.9) | 60 (36.1) | 85 (43.3) | — |
| BMI (kg/m2), mean (SD) | 27.0 ± 7.6 | 25.3 ± 5.5 | 24.9 ± 5.5 | <0.001 |
| Disease duration, y, mean (SD) | 17.6 ± 11.7 | 18.6 ± 12.2 | 19.3 ± 12.9 | 0.164 |
| Prior IBD-related surgery, n (%) | 274 (39.4) | 54 (32.5) | 53 (27.0) | 0.004 |
| Smoking history | <0.001 | |||
| Never, n (%) | 489 (70.4) | 122 (73.5) | 151 (77.0) | — |
| Past, n (%) | 188 (27.1) | 40 (24.1) | 43 (21.9) | — |
| Current, n (%) | 18 (2.6) | 4 (2.4) | 2 (1.0) | — |
| Family history, n (%) | 18 (2.7) | 6 (3.7) | 2 (1.0) | 0.254 |
| Active IBD, n (%) | 361 (51.9) | 39 (23.4) | 25 (12.7) | <0.001 |
| Laboratory results (reported by patient) | ||||
| Anemia, n (%) | 171 (25.3) | 25 (15.4) | 26 (13.5) | <0.001 |
| Low vitamin D, n (%) | 235 (34.8) | 41 (25.2) | 44 (23.0) | 0.002 |
| Low vitamin B12, n (%) | 147 (21.9) | 27 (16.8) | 17 (9.0) | <0.001 |
| Low iron, n (%) | 191 (28.3) | 36 (22.4) | 27 (14.1) | <0.001 |
| Current medical therapy | ||||
| 5-ASAs | 220 (31.7) | 58 (34.9) | 83 (42.4) | 0.020 |
| Steroid therapy, n (%) | 68 (9.8) | 7 (4.2) | 11 (5.6) | 0.022 |
| Vitamin B12 supplementation, n (%) | 265 (38.1) | 51 (30.7) | 45 (23.0) | <0.001 |
| Vitamin D supplementation, n (%) | 386 (55.5) | 83 (50.0) | 106 (54.1) | 0.434 |
| Narcotics, n (%) | 48 (6.9) | 3 (1.8) | 1 (0.6) | <0.001 |
| Immunomodulators, n (%) | 199 (28.6 | 32 (19.3) | 51 (26.0) | 0.049 |
| Biologic therapy, n (%) | 393 (56.6) | 87 (52.4) | 93 (47.5) | 0.069 |
| Past biologic therapy, n (%) | 505 (72.7) | 105 (63.3) | 116 (59.2) | <0.001 |
| Diagnosis | ||||
| Depression, n (%) | 149 (23.6) | 13 (8.2) | 6 (3.8) | <0.001 |
| Anxiety, n (%) | 147 (23.4) | 14 (8.9) | 4 (2.5) | <0.001 |
| Sleep disorder, n (%) | 95 (15.2) | 16 (10.0) | 3 (1.9) | <0.001 |
BMI indicates body mass index; 5-ASAs, 5-aminosalicylates.
We then compared patients with episodic fatigue with those who reported persistent fatigue. Patients who reported persistent fatigue were more likely to be female (OR, 1.76; 95% CI, 1.21-2.57), have CD (OR, 2.83; 95% CI, 1.94-4.12), be younger (OR, 0.98; 95% CI, 0.97-0.99), have a higher body mass index (OR, 1.06; 95% CI, 1.03-1.09), have active disease (OR, 6.35; 95% CI, 4.29-9.41), and have a prior diagnosis of depression (OR, 2.57; 95% CI, 1.31-5.04) or anxiety (OR, 2.55; 95% CI, 1.34-4.85).
Predictors of Incident Fatigue
Among patients who were not fatigued (n = 265) at baseline and completed the follow-up survey at 6 months, 26% (n = 69) reported incident fatigue. This included 24% of those who were in symptomatic remission at baseline and 34% of those with active disease (P = 0.20; Table 2). The strongest predictor of incident fatigue was the presence of sleep disturbance at baseline (OR, 2.91; 95% CI, 1.48-5.72; Table 3). When we restricted the analysis to those with quiescent disease at baseline, we found that the presence of sleep disturbance at baseline was still significantly associated with incident fatigue at 6 months (OR, 3.34; 95% CI, 1.57-7.09).
TABLE 2.
Characteristics of Patients With IBD Without Fatigue at Baseline With Subsequent (Incident) or No Fatigue at 6 Months
| Characteristic | Incident Fatigue (n = 69) | Not Fatigued (n = 196) | P |
|---|---|---|---|
| Female, n (%) | 44 (63.8) | 129 (65.8%) | 0.759 |
| Age, mean (SD) | 49.3 ± 15.3 | 51.0 ± 14.1 | 0.416 |
| IBD type | 0.410 | ||
| CD, n (%) | 43 (62.3) | 111 (56.6) | — |
| Ulcerative colitis, n (%) | 26 (37.7) | 85 (43.3) | — |
| BMI (kg/m2), mean (SD) | 25.1 ± 4.8 | 24.9 ± 5.5 | 0.730 |
| Disease duration, y, mean (SD) | 19.7 ± 12.2 | 19.3 ± 12.9 | 0.846 |
| Prior IBD-related surgery, n (%) | 28 (40.6) | 53 (27.0) | 0.036 |
| Smoking history | 0.237 | ||
| Never, n (%) | 46 (66.7) | 151 (77.0) | — |
| Past, n (%) | 22 (31.9) | 43 (21.9) | — |
| Current, n (%) | 1 (1.5) | 2 (1.0) | — |
| Family history, n (%) | 1 (1.5) | 2 (1.0) | 0.754 |
| Active IBD, n (%) | 13 (18.8) | 25 (12.7) | 0.204 |
| Laboratory results (reported by patient) | |||
| Anemia, n (%) | 13 (19.1) | 26 (13.5) | 0.268 |
| Low vitamin D, n (%) | 20 (29.4) | 44 (23.0) | 0.295 |
| Low vitamin B12, n (%) | 15 (22.4) | 17 (9.0) | 0.004 |
| Low iron, n (%) | 16 (23.9) | 27 (14.1) | 0.063 |
| Current medical therapy | |||
| 5-ASAs | 25 (36.2) | 83 (42.4) | 0.374 |
| Steroid therapy, n (%) | 3 (4.4) | 11 (5.6) | 0.686 |
| Vitamin B12 supplementation, n (%) | 24 (34.8) | 45 (23.0) | 0.054 |
| Vitamin D supplementation, n (%) | 37 (53.6) | 106 (54.1) | 0.948 |
| Narcotics, n (%) | 1 (1.5) | 1 (0.6) | 0.438 |
| Immunomodulators, n (%) | 11 (15.9) | 51 (26.0) | 0.089 |
| Biologic therapy, n (%) | 43 (62.3) | 93 (47.5) | 0.034 |
| Past biologic therapy, n (%) | 47 (68.1) | 116 (59.2) | 0.190 |
| Diagnosis | |||
| Depression, n (%) | 8 (12.1) | 6 (3.8) | 0.018 |
| Anxiety, n (%) | 5 (7.6) | 4 (2.5) | 0.078 |
| Sleep disorder, n (%) | 8 (11.9) | 3 (1.9) | 0.001 |
BMI indicates body mass index; 5-ASAs, 5-aminosalicylates.
TABLE 3.
Independent Determinants of Incident Fatigue Among Patients With IBD
| Predictors | OR (95% CI) |
|---|---|
| Sleep disturbance symptoms at baseline | 2.91 (1.48-5.72) |
| Prior diagnosis of sleep disorder | 10.99 (2.15-56.02) |
Variables entered in the stepwise multivariable model included sex, IBD type, age, body mass index, presence of active disease at baseline, narcotic use, anxiety, depression, sleep scores, and presence of a diagnosed anxiety, depression, or sleep disorder.
Resolution of Fatigue
Only 12% of those with fatigue at baseline had symptom resolution by 6 months. A total of 7% of the patients with active IBD at baseline had resolution of fatigue symptoms whereas 19% of the patients with IBD with quiescent disease at baseline experienced improvement of fatigue symptoms. Resolution of fatigue was more common in those with UC (OR, 1.74; 95% CI, 1.03-2.95), quiescent disease at baseline (OR, 2.63; 95% CI, 1.54-4.47), and no biologic therapy at baseline (OR, 1.79; 95% CI, 1.10-2.89) and the absence of sleep disturbance (OR, 2.28; 95% CI, 1.42-3.66), anxiety (OR, 2.29; 95% CI, 1.31-4.00), and depressive symptoms (OR, 2.27; 95% CI, 1.14-4.49) at baseline (Table 4).
TABLE 4.
Independent Determinants of Resolved Fatigue Among Patients With IBD
| Predictors | OR (95% CI) |
|---|---|
| UC | 1.75 (1.03-2.95) |
| Not receiving biologic therapy at baseline | 1.79 (1.10-2.89) |
| Quiescent disease at baseline | 2.63 (1.54-4.47) |
| No anxiety symptoms at baseline | 2.29 (1.31-4.00) |
| No depressive symptoms at baseline | 2.27 (1.14-4.49) |
| No sleep disturbance symptoms at baseline | 2.28 (1.42-3.66) |
Variables entered in the stepwise multivariable model included sex, IBD type, age, body mass index, presence of active disease, use of narcotics, and absence of sleep disorders, anxiety, or depression.
One-Year Follow-Up
Extending the analysis to 1 year after the baseline questionnaire revealed similar findings. Nearly one-quarter (22.6%) of the patients who completed follow-up questionnaires at 1 year reported fatigue at this follow-up and were not fatigued at baseline. A diagnosis of CD was associated with a 3-fold increase in the likelihood of fatigue at 1 year (OR, 3.31; 95% CI, 1.10-9.93). A total of 355 patients completed the fatigue module at all 3 timepoints (Table 5). The most common presentation in this cohort was the persistence of fatigue at all 3 timepoints, which was noted in 62% of the cohort.
TABLE 5.
Long-Term Patterns of Fatigue Over 12 Months
| Long-Term Patterns of Fatigue (n = 355) | % |
|---|---|
| Fatigue at 0, 6, and 12 months | 61.7% |
| Fatigue at 0 and 12 months, but not 6 months | 8.5% |
| Fatigue at 0 months, but not 6 and 12 months | 4.2% |
| Fatigue at 12 months, but not 0 and 6 months | 3.4% |
| Fatigue at 0 and 6 months, but not 12 months | 5.4% |
| Fatigue at 6 and 12 months, but not 0 months | 1.7% |
| Fatigue at 6 months, but not 0 and 12 months | 3.7% |
| Never fatigue | 14.4% |
DISCUSSION
Fatigue is a prevalent and disabling symptom in patients with IBD. Although many studies have described the prevalence of fatigue in diverse IBD cohorts, little is known about its longitudinal trajectory. Through this prospective and longitudinal study of fatigue in a large IBD cohort, in addition to confirming the high baseline prevalence and impact of fatigue we make several novel observations. First, nearly one-quarter of patients who were not fatigued at baseline developed fatigue by 6 months; sleep disturbance at baseline was the strongest predictor of incident fatigue. Second, only a small proportion (12%) of those fatigued at baseline reported fatigue resolution by 6 months. This resolution was predicted by a diagnosis of UC (compared with CD), quiescent disease, and the absence of disturbed sleep, depression, or anxiety at baseline.
The most important finding in our study is that fatigue is highly prevalent in patients with IBD. Equally important, under current standards of care, most patients with fatigue continue to experience this symptom over a 1-year follow-up with few showing resolution. The literature on the longitudinal course of fatigue in IBD is scarce. Van Langenberg and Gibson23 surveyed 86 patients with CD longitudinally at 2 timepoints and found overall consistency in fatigue scores between baseline and follow-up. Improvement in physical fatigue was associated with avoidance of corticosteroids and regular exercise. Graff and colleagues24 assessed disease activity and fatigue every 6 months for a 2-year period in a Manitoba (Canada) IBD cohort. They found that fatigue increased over time regardless of disease pattern, although its prevalence was higher in those with symptomatic active disease. Reduced psychological well-being and poor sleep quality independently were associated with fatigue cross-sectionally, consistent with our longitudinal observations. Using the IBD Partners cohort, Conley et al25 also found significant stability in symptom cluster membership with a probability of remaining in the physical (including fatigue) and psychological (depression and anxiety) symptom clusters at 6 months of 0.88 and 0.81, respectively. Together, these findings suggest that fatigue is a persistent problem in patients with IBD, occurring more frequently than any other extraintestinal manifestation and rarely resolving. Consequently, a greater understanding of its pathogenesis and the development of therapeutic options (pharmacologic and nonpharmacologic) to ameliorate its impact is an important and urgent unmet need.
A second important observation is our prospective analysis showing an association between baseline disturbed sleep quality and subsequent development of fatigue even among those not fatigued at baseline. In addition, we identified the incidence of fatigue to be 26% at 6 months. Because of their cross-sectional design, few studies have been able to examine the incidence of fatigue in patients with IBD. Our incidence of fatigue was significantly higher than that noted for other clinical diagnoses along the brain-gut axis. A retrospective cohort of 393 patients identified an incidence of depression of 15% after the diagnosis of IBD.26 Choi et al27 identified the incidence of depression and anxiety over a 6-year period to be 12.2% and 8.0%, respectively. Disturbed sleep at baseline was the strongest predictor of incident fatigue, conferring a 2-fold increase in risk at 6 months. In contrast, neither symptomatic disease activity at baseline, use of medications, or other psychologic comorbidity predicted incident fatigue. Cross-sectional observations have shown an association between sleep quality and fatigue in patients with IBD.24, 28 In addition, in the general population, studies have similarly indicated this association between sleep disturbance and fatigue.29, 30 Thus, screening for disturbed sleep is an important component of evaluating fatigue in patients with IBD, and interventions that address such disturbances may play a role in preventing the development of fatigue.
The absence of significant depressive or anxiety symptoms at baseline and lack of sleep disturbance predicted the resolution of fatigue among the few patients who experienced resolution. The association between psychological symptoms and fatigue has been well established in cross-sectional studies. That resolution of fatigue was 2 times more likely in the absence of such disturbances suggests indirectly that interventions addressing sleep, depression, and anxiety may hold promise in treating fatigue. However, evidence in support of such interventions has been scant because of a paucity of studies. A recent systematic review concluded that there was insufficient evidence for either cognitive-behavioral therapy or solution-focused therapy for the relief of fatigue in patients with IBD.31 The association with quiescent disease was also consistent with the higher prevalence of fatigue in those with active IBD. A prior study noted that among the 61% of patients who were fatigued at the time of initiating biologic therapy, nearly 63% remained fatigued at week 30 although the prevalence of significant fatigue was lower among those attaining remission (30%).9
Our study has notable strengths. First, we systematically examined the presence of fatigue using validated questionnaires at up to 3 separate timepoints over a 1-year period. This process allowed us to both define the longitudinal trajectory and define the factors associated with resolution or new onset of fatigue. The questionnaires used to ascertain fatigue were previously validated for use in those with IBD and span complementary domains of this disabling symptom. Second, this is the largest longitudinal examination of fatigue in patients with IBD. Proactively identifying the determinants of fatigue and intervening to reduce the burdens resulting from fatigue may not only have direct benefits in improving health-related quality of life but may also have more far-reaching consequences including reducing temporary or permanent disability and lost economic productivity.
We acknowledge several weaknesses. First, the cohort of patients responding to the supplemental fatigue questionnaire may have been biased toward those with a higher perceived burden of fatigue. However, although this potential bias may have influenced the prevalence at baseline, it is unlikely to influence our analysis of symptom resolution and the development of new fatigue symptoms on follow-up. There was the potential for selection bias via loss of follow-up in that 43.6% of the cohort completed follow-up at the primary 6-month outcome. Second, patients in an internet-based IBD cohort may not be representative of a population-based IBD cohort. However, other observations from the IBD Partners cohort have been replicated in non-internet-based IBD cohorts, indicating its validity. Third, the cohort of patients with fatigue was consistent with a greater fraction of women than those observed in an unselected population with IBD with a higher median age. To some degree, this factor may be a reflection of the higher prevalence of fatigue in this demographic, but extrapolation to other populations should be made with caution. We also did not have objective measures of inflammation such as fecal calprotectin or C-reactive protein and consequently, reliance on symptom-based scores for defining quiescent disease may have under- or overestimated patients with active inflammation. Finally, we did not have a general population comparison for the development of incident fatigue, but this consideration does not affect the internal validity of our sample.
CONCLUSIONS
We highlight fatigue as a highly prevalent symptom in patients with IBD. Few patients experience resolution of fatigue under current standards of care, highlighting an urgent and important unmet need to better understand its pathogenesis and to develop effective interventions to treat it. Screening and treating disturbed sleep quality may help reduce incident fatigue in patients with IBD. Finally, the absence of psychological comorbidity and quiescent disease predicts the resolution of fatigue in a small proportion of patients. This finding can be used to reassure patients with fatigue who may have this profile and indirectly supports the role of interventions addressing psychological comorbidity and inflammation to improve fatigue in some patients.
ACKNOWLEDGMENTS
We acknowledge the valuable contributions of the participants and the research staff of the Crohn’s & Colitis Foundation IBD Partners cohort. The data underlying this article cannot be shared publicly because of data use agreement policies of the IBD Partners cohort. The data will be shared on reasonable request to the corresponding author after required institutional approvals.
Supported by: The research was supported in part by a grant from the National Institutes of Health (P30 DK034987).
Author contributions: Borren, Ananthakrishnan: designing survey, analysis and interpretation of data, drafting of manuscript, critical revision of manuscript for important intellectual content. Long, Sandler: interpretation of data, critical revision of manuscript for important intellectual content, supervision of study cohort.
Conflicts of interest: Ananthakrishnan: scientific advisory boards for Gilead. Long: consulting for Pfizer, AbbVie, Takeda, Janssen, Prometheus, Target Pharmasolutions, Salix, UCB, and Genentech; research support for Pfizer and Takeda; and an educational grant from Pfizer. The remaining authors report no conflicts of interest.
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