Inflammatory bowel disease (IBD) is an idiopathic chronic disease that affects around 250,000 patients in the United Kingdom and around 28 million people worldwide [1
]. IBD incidence is increasing with future prevalence likely to be considerably greater than at present [3
]. With no imminent prospects of cure, the need for effective symptom management is becoming ever more pressing. Part of the development of such interventions to relieve symptoms requires a better understanding as to what actually triggers those symptoms.
IBD encompasses various different conditions, with the main two types being Crohn’s disease (CD) and ulcerative colitis (UC). Both conditions are characterized by chronic inflammation of the gastrointestinal tract. Clinically, they are often considered together given their similar aetiology and symptoms, but they differ in terms of which part of the digestive tract they affect and in the nature of the inflammation that they cause [4
The symptoms experienced by this group of patients are often distressing. They include abdominal pain, bloody diarrhoea, nutritional failure and weight loss. However, they are not limited to the gastrointestinal tract only and can also cause ocular, musculoskeletal and skin pathologies [5
]. All can occur intermittently, with periods of remission and exacerbation being experienced throughout the patient’s life. The impact of these IBD symptoms can adversely affect patients’ quality of life, affecting them psychologically, socially, educationally and vocationally [6
Evidence suggests that a high proportion of IBD patients suffer from anxiety and depression, a percentage that is more than double when compared to healthy population [7
]. This observed high anxiety and depression comorbidity in IBD patients have led many researchers and clinicians to believe that there could be a causal relationship between anxiety, depression (psychological factors in general) and IBD symptoms, even more so when other chronic diseases have established such links [8
The idea about possible causality between psychological factors and IBD symptoms is not new and firstly emerged in the 1930s [11
]. Since, there have been a number of reviews examining the evidence concerned with the issue, and to date, their conclusions remain somewhat contradictory [12
]. Some have concluded that psychological factors contribute to exacerbations of symptoms [15
] while others have refuted it [14
]. More recent reviews, however, are leaning towards psychological factors having an impact on IBD symptomology, but they remain controversial and unclear [12
This lack of clarity has brought a lot of confusion [21
], particularly when empirical evidence from animal studies is suggesting potentially causal mechanisms between depression and inflammation [22
]; and around 74% of IBD patients seem to believe that psychological factors such as anxiety and depression contribute towards symptom exacerbation [24
This potentially causal mechanism between depression and inflammation and the patient’s belief are noteworthy influences when considering why the previous reviews have arrived at contradictory findings. Methodological weaknesses of the reviews themselves and weaknesses of the studies on which they were based on are just some of the possibilities explored by previous researchers [25
] as well as the conceptual limitations [16
]. Both methodological and conceptual limitations have stemmed from the complexity of the disease, the difficulty in defining psychological factors and their relationship with symptom exacerbation. All of them need a careful consideration when planning and determining the objectives of a systematic review such as this one. A summary of those identified potential limitations and recommendations are as follows:
1. The aggregation problem: some studies have assumed the psychological-physical symptom relationship to be the same for both UC and CD [19
2. Disease activity measures: different measures of disease activity have varying levels of validity and reliability. Contrasting findings may thus have resulted depending on which tools were used [12
3. Definition and measurement of psychological factors: psychological factors are complex and encompass a range of aspects and degrees of severity which could each have different implications for disease symptoms [17
]. Similarly, utilising different tools may lead to apparently contradictory findings [28
4. Direction of causality: studies available to previous systematic reviews have been unable to disentangle whether stress causes symptoms or symptoms cause stress, which more recent studies may have addressed [17
5. A moderation affect: psychological factors may be an important factor for some personality types but less so, or even not at all, for others [29
]. Study participants will have had different degrees of coping skills with implications for the relationship between psychological factors and disease activity. Those with more effective ability to cope will potentially have been less at risk of experiencing exacerbation of symptoms [30
Systematic reviews provide robust and comprehensive overviews of research findings within a specified topic area. The aim of systematic reviews, unlike the non-systematic approach of literature reviews and overviews, is to minimise bias and offer reproducibility while using scientific and transparent approach [32
]. The approach is achieved by following transparent, systematic and robust procedures.
A number of previous reviews concerned with the role of psychological factors and symptom exacerbation have not followed a systematic approach [12
]. These papers were limited because only a single database was searched and potentially important studies were missed. This limitation might have resulted in the authors arriving at misleading conclusions. Others did not provide a clear description of their methods [19
], denying other researchers the opportunity to make judgments on their scientific robustness [12
Some reviews have treated IBD as a single entity [17
] while others analysed specifically UC patients [14
] or CD patients [15
]. We highlighted earlier that IBD consists of two different diseases. For most purposes they are so similar that aggregating them together makes sense [33
]. However, it has been shown that patients with clinically similar disease might vary physiologically, at a molecular level [34
], which makes its just possible that the relationship between the psychological and physical symptomology differs in individual patients. If this were the case, then the constituent conditions should be disaggregated for analytical purposes where psychological influences are being considered. The subtlety different focuses may be a reason why the papers arrived at differing conclusions and why a review is required that distinguishes between UC and CD.
Among the criticism about methodological and conceptual limitations, there are recommendations of previous robust reviews that should not be ignored [14
]. However, the most recent of these is now more than a decade old, a period of time during which many more studies are likely to have been carried out. Hence, that makes a clear justification for this review to fill such a literature gap.
Simply reporting an association between psychological factors and symptom exacerbation in IBD is not sufficient to establish causality. To prevent misleadingly causal associations, the epidemiologist Bradford Hill proposed a number of viewpoints later used as criteria that should be considered before declaring a causal relationship truly exists [36
]. To date, no systematic review examining causality between psychological factors and symptom exacerbation in IBD has explicitly applied the Bradford Hill criteria to assess the evidence supporting a potentially causal association between the two.
Hence, in this paper we set out a protocol that lays the foundations for such a systematic review that will apply the Bradford Hill criteria for causality while bypassing the limitations noted from previous studies. The outcome of this review will provide clinicians with a clear foundation on which they might be able to develop therapies that reduce the likelihood of symptom exacerbation and therefore improve patient quality of life.
Study aim and objectives
The aim of this study is to provide researchers and clinicians with clarity on the role of psychological factors in IBD symptom exacerbation. In doing so, we will conduct a systematic review that will synthesise available evidence from prospective cohort studies that are reporting on causal associations between psychological factors and symptom exacerbation in IBD and on which we will apply the Bradford Hill criteria for causality. Guided by the recommendations from previous reviews outlined in the background section, the specific objectives that will help us attain our aim are:
1. To determine whether there is a causal relationship between minor stressors and exacerbation of symptoms in IBD patients and if any causality differ between UC and CD patients;
2. Whether there is a causal relationship between life events and exacerbation of symptoms in IBD patients and if any causality differ between UC and CD patients;
3. Whether there is a causal relationship between personality type/trait and exacerbation of symptoms in IBD patients and if any causality differ between UC and CD patients.
To address the above specific objectives we will firstly identify and then examine studies concerned with the relationship between minor stressors and symptom relapse, life events and symptom relapse, and personality and symptom relapse in all IBD population. We will then synthesise and evaluate data against Bradford Hill criteria for causality and do meta-analysis if deemed appropriate.