In our time-to-event analyses, Type D was a significant predictor for active disease, new extraintestinal manifestations and clinical recurrence in IBD patients. Type D was associated with depressive symptoms at enrolment and occurrence of depressive symptoms over time; however, Type D comprises predictive information beyond depressive symptoms since the combination of Type D and depressive symptoms was associated with higher hazards for deteriorating disease compared to each condition alone. Nevertheless, the main effects of Type D seem to arise from its association with depressive symptoms.
The prevalence of Type D in our study population was 29.5%. Previous findings in non-patient populations demonstrated similar rates between 20% and 40%. Patients with Type D had significantly higher disease activity levels and more prior or present extraintestinal manifestations. However, there was no indication of more severe or stressful past disease courses in patients with Type D as numbers of current therapies, disease-related surgery prior to enrolment, fistula, stenosis, or complications at or prior to enrolment were similar compared to individuals without Type D. This suggests that Type D is not just the result of trauma or stress due to severe prior disease and supports findings that Type D status is rather stable over time. Subgroup analyses provided no evidence for differences between UC/IBDu and CD patients.
In our analysis, Type D was a strong and significant risk factor for future clinical deterioration according to different clinical measures including well-established disease scores (CDAI ≥150/MTWAI ≥10), the occurrence of any new extraintestinal manifestation and two pre-defined definitions for clinical recurrence, FNCE and AFFSST, respectively (aHR: 1.15–1.60). All components of these composite endpoints (eg, surgery, new fistula, new systemic therapy) are clinically highly relevant.
Type D also increased the hazards for nearly all other IBD-related endpoints tested (Supplemental digital contents 1–4), although significance was not uniformly achieved. This suggests that Type D promotes IBD-related inflammation and findings remain robust independent of the precise definition of inflammation.
In line with prior studies,[43,44] Type D was significantly associated with depressive symptoms (OR: 6.69) at enrolment and the occurrence of depressive symptoms during follow-up (aHR: 3.30, P < 0.001).
The association of Type D with IBD deterioration might be partially mediated by associated depression: After correction for depressive symptoms Type D lost part of its predictive value and significance was lost for most endpoints. This could be due to the predictive power of Type D regarding depressive symptoms. However, statistical significance for the FNCE endpoint remained even after correction for depressive symptoms (aHR: 1.19, q = 0.043), indicating that Type D carries modest additional independent information regarding the risk for clinical deterioration. In line with this interpretation, patients with both, Type D and depressive symptoms, had a greater risk for clinical deterioration than patients with only one condition. This additive effect was uniformly observed for nearly all endpoints tested.
Type D, representing a predisposition or vulnerability to stress, constitutes a concept fundamentally different from depression. Thus, Type D would be a vulnerability factor preceding depression and stress, which in turn would trigger IBD recurrence. Conceptual difference between Type D and depression in IBD is also supported by our finding of a similar prevalence of Type D in the Swiss IBD cohort study compared to the general population, while rates of depressive symptoms were considerably elevated (7.5% vs 3% in the general population).[45–47]
Type D with its key compounds negative affectivity and social inhibition might be considered an indicator for limited abilities to cope with stressful challenges. Type D individuals are thus vulnerable to stressors and will experience more stress for longer periods of time compared to non-affected counterparts.[12,48] In general, population Type D has been associated with increased cardiac output, heightened blood pressure reactivity during episodes of stress and with decreased activity of the amygdala in response to fearful expressions, indicating disturbed emotion-processing. In coronary heart disease patients, Type D increased the activity of the hypothalamus-pituitary-adrenal axis, resulting in a larger cortisol response upon exposure to a stressor. Type D has also been associated with combined activation of the parasympathetic and sympathetic nervous system and immune dysfunctions.[12,48] Stress might thus be the common mediator between Type D, depression and inflammation. Psychological stress, depression and Type D have all been associated with higher levels of inflammation markers such as TNF and CRP[13–16] and inflammatory state in general.[44,49–51]
Besides vulnerability to stressors, other possible mechanisms of associations of Type D with depressive symptoms and adverse health outcomes include limited social support, reduced health-related behaviour, lower socio-economic status and poor medication adherence.[48,52] A corresponding analysis with our data revealed significantly lower adherence levels amongst patients with Type D. Lower adherence to therapy might thus contribute to the observed association between Type D personality and disease recurrence.
Type D might serve as an independent risk assessment tool for IBD prognosis, similarly as for cardiovascular diseases. The Type D Scale-14 questionnaire contains only 14 items; therefore, allowing fast assessment that can be easily implemented during a patient visit. A further advantage of Type D is its temporal stability[19–22] contrasting other psychological parameters as for instance HADS-D which refers only to the week previous to assessment.
Currently, there is no established psychological intervention for Type D. Nevertheless, psychotherapy to treat associated psychiatric comorbidities such as depression was shown to be beneficial for coronary heart disease patients with Type D, an observation that should also be tested in IBD. Overall, evidence on psychological interventions in IBD remains limited due to a lack of high-quality research (eg, intervention trials).[53,54] Nevertheless, recent evidence indicates that psychotherapy can be effective for IBD patients, especially in the presence of overt psychiatric co-morbidity. Improvements in mood and quality of life have been observed and some studies showed reduced gastrointestinal symptoms. Strongest benefits have been observed with multidisciplinary approaches that consider the biopsychosocial context of IBD and combine psychological interventions with pharmacotherapy. However, as evidence for psychological interventions in IBD remains limited, further interventional studies are desirable and Type D might be considered as a potentially relevant factor.
Our study has several strengths and limitations. A particular strength represents the excellent clinical characterisation of the IBD course. The composite endpoints used (FNCE, AFFSST) integrate several highly relevant clinical aspects of IBD (eg, non-response to therapy) as well as objective biological outcomes (eg, new fistula). Further, the longitudinal assessment of depressive symptoms and all clinical data over a long follow-up period enabled us to combine cross-sectional and time-to-event analyses. Limitations include the assessment of depression. Although periodical measurements of HADS-D scores were available and a HADS-D ≥11 represents a well-established cut-off strongly indicating depression,[31–34] the formal diagnosis of depression requires assessment by a mental health specialist. Furthermore, independent validation of our results in another IBD cohort would be desirable. Further studies should consider relating the observed effects of Type D personality on IBD with other concepts of personality characterisation (eg, NEO Five-Factor Inventory)[55,56] and test for similar effects.
In conclusion, there seemed to be no difference in Type D prevalence amongst IBD patients compared to the general population. Nevertheless, the presence of Type D might be relevant for IBD as we demonstrated predictive value for Type D regarding the clinical deterioration in IBD. Type D with high negative affectivity and high social inhibition indicates a vulnerability to stressors, yielding in higher levels of stress and consequent disease deterioration. Lower therapy adherence amongst patients with Type D might also contribute to that finding. In our study, Type D and depressive symptoms were strongly associated and represent partially redundant and partially complementary concepts for the prediction of unfavourable IBD course. However, Type D's association with IBD prognosis appears to be modest compared with depressive symptoms. Nevertheless, Type D assessment could prove useful to identify at-risk IBD patients for flares and incident psychiatric co-morbidity. Future studies are warranted to validate our findings and identify interventions improving the care for IBD patients with Type D.
This work was supported by the Swiss National Science Foundation (SNSF), [grant number 33CS30-148422 to GR].
The authors would like to thank SIBDC patients and SIBDC staff for their commitment.
Guarantor of the article
Prof. Benjamin Misselwitz.
Ethical Approval and Informed Consent
The SIBDC operates with the approval of local ethics committees of each participating centre as well as the lead ethics committee in Zurich (institutional review board approval No. EK-1316, approved on February 5, 2007, and KEK Zurich, March 9, 2020; BASEC 2018–02068). Only patients who provided written informed consent were included in the SIBDCS. Analysis of patient data for this study was approved by the scientific board of SIBDCS.
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy protection of individuals that participated in the study in compliance with Swiss law. The data will be shared at reasonable request to the corresponding author and the Swiss IBD cohort scientific committee.
Aliment Pharmacol Ther. 2021;54(1):53-67. © 2021 Blackwell Publishing