Comorbidities in inflammatory bowel disease: a call for action

Review

Comorbidities in inflammatory bowel disease: a call for action Marjorie Argollo, Daniela Gilardi, Carina Peyrin-Biroulet, Jean-Francois Chabot, Laurent Peyrin-Biroulet, Silvio Danese

Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition. Previously, the focus has been on extraintestinal manifestations of IBD, including arthritis, psoriasis, and uveitis. Although comorbidities have long been the subject of intensive research in other chronic inflammatory diseases such as rheumatoid arthritis, the concept of comorbidities is only beginning to emerge in IBD. Several comorbid conditions have been proposed to be related to IBD, including cardiovascular disease, neuropsychological disorders, and metabolic syndrome. Recognition of these conditions and their treatment could lead to better management of IBD. This Review aims to explore current knowledge regarding classic and emerging comorbidities related to IBD.

Introduction Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition. Previously, attention was focused on the extraintestinal manifestations of IBD, most frequently those affecting the joints, skin, eyes, and hepatobiliary system.1,2 By contrast, comorbid diseases, defined as an association of a group of diseases with a given condition, in IBD have been largely ignored.3 However, like other immune-mediated diseases, including psoriasis and rheumatoid arthritis, IBD is associated with several comorbid conditions (panel).4,5 In the mid-1990s, Hudson and colleagues6 were among the first to consider IBD as an independent factor for increased cardiovascular risk. An increased prevalence of non-alcoholic fatty liver disease (NAFLD), obesity, chronic fatigue, and erectile dysfunction have been shown in patients with IBD.3,7–9 Lifestyle factors such as smoking have also been shown to contribute to these comorbidities.10 Early identification of comorbid conditions is crucial when managing patients with IBD because they can alter or be confused with disease activity and extraintestinal manifestations, influence disease prog­ nosis, and alter pharmaco­logical therapeutic approach (eg, drug inter­actions with an increased risk of collateral effects, diminished drug bioactivity, and contra­ indication in some conditions, including cardiac disease). The presence of comorbidity in IBD has not been well assessed in randomised controlled trials because most comorbidities are treated as exclusion criteria.3 Comorbidities in IBD are associated with a substantial decrease in quality of life, emotional effects, and reduced ability of patients to cope; all of which affect disease outcomes and cost of care largely because of mort­ality, amount of time spent in hospital, and postoperative complications.11,12 Although no specific guidelines on comorbidity in IBD are available, data from other immune-mediated diseases support the use of nurse-led programmes to improve the cost-effectiveness for the management of cardiovascular risk factors, increase rates of pneumo­ coccal vaccination in high-risk patients, and provide preventive measures against osteoporosis and increased fracture risk in older women.13,14 www.thelancet.com/gastrohep Vol 4 August 2019

The COMEDRA trial15 confirmed that close monitoring by a multidisciplinary team for identification and management of comorbidities was beneficial, improving assessment of disease activity and optimising treatment. In this Review, we discuss the most relevant and emerging comorbidities that are under-diagnosed occurring in patients with IBD seen in clinical practice, and outline the best ways to identify, assess, and manage these comorbidities (figure 1).

Lessons from psoriasis and rheumatoid arthritis In recent years, there has been considerable interest in the presence of comorbidities in rheumatoid arthritis and psoriasis, with close to 3000 references as of December, 2018, on this topic in PubMed, highlighting a shift from a disease-centred to a goal-oriented approach: a necessary shift for achieving adequate health care for these patients.16 Rheumatoid arthritis and psoriasis are both known to have a high disease burden and are associated with a

Lancet Gastroenterol Hepatol 2019; 4: 643–54 Published Online June 3, 2019 http://dx.doi.org/10.1016/ S2468-1253(19)30173-6 IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Centre, Milan, Italy (M Argollo MD, D Gilardi PharmaD, Prof S Danese PhD); Universidade Federal de São Paulo, São Paulo, Brazil (M Argollo); Department of Pneumology (C Peyrin-Biroulet MD, J-F Chabot PhD); Department of Gastroenterology and Inserm U954, (L Peyrin-Biroulet PhD) Nancy University Hospital, Lorraine University, Nancy, France; and Department of Biomedical Sciences, Humanitas University, Milan, Italy (Prof S Danese) Correspondence to: Prof Silvio Danese, IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy [email protected]

Panel: Comorbidities in inflammatory bowel disease Classic • Psoriasis and psoriatic arthritis • Psychological and psychiatric disorders • Osteoporosis Emerging • Metabolic syndrome and its components • Cardiovascular diseases • Atherosclerosis • Fatigue • Chronic obstructive pulmonary disease • Sexual dysfunction • Parkinson’s disease Related to lifestyle • Smoking • Alcohol consumption • Anxiety and stress • Substance misuse Related to treatment • Skin cancer • Lymphoma • Dyslipidaemia

643

Review

Patient HOSPITAL

Future approach

Comorbidities

Yes

Referral to multidisciplinary team: IBD team and specialist consultant (eg, cardiologist, oncologist, psychologist, and nutritionist)

IBD centre Medical team Nurse-led programme

Medical history Clinical examination First-level diagnostic tests

Current approach

Current extraintestinal manifestations?

No

Yes

Referral to multidisciplinary team, IBD team, and specialist consultant (eg, dermatologist, rheumatologist, and ophthalmologist)

No

Referral to IBD team

Figure 1: Comorbidities in Inflammatory bowel disease: a complex journey IBD= inflammatory bowel disease.

substantial economic effect.17 Indirect costs in rheumatoid arthritis, mostly related to work disability, have been reported to be as high as €6·75 billion per year in numerous countries,18 with a considerable proportion of these costs related to the presence of comorbidities.19 Another study20 showed a substantial increase in total health-care resources use ($23 000 per year per patient) in patients with psoriasis, partially associated with comorbidities, when compared with the general population. Initial reports identified cardiovascular disease, malignancies, osteoporosis, and psychological disorders as the major comorbidities among patients with rheuma­ toid arthritis and psoriasis.16 Only recently have several other comorbidities, such as metabolic syndrome and neuro­ logical diseases, been described as important emerging conditions among this population.17,21 Robust evidence suggests a causative effect of continuous systemic inflammation and immune dysfunction, which are characteristic of immunemediated diseases, and the development and worsening of comorbidities.22–24 It has been hypothesised that psoriasis and rheumatoid arthritis have a causative role in the development of cardiovascular and metabolic comorbidities, on the basis of patho­physiological concepts establishing a link between chronic inflam­mation and endothelial dysfunction, formation of atherosclerotic plaques, and other features of metabolic syndrome.23,25 Large cohort studies24,26,27 have shown that patients with psoriatic and rheumatoid arthritis are at an increased risk of developing several comorbidities. In rheumatoid arthritis, the most prevalent and noteworthy comor­bidities are cardiovascular diseases (for which rheumatoid arthritis is considered as an independent risk factor even in the absence of traditional risk factors for cardiovascular 644

disease in young adults),28 metabolic syndrome, and psychological dis­orders. These comor­bidities affect nearly a third of patients22,29 and therefore raise concerns about the need for point-of-care diagnostics and interventions.30 Similar comorbidities are also seen in psoriasis. The CORRONA and PSOLAR registries highlighted a sub­ stantially elevated prevalence of comorbidities in this group of patients: almost 60% of patients reported having two or more comorbidities,22 which has an effect on treatment selection and disease outcomes.17

Prevalence and categories of the major emerging comorbidities in IBD Cardiovascular risk Cardiovascular diseases

Chronic systemic inflammation is involved in the pathogenesis of atherosclerosis, which is associated with an increased risk of acute arterial events and has been extensively assessed as a comorbidity in rheuma­tological diseases.31 In IBD, gut-related microvascular dysfunction results in diminished vasodilatory capacity and tissue hypoperfusion, which could be due to a reduced response to pharmaco­ logical treatment, as well as lower rates of mucosal healing and refractory inflamma­ tory ulcerations. Furthermore, persistent inflammation increases the risk of venous and arterial thrombosis at an earlier age.32 A large French cohort study33 found an increased risk of acute arterial events in patients with Crohn’s disease and ulcerative colitis, including ischaemic heart disease, cerebr­ovascular disease, and peripheral artery disease. Patients at higher risk were young (<55 years), with severely active disease being an independent major risk factor. A markedly increased risk of ischaemic heart disease during the first year after initial IBD diagnosis and association between early implementation of IBD treatment after the diagnosis and a lower risk of ischaemic heart disease has been reported, suggesting that early implementation of IBD treatment can help to reduce this increased risk in the long term.34 Moreover, older patients (>64 years) with IBD are much more likely to be hospitalised because of cardiovascular complications than because of IBD-related complications.35

Coronary artery disease and myocardial infarction Numerous studies36 show a possible association between IBD and an increased risk of coronary artery disease. An IBD cohort (n=357), followed up for over 50 months, found an increased risk of coronary artery disease among patients with IBD compared with controls (hazard ratio 2·85, 95% CI 1·82–4·46).37 This increase was not related to classic risk factors such as hypertension, diabetes, dyslipidaemia, and obesity, but rather to an increased white blood cell count, described as a non-traditional risk factor, leading to speculation around a possible association with IBD activity.37 www.thelancet.com/gastrohep Vol 4 August 2019

Review

Cerebrovascular events Although initial data proposed that only patients with Crohn’s disease and not patients with ulcerative colitis had an increased risk for cerebrovascular disease,36 a substantial risk of stroke in young female patients with Crohn’s disease and ulcerative colitis has been shown.38,39

diseases was found more often in the NAFLD group than in the non-NAFLD group, suggesting that routine non-invasive screening strategies for detecting liver diseases could aid early diagnosis and initiation of interventions, including weight loss, correction of dyslipidaemia, and linkage to care.

Peripheral arterial events

Obesity

Although there have been only a few studies to date that have addressed the occurrence of peripheral arterial events in IBD,36,38 a meta-analysis did not reveal a sub­ stantially increased risk.39 However, independent studies38 give conflicting results, finding an increased risk of acute mesenteric ischaemia in patients with IBD.

The prevalence of obesity, defined as a body-mass index of 30 kg/m² or greater, has risen in parallel with the rise in IBD.50 It has been shown that the adipose tissue represents a metabolically and hormonally active organ, producing proinflammatory adipokines that exert a deleterious effect on disease activity.9 Moreover, some studies45,51–54 have shown that obesity affects disease development, response to therapy, and hospitalisation costs.

Venous thromboembolism Several studies40,41 have shown an increased risk of venous thromboembolism in patients with IBD. In ulcerative colitis, disease extent and severity, smoking, and need for steroids are associated with a higher risk for venous thromboembolism. However, a recent review42 reported low rates of prophylaxis implementation for venous thromboembolism.

Metabolic syndrome Metabolic syndrome affects approximately 20–25% of the world’s adult population and features a constellation of central obesity, dyslipidaemia, impaired glucose meta­ bolism, and often hypertension, as well as insulin resistance and chronic inflammation. Metabolic syndrome is associated with a marked increase in risk of cardio­vascular disease and type 2 diabetes, with an associ­ ated high mortality rate.43,44 Nonetheless, epidemiological studies9,45 have shown a parallel rise in the prevalence of obesity and of IBD, supporting a possible shared environmental link between these two conditions. Researchers have reported similarities in pathophysio­ logical features between metabolic syndrome and IBD, including adipose tissue deregulation, inadequate immune response, and chronic inflammation.7,46

NAFLD NAFLD represents a spectrum of disorders ranging from benign hepatic steatosis to non-alcoholic steato­hepatitis.7 An overlap between IBD and NAFLD has been reported, with NAFLD being the most common diagnosis for elevated aminotransferases, present in 1·5–55% of patients with IBD, with an overall three-fold increase in risk.47,48 A complex interaction of chronic inflammation, gut dysbiosis, and long-term drug-treatment exposure could account for a relationship between these diseases.47 A prospective study49 investigated the prevalence and predictors of NAFLD and liver fibrosis in patients with IBD, assessed by transient elastography, as part of a routine screening programme. Authors described NAFLD and substantial liver fibrosis as frequent comorbidities. Association with other extrahepatic www.thelancet.com/gastrohep Vol 4 August 2019

Fatigue Chronic fatigue is a prevalent and frequent patientreported complaint in IBD. National registries have reported rates of fatigue as high as 80%, with a large negative effect on quality of life in patients with IBD.55,56 Several factors can contribute to the development of fatigue in patients with IBD such as anaemia, iron deficiency, nutritional deficiencies, hormonal disturb­ ances, drug-related factors, poor sleep quality, and psychological factors. Additionally, patients with active disease report higher rates of fatigue (60–80%) than do patients in clinical remission (20–40%),57 suggesting that proinflammatory cytokines can act on the brain, inducing symptoms that resemble sickness behaviour.58 Improvement of patient quality of life requires management of chronic fatigue, highly prevalent even in quiescent IBD, and should be considered as a therapeutic goal in clinical trials and clinical practice.

Osteoporosis The mechanisms involved in the pathogenesis of bone loss in patients with IBD are still not completely understood, but the increased risk for loss of bone mass certainly involves a complex interaction of diverse factors such as steroid treatment, systemic effects of chronic inflammation, decreased body-mass index, dietary deficiency, mal­ absorption of vitamin D and calcium, and malnutrition. Reduced bone mineral density and bone fractures are described to be more common among the IBD population, with an estimated frequency for osteoporosis of 14–42% in this group of patients. Compared with controls, the fracture risk for patients with IBD is increased by approximately 40–60%. It is recommended that patients with IBD with conventional risk factors (eg, history of fracture, older age, low bodyweight) for abnormal bone mineral density should be screened for osteoporosis with dualenergy x-ray absorptiometry (DXA) scanning at the time of diagnosis and periodically after diagnosis. 645

Review

Population

Year

Results

210 162

2017

Acute arterial events (n=5·554); Crohn’s disease: SIR 1·35 (95% CI 1·30–1·41); ulcerative colitis: SIR 1·10 (95% CI 1·06–1·13)

anti-tumour necrosis factor (anti-TNF) drugs can improve cognitive function in patients with dementia.67 Ongoing interventional studies68,69 are being done to assess whether the use of immunosuppressive therapies can delay or halt cognitive function deterioration in adults with an early diagnosis of dementia.

2013

Ischaemic heart disease: IRR 2·13 (95% CI 1·91–2·38)

Parkinson’s disease

356

2011

Coronary artery disease: HR 2·85 (95% CI 1·82–4·46)

8054 8060

2010 2008

Stroke: young age OR 2·93 (95% CI 1·44–5·98) vs older age OR 0·99 (95% CI 0·75–1·30); coronary artery disease: IRR 1·26; cerebrovascular events: IRR 1·32 (only in Crohn’s disease; undifferentiated ATED: IRR 1·96 (females); IRR 19·95 (0–39 years); IRR 3·17 (40–59 years)

384

2018

Prevalence NAFLD 32·8% and liver fibrosis 12·2%; NAFLD group: 11·3% CVD and 10·3% chronic kidney disease; non-NAFLD group: 4·7% CVD and 2·3% chronic kidney disease (p=0·02 and p<0·001, respectively)

8373

2016

Increased incidence of Parkinson’s disease: CHR 1·43 (95% CI 1·15–1·79)

432

2018

Prevalence 44% anxiety and depression

Cardiovascular diseases Kirchgesner et al33

Rungoe et al34 Yarur et al37 Andersohn et al82 Bernstein et al36

4·6 milion

Metabolic syndrome Palumbo et al49

Neurological and psychological disorders Lin et al83 Navabi et al80

ATED=arterial thromboembolic disease. CHR=crude hazard ratio. CVD=cardiovascular disease. IHD=ischaemic heart disease. IRR=incidence rate ratio. HR=hazard ratio. NAFLD=non-alcoholic fatty liver disease. OR=odds ratio. SIR=standardised incidence ratio.

Table 1: Emerging comorbidities in inflammatory bowel disease

Guidelines recommend that DXA scanning be performed in individuals with high steroid use (dose ≥7·5 mg per day of prednisone or equivalent) longer than 3 or 6 months or recurrent or persistently active disease. Despite consistent results showing an increased risk for bone mineral density abnormalities in patients with IBD, analysis has described inconsistent use of osteoporosis screening and underuse of osteoporosis treatment with calcium, vitamin D, and bisphosphonates.59,60

Neurological and psychological disorders Dementia disorders: Alzheimer’s disease and vascular dementia There is growing evidence that cerebral-neural and systemic inflammation have an important role in dementia disorders,61 the two major types of which are Alzheimer’s disease and vascular dementia.62 Cerebral inflammation secondary to β-amyloid plaques and raised levels of serum inflammatory molecules and cytokines are present in Alzheimer’s disease, whereas systemic inflammation is potentially associated with cerebral microvasculature disease in vascular dementia.63,64 Previous studies65,66 on rheumatoid arthritis have evaluated the effect of systemic inflammation on neurological comorbidities and suggested that the use of 646

Parkinson’s disease is a neurodegenerative disorder characterised by cardinal motor features of bradykinesia, rigidity, rest tremor, and postural instability. Non-motor features, including obstipation, depression, anxiety, and cognitive decline can also be present, estimated to affect about 1% of the general population older than 60 years.70 Evidence suggests possible shared genetic mech­ anisms involved in the development of IBD and Parkinson’s disease.71 A nationwide cohort study72 showed that patients with IBD had a substantial increased risk of developing Parkinson’s disease when compared with the non-IBD group; these finding are supported by further studies,73,74 suggesting a potential role of gastrointestinal inflam­ mation in the development of Parkinsonian disorders. Early exposure to anti-TNF therapy has been shown to be associated with a substantial reduction in Parkinson’s disease incidence, leading researchers to speculate that early and aggressive control of the inflammatory burden could positively affect subsequent development of the disease.75 The concomitance of IBD and Parkinson’s disease has only been investigated to a small extent with inconsistent results.76 Further studies are required to find out how to best interpret this possible association, and whether anti-TNF treatment administered to high-risk individuals could mitigate Parkinson’s disease risk.

Multiple sclerosis and demyelination Previous data have suggested that patients with IBD are at increased risk of demyelinating events in both the central and peripheral nervous system compared with people without IBD. The real association between multiple sclerosis and IBD remains unclear, and current understanding is based on the fact that these conditions share some epidemiological and immuno­logical patterns and that there is an increased incidence of both IBD among patients with multiple sclerosis and multiple sclerosis among patients with IBD. A substantial systematic review and meta-analysis,77 comprising a total of 1 086 430 patients found that those with IBD and multiple sclerosis have a 50% increased risk of multiple sclerosis or IBD comorbidity, respectively, with no apparent differences between patients with Crohn’s disease or ulcerative colitis.

Psychological and psychiatric disorders Several biological pathways have been described in attempts to explain ways in which stress might have a deleterious role in IBD, including those associated with www.thelancet.com/gastrohep Vol 4 August 2019

Review

increased intestinal permeability, which facilitates intestinal bacterial translocation, stimulating both innate and adaptive immune responses. Moreover, increased perceived stress is associated with increased symptomatic disease.78 Data from three different immune-mediated diseases cohorts (IBD, multiple sclerosis, and rheumatoid arthritis) showed an increased risk of psychiatric comorbidities (depression, anxiety, and bipolar disorders) among these populations.79,80 Moreover, the presence of mental health disorders, such as depression, anxiety, or bipolar disorders, is associated with higher mortality, suicide, and annual rates of suicide attempts in immune-mediated diseases than in matched controls.81 Additionally, eating disorders, mostly anorexia and bulimia nervosa, are also described at higher rates in individuals with IBD (table 1).84

Reproductive and sexual issues IBD is most prevalent during reproductive years. IBD is a chronic and and progressive disease that does not resolve by itself; therefore, issues related to sexuality, fertility, fecundity, pregnancy, delivery, and lactation are of extreme importance.85,86 The erratic and unpredictable nature of IBD symptoms, perianal complications, fatigue, and the psychological profile of the patient can influence body image perception, intimacy, and sexual desire. Moreover, relationship status, lack of general education, misconceptions about the disease, fertility concerns in both men or women, and erectile function also affect sexual satisfaction and patient wellbeing.87,88 Few studies have assessed sexual and reproductive health issues in males with IBD. Erectile dysfunction in men is influenced by depression, medication use (corticosteroids, antidepressants, and narcotics), and pelvic surgery (ileo-anal pouch surgery and rectal resection). Additionally, comorbidities such as cardio­vascular disease, diabetes, and lifestyle habits (smoking and alcohol consumption) also contribute to erectile dysfunction.89,90 Notably, Friedman and colleagues8 showed that male patients with IBD use erectile dysfunc­tion medications more frequently than do males without IBD, regardless of previous IBD surgery. In this context, a management plan for sexual and reproductive issues among males with IBD has been proposed by Allocca and colleagues.91

Lifestyle factors It is strongly advocated that all patients with IBD, and even patients with ulcerative colitis, who smoke be encouraged to quit given the risks of long-term extra-digestive effects. The effect of smoking on health status, with the increase in risk for malignancy, outweighs the risk of disease relapse. In Crohn’s disease, smoking increases the risk of hospitalisation, need for steroids, cumulative risk for complications, and surgical resection, as well as postoperative recurrence. These risks are reduced in patients who quit smoking at an early stage of life.10,92 www.thelancet.com/gastrohep Vol 4 August 2019

Alcohol consumption is a potential trigger for IBD flares due to its pro-oxidant and deleterious effects on the gut barrier function. Additionally, acute and chronic alcohol consumption can interfere with the immune system.93,94 Narcotics have been increasingly prescribed for the management of chronic pain in IBD, even in paediatric patients (5·6% vs 2·3% in patients without IBD).95 Factors associated with outpatient narcotic use include psychiatric comor­bidities (depression and anxiety), history of abuse, female sex, and symptomatic disease.96

Effect of comorbidity on disease outcomes, response to treatment, adherence, and costs The presence of comorbidities in psoriasis and rheumatoid arthritis results in increased costs, reduced adherence to treatment (eg, pharmacological therapies and lifestyle changes) and poorer response to treatment, increased mortality, higher levels of functional disability, and reduced quality of life independent of disease activity.97–99 Results from an extensive literature review100 confirmed that the presence of comorbidity is common in patients with rheumatoid arthritis (average of two comorbidities per patient), and that nearly 80% of patients will develop at least one comorbid condition over time. In psoriasis, better control of disease activity is associated with an improvement in mental health and quality of life.101,102 The PSOLAR registry103 showed that the incidence of depressive symptoms is lower in patients receiving biological therapy than in patients receiving conventional treatment, suggesting a potential protective role of biologics in reducing the risk of depressive symptoms. Epidemiological studies24,25,27,104 of rhuematoid arthritis have extensively assessed the frequency of comorbidities and the effect of pharmacological treatment on comor­ bidity outcomes, particularly with regards to the risk of cardiovascular events.65,105–107 Although there are data from studies on other immune-mediated diseases such as rheumatoid arhtitis and psoriasis, there are few date available on overall IBD disease assessment and comorbidity. The prevalence and effect of comorbidities on IBD-related postoperative outcomes showed that the presence of comorbidities was associated with an increased risk of mortality (up to 7·9% in patients with three or more comorbidities). Addition­ ally, the presence of comor­ bidities such as congestive heart failure and liver, thromboembolic, and renal diseases were associated not only with an increase in risk of mortality, but also with a substantial increase in length of hospital stay and in hospital charges.108 The presence of multiple chronic conditions is one of the best predictors of sustained high costs. Patients with such comorbidities have become the focus for a multidisciplinary approach to reduce disease-related costs and improve outcomes.109 647

Review

Year

Number of diseases included

Type of data collection

Population

Main studied outcome Additional outcomes

Limitations

Charlson comorbidity index

1987

17

Administrative database and self-report

Medical inpatients; patients with breast cancer

1-year mortality

Does not account hypertension, metabolic syndrome, and psychiatric conditions

Elixhauser comorbidity measure

1998

30

Administrative database

Medical inpatients

Length of stay; hospital ·· costs; hospital mortality

Does not account hypertension, metabolic syndrome, and mental disorders

Functional comorbidity index

2005

18

Administrative database

General population; patients at spine centre

Physical function

Better predictor of general health status

Not ideal for mortality assessment

Multimorbidity index

2015

40

Administrative database

Patients with rheumatoid arthritis

Health-related quality of life

··

Designed for specific population

Rheumatic disease comorbidity index

2007

11

Administrative database and self-report

Patients with rheumatoid arthritis; lupus; osteoarthritis; fibromyalgia

Mortality; hospitalisation; disability; costs

··

Designed for specific population

Predictor; 1-year subsequent hospitalisations and high health costs; disability and functional status; mortality

Table 2: Validated comorbidity indices

How to evaluate comorbidities? Several studies have addressed different tools for improving identification and treatment of comorbidities for achieving better outcomes in immune-mediated conditions (table 2). Although several indices have been developed to assess comorbidity and its effect on health, including the Charlson comorbidity index, the Elixhauser co­morbidity measurement, and the functional comorbidity index, no gold standard assessment has yet been identified.109,111,112 Choosing the optimal index will allow proper evaluation of comorbidity and its influence on disease and treatment outcomes. Application of such indices has not yet been investigated in IBD clinical practice. 21,110

The Charlson comorbidity index The Charlson comorbidity index, the most widely used comorbidity index, is a composite score summarised by a weighted combination of 17 conditions on the basis of their association with mortality and then added together to provide a final result that can vary from 0 to 33. Although this index was originally developed to prospectively predict 1-year mortality in patients with breast cancer, it has subsequently been adapted for predicting in-hospital mortality, length of hospital stay, readmission rate, functional decline, and costs.109,111,112 The use of the Charlson comorbidity index has scarcely been described in the IBD population, particularly among the elderly, to assess hospitalisation, mortality rates, and response to treatment.113,114 It has been shown that the presence of comorbidities, measured by this index, and not age, directly affect the introduction of immuno­ suppressant drugs for the treatment of IBD.115 Moreover, this index has been used as an adjustment index to assess more accurately the real effect of age and medications on 648

anti-TNF therapy efficacy and safety analysis.116 Another study reported the use of the Charlson comorbidity index to identify the presence of comorbidities and their association with the risk of surgical site infections in patients with IBD who are treated with vedolizumab compared with patients treated with anti-TNF drugs in propensity-matched cohorts.117 When assessing in-hospital mortality over a 13-year period, the Charlson comorbidity index showed a positive association with this specific outcome (OR 1·29 per one-point increase, p<0·001).118

The Elixhauser comorbidity measurement The Elixhauser comorbidity measurement was developed using an adult population dataset of inpatients, mainly for use with administrative data, and is one of the most widely used indices in comorbidity research. It includes a set of 30 comorbidities without weighting and thus without a single score. Limitations of this measurement are mostly related to unmeasured or unaccounted for confounding in the relationship between exposures and outcomes. Moreover, it does not include conditions such as hypertension, obesity, mental health disorders, and alcohol consumption.119 Furthermore, alternative use of the Elixhauser comorbidity measurement to obtain a single score after adding up all present comorbidities (one point for each comorbidity) or assigning weights to different comor­ bidities related to the disease being studied, has been described.120

Functional comorbidity index The functional comorbidity index was developed to assess physical disability on the basis of a general population, to try to improve indices designed to predict mortality and other measures. It includes a pool of 30 comorbidities as potential predictors, giving a score from 0 to 18. www.thelancet.com/gastrohep Vol 4 August 2019

Multisciplinary approach

Review

IBD centre

Medical team

Nurse-led programme

Comorbidities

Emerging comorbidites

Cardiovascular diseases Metabolic syndrome

Well established comorbidities

Fatigue Neurological and psychological disorders Reproductive and sexual dysfunction

Lifestyle factors

Cancer

Infections

Osteoporosis

HBV HCV HIV HPV VZV EBV Dental examination

Calcium levels Vitamin D levels DXA scan

Vaccinations (HAV, HBV, influenza, pneumococcal, meningococcal) Dental care

Calcium supplementation Vitamin D supplementation Physical activity

Assessment

Detection

Medical history and clinical examination

Bodyweight and BMI Waist circumference Blood pressure

HRQoL questionnaires Disability questionnaires Basic neurological evaluation

Lipidogram Blood glucose/HbA1c Liver profile Renal function

HRQoL questionnaires Disability questionnaires

Liver ultrasound Elastogram ECG/stress ECG/ echocardiogram (specialist evaluation)

Specialist evaluation

Diet Smoking Alcohol intake Substance abuse

Digital rectal examination Dermatological evaluation Breast self-examination

PSA Screening colonoscopy Mammography Breast ultrasound Pap test

Active measures

IBD comorbidity index

Lipid-lowering therapy Anti-platelet therapy Nutritional support Psychological support

Early referral to specialised centre for effective treatment

Alcohol discontinuation Physical activity Smoking cessation Diet orientation Nutritional support Psychological support

Early referral to specialised centre for effective treatment

Outcome measures

Osteoporosis treatments

Closer monitoring of patients Prognosis Adherence and response to treatment Treatment optimisation

Figure 2: Proposed algorithm for the management of comorbidities in Inflammatory bowel disease BMI=body-mass index. DXA=dual energy x-ray absorptiometry. EBV=Epstein-Barr virus. HBV=hepatitis B virus. HbA1c=glycated haemoglobin. HCV=hepatitis C virus. HAV=hepatitis A virus. HRQoL=health-related quality of life. HPV=human papillomavirus. IBD=inflammatory bowel disease. PSA=prostate specific antigen. VZV=varicella zoster virus.

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The functional comorbidity index is considered more useful to assess disability than the Charlson comorbidity index, but not ideal for evaluating mortality.121 Although the utility of comorbidity indices is restricted in clinical practice, their use is accepted as an adequate assessment for the study of comorbidities and their comparison among individuals. Therefore, developing a specific method to identify and manage comorbidities in the IBD population could be an important step for improving disease outcomes, response and adherence to treatment, and identifying patients who are most likely to have sustained high costs, thus reducing overall costs.

How to manage comorbidities in clinical practice? Lessons from rheumatoid arthritis Because there are currently no available data on how best to detect and manage comorbidities in the IBD population, some extrapolation could be made, based on a similar chronic debilitating inflammatory disease such as rheumatoid arthritis. The COMEDRA trial15 evaluated the effect of a nurseled programme (early detection, diagnosis, and treatment implementation and management) on comorbidities (active arm) compared with a self-assessment group in 970 patients with rheumatoid arthritis. Measurements taken during the study were classified as: cardiovascular diseases (blood pressure measurement, purchasing of blood pres­sure self-measurement devices, diet, smoking cessa­tion, initiation of lipid-lowering therapy, initiation of antiplatelet therapy, serum creatine measurement, and nephrology consultation); infection (influenza, pneumo­ coccal, hepatitis A and B, and meningococcal vaccination); cancer (mammography, blood-in-stool smear, screening colon­ oscopy, dermatological consultation, digital rectal examina­tion, and urological consultation); osteoporosis (DXA scan, initiation of osteoporosis therapy, vitamin D or calcium supplementation, increased calcium intake, and physical activity); and alcohol discontinuation. The mean number of measures taken per patient was substantially higher in the nurse-led group than in the self-assessment group for all categories (4·54 [SD 2·08] vs 2·65 [1·57]; p<0·001). Patients in both groups had an average of 1·8 additional comorbid conditions, with 50% having at least two additional conditions. Furthermore, the percentage of patients with treatment intensification was also significantly higher in the nurse-led group (17·2% vs 10·9%; p=0·006). Results showed that in a chronic, debilitating disease close monitoring by a dedicated nurse substantially improved the acceptance of treatment optimisation proposed by the rheumatologist, showing a considerable benefit of implementation of a multidisciplinary approach for comorbidity detection and management, with an effect on disease outcomes and treatment optimisation. Additional data from the same multicentre study showed that having anxiety or depression or both, which were reported by more than half of the patients, was 650

strongly associated with severe fatigue (found in 40% of the studied population), and that low physical activity, hypertension, obesity, chronic obstructive pulmonary disease, and multimorbidity contributed to chronic fatigue.122 Major interventions done by a nurse such as prescription of vitamin D and calcium supplements (31·2%), influenza vaccination (13·4%), serum creatinine measurement (12·5%), increased intake of dietary calcium (11·2%), and bone density assessment (9·4%) focused on the prevention and management of these comorbidities (as recommended by guidelines) and were considered as useful, acceptable to patients, and econ­ omically viable approaches.123 Furthermore, the COMORA study104 emphasised the need for a close-care systematic monitoring with general orientation, vaccination, dental examination, bone densitometry, and optimal screening for malignancies. Based on the elevated risk of cardiovascular events in rheumatoid arthritis and other forms of inflammatory arthritis, the European League Against Rheumatism evidence-based recom­ mendations for cardiovascular risk management advise an annual cardiovascular risk assessment using national guidelines.31

Conclusion There is increasing evidence to support a plausible association between IBD and several comorbidities, related to poorer disease outcomes, higher mortality, and increased hospitalisation rates. Management of comorbidity in IBD, especially before choosing a systemic immune-modulating therapy, needs to include early identification and treatment of neurological and psychological disorders, addictions, and associated cardiovascular and metabolic diseases. A proper assess­ ment for detection of comorbidities and investigation of lifestyle habits should be performed by taking a complete history (smoking status, alcohol intake, and sexual dysfunction), clinical examination (body­ weight, height, body-mass index, waist circumference, and blood pressure), and complementary tests (blood glucose, lipidogram, liver profile, renal function, screening for osteoporosis, and urogynaecological, dermatological, and colon cancer) followed by taking of appropriate active measures (initiation of osteoporosis therapy, vitamin D or calcium supplementation, vaccination, smoking cessation pro­ grammes, diet orientation, and psychological and psych­iatric support). Scales for the assessment of disability, anxiety, and depression might be beneficial for improving quality of life and long-term disease control because of better adherence and response to treatment. A healthy lifestyle should always be advised and encouraged, and an aligned multidisciplinary team should be mandatory. In conclusion, a multidisciplinary approach, with close monitoring of disease activity and early detection of comorbidities can be expected to benefit patients with IBD and lead to better disease outcomes, improved response and adherence to treatment, quality of life, www.thelancet.com/gastrohep Vol 4 August 2019

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Search strategy and selection criteria We did an extensive review of the literature in PubMed, Medline, and Scopus databases to search the most relevant available data on newly emerging comorbidities affecting patients with inflammatory bowel diseases, including pivotal trials, cohort studies, real-life experience data, among others, published in the English language, at any time of publication. Search terms used for this manuscript were: “comorbidities”, “inflammatory bowel disease”, “prevalence”, and “treatment”.

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and decreased costs. The association between IBD and infection and association between IBD and cancer has been extensively studied, and therefore the assessment and management of these comorbidities has already been incorporated into international guidelines and hence is not discussed in this Review, but these will need to be considered for the development of a comorbidity assessment algorithm.124,125 Further studies are urgently needed to identify and validate an IBD comorbidity index, with particular emphasis on accuracy for use in routine practice, clinical trials, telemedicine systems, and health-care programmes that focus on the economical value of the treatment (figure 2).

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Contributors All authors contributed equally in the preparation of the manuscript. Declaration of interest LP-B has served as a speaker, consultant, and advisory board member for Tillots, Celltrion, Allergan, Biogen, MSD, Genentech, Index Pharmaceuticals, Ferring, Roche, Arena, Sterna, Gilead, Nestlé, Boerhinger Ingelheim, Sandoz, Celgene, Enterome, Pfizer, Samsung, Abbvie, Takeda, Pharmacosmos, Janssen, Hikma, Alma, and Amgen. SD has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, MSD, UCB Pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Alphawasserman, Genentech, Grunenthal, Pfizer, AstraZeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor and Johnson and Johnson, and Nikkiso Europe GMBH. MA has served as speaker, consultant, and advisory board for Abbvie, Janssen, Takeda, and Pfizer. DG has served as a scientific consultant for Nikkiso GMBH, Sofar Spa, and Biofer Spa; as a speaker for Janssen and Pfizer; and as a member of advisory board for Roche and Pfizer. CP-B and FC declare no competing interests.

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Acknowledgments English language assistance was provided by Marie Cheeseman.

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