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IRELAND

Resolving Disorders of Chronic Inflammation Across Europe: Detection, Intervention and Prevention

1.Theme for the Joint Programming Initiative

Inflammation is a familiar ally in helping us fight infection. However, almost all ailments that afflict people of developed countries, including those of the EU, are fundamentally disorders of inflammation. Some are well known; the crippling inflammation that affects the joints of rheumatoid arthritis sufferers, for example, results from persistent attack by the body’s own immune defences. Similarly, inflammatory bowel disease (IBD) results from inappropriate and severe responses of our immune systems to gut bacteria.

Inflammation is also at the core of many more prevalent conditions and across Europe, atherosclerosis is perhaps most familiar. This is a complex disorder, exacerbated by environment, lifestyle and genetic factors resulting in an inflammatory deposition on blood vessel walls and ultimately in coronary artery disease. Obesity too has an underlying inflammatory component, with adipose and fat tissue harbouring large numbers of inflammatory cells. With obesity now reaching epidemic proportions in many countries, there is growing appreciation of the enormity of its impact on metabolism and its multiple unwanted downstream consequences, including type-2 diabetes. Among the many other conditions with an underlying inflammatory component or origins are neurodegenerative disorders, such as Alzheimer’s disease, a range of allergies, pulmonary disorders and cancers.

Major problems

Significant increase in inflammatory disorders in the past 20 years across all member states (obesity reaching epidemic proportions)

Many of the disorders if left unchecked have the potential to trigger major economical burden due to illness and premature death.

Current research efforts are fragmented and don’t include a societal-clinical-scientific framework

As distinct as these diseases are, they share many of the same key mechanisms of inflammation. The principal aim of this joint programming proposal is to achieve a cohesive European approach to understanding the similarities and differences in inflammatory processes across broad sectors of disease. In so doing, joint programming would to bring together the strands of research, clinical expertise and therapeutic approaches and approaches of different healthcare systems.

When considered together, inflammation-based diseases continue to present a growing problem of immeasurable socio-economic proportions. Research funding invested by individual nations each year into the fundamental aspects of inflammation are considerable; Focus is intensive at the molecular and cellular levels, as well as in how this applies to the broader pathophysiology of a diverse array of diseases. Importantly, considerable research dollars and Euros are also spent in untangling the complex risk factors and genetic associations that underpin many conditions and diseases.

PRIMARY GOALS

  • A classification of key those factors (societal, environmental, genetic) that increase inflammatory disease onset
  • Improved understanding of key inflammatory pathways across diseases, shared and distinct mechanisms.
  • Development of diagnostics and medical devices that allow for early diagnosis
  • The development of drugs and therapeutics that will promote recovery

2.Proposing GPC member/members

Ireland and

3.Objectives

The proposal recognises three broad themes underpin the challenge posed by inflammatory diseases collectively representing significant social, clinical and scientific challenges.

  1. Detection- Improved detection of common and distinct pathways of pathways will build on capacity in basic research in common mechanisms of inflammation, genetics of disease susceptibility, biosensors and population and individual level monitoring of disease and of inflammation.
  1. Intervention – Through a more comprehensive investigation of the inflammatory responses associated with the disease sectors at basic scientific and clinical levels, the mechanisms of the disease will be identified. Effective treatments and interventions for chronic inflammatory diseases remain a priority and outputs from basic and clinical work will help identify targets and new therapies developed. In addition, effective intervention will explore new modes of drug formulation and delivery.
  1. Prevention- Ultimately, the premise is that many of inflammatory diseases are preventable, with changes to lifestyles and improved understanding of risk factors making a significant difference. The prevention of disease in the first place must always be a chief goal, but realistically cannot be pursued in the absence of better understanding of disease mechanisms, risk factors, genetics, pathophysiology and diagnosis culminating from objectives 1 and 2.

4. Research Questions To Be Addressed

The programming research questions will focus on better detection across two broadly defined disease sectors: gastrointestinal disorders and obesity and metabolic diseases. The overarching concept is that with shared and distinct mechanisms of inflammation underlying each disease, a comparative approach to understanding their genetics, distinct and common inflammatory pathways and pathophysiology will ultimately lead to more accurate detection and early diagnosis. Thus, uniting the two disease sectors are the common goals of detection, intervention and prevention. The disease areas affect EU countries differently and variation will also exist in the strengths and capacity between member states in the priorities of basic research, medical care and initiatives aimed at improving lifestyle and environment. For this reason, it is anticipated that a JPI in this area would have particular benefits in drawing the priorities and relative strengths of different contributing members together in a productive and effective manner.

4.1Obesity and Metabolic Disorders

4.1.1Chronic Inflammation and Obesity

In recent years it has become evident that inflammatory responses play a central role in obesity and its associated disease states (type II diabetes, atherosclerosis). Our body’s adipose tissue provides a flexible storage depot for excess nutrients, in addition the adipose tissue is also responsible for the release of cytokines that regulate energy within the body. However, when the adipose tissue’s ability to store lipid and regulate nutrient metabolism becomes imbalanced due to the presence of excess nutrient inflammatory marker expression increase, initiating an inflammatory response.

In the US a study on childhood obesity identified a dramatic rise in the prevalence of obesity in the space of two decades, from about 5% in 1980 to 20% in 2000. What was also noted in this study was that that during this same time period allergic response to skin tests has almost doubled in children from 22% to 42% in children. Visness et al examined the results from the National Health and Nutrition Examination Survey 2005-2006 in the US and identified that.

  • Allergies were more prevalent among obese and overweight children.
  • Obesity was associated with chronic inflammation.
  • Allergy was also associated with inflammation.

Our understanding of complex relationship between inflammation, obesity and disease progression is still very much in its infancy and the research in this area requires a coherent structured approach considering the scale of the problem (see below).

Why does Obesity require a Joint Programming Approach?

The prevalence of obesity is currently on the rise in almost all industrialized countries and has become such a prominent problem that many countries have set up national taskforces (Ireland, Australia, Greece, UK), in addition to the already established international obesity task force (IOTF The most worrying statistic is that childhood obesity has reached epidemic proportions in Europe, with body weight now the most prevalent childhood disease. In a 2005 EU platform paper on obesity, the Mediterranean islands of Malta, Sicily, Gibraltar and Crete as well as the countries of Spain, Portugal and Italy reported overweight and obesity levels exceeding 30% among children aged 7-11. In addition England, Ireland, Cyprus, Sweden and Greece report levels above 20%, while France, Switzerland, Poland, the Czech Republic, Hungary, Germany, Denmark, Netherlands and Bulgaria reported overweight levels of 10- 20% among this age group. In Ireland there is thought to be in the region of 300,000 overweight and obese children with this number rising by a rate of over 10,000 per year. In Europe this rate of increase is thought to be in the region of 400,000 children per year.

Because obesity is associated with premature death, excessive morbidity and serious psychosocial problems the damage it causes to the welfare of citizens is extremely serious and for this reason a concerted intervention is necessary and warranted. In 2009 it is believed that 2,000 premature deaths in Ireland will be attributed to obesity with this number set to rise in future years. In addition to the in care hospital costs, obesity results in many indirect costs such as days lost to the workplace due to illness arising from obesity and output foregone as a result of premature death and this is estimated to cost Ireland alone approximately €4 billion per year.

4.1.2Type II Diabetes

Obesity is a major risk factor for the development of type II diabetes. Type II diabetes accounts for approximately 90% of cases of diabetes and is characterised by insulin resistance in combination with dysfunction of insulin producing cells. Insulin is a hormone produced by the pancreas that plays an essential role in regulation of blood sugar levels. Individuals with diabetes fail to make insulin (Type I diabetes) or to respond to it (type II diabetes) resulting in elevated blood glucose levels. Long term complications of diabetes include damage to the blood vessels, eyes, kidneys, and nerves. Early diagnosis and appropriate management, such as increased exercise and dietary modification, is essential to reduce the occurrence of these complications.

Chronic low grade inflammation underlies the pathogenesis of type II diabetes and circulating markers of inflammation, such as IL-6 and C-reactive protein (CRP), are strong predictors of development of the disorder. Many of these inflammatory markers, such as CRP, are also shared with CVD and it is now believed that activation of inflammation is a common antecedent to both Type II diabetes and CVD. Patients with Type II diabetes are at an increased risk of developing CVD. The exact effect of these inflammatory markers on glucose metabolism is still unclear but it is clear that cytokines such as IL-6 and TNF can directly interfere with insulin signaling. Early studies also indicate that anti-inflammatory drugs, such as salsalate, may help prevent type II diabetes.

Why does Type II Diabetes require a Joint Programming Approach?

We are currently in the midst of a diabetes epidemic. The International Diabetes Foundation has estimated that the number of people affected will increase by more than 50% in the period from 2003-2025, with a predicted 333 million people affected by 2025. Both industrialized and developing countries will be affected. In the US prevalence rates have doubled between 1990 and 2005 and the Centre for Disease Control (CDC)has characterized the increase as an epidemic. Within Europe an increase from 7.8% to 9.1% (58.1 million persons) is predicted. In a study by the International Diabetes Federation-European Region (IDF-Europe) and the Federation of European Nurses in Diabetes (FEND), the prevalence of diabetes is predicted to rise from 7.5% to 16% over the next 20 years with an increasing prevalence of Type 2 diabetes being the main driving force behind the increase. In the Republic of Ireland, the WHO estimated that in 2000 there were 86,000 cases of diabetes with the number of cases expected to rise to 157,000 by 2030. In 2005, 141,063 adults in the Republic of Ireland (4.7%) had diabetes (diagnosed or undiagnosed).

Type II diabetes has traditionally been considered an adult disorder. However, the prevalence of this disorder within children is particularly on the rise, in parallel to rising obesity rates and altered dietary and life style factors during childhood. Genetic factors also interact with these environmental factors to determine the overall individual risk of developing the illness. A greater understanding of the causative genetic factors will reveal the mechanistic basis of this metabolic disorder. This JPI is therefore timely and will build upon the recent large scale genomic studies to develop new diagnostics and therapies.

4.1.3 Ireland’s Contribution to Research in the Area of Obesity and Metabolic Diseases

Ireland has set up a national task force to specifically address the issue of obesity and related disorders and in doing so have identified the scale of the problem that the will face if the spread of the disease is left unchecked. To this end an evaluation of the population, their diets, lifestyles and social settings is beginning to identify communities, population clusters and individuals that are at most risk of becoming obese and thus having the secondary development of type-II diabetes and other secondary disease.

At a basic research level Ireland has invested approximately €10 million in this past ten years in basic and clinical research in projects mainly focused on the characterization of specific problems associated with diabetes (diabetic nephropathy, diabetic retinopathy, circulation) and the development of diagnostics (Prof Holthofer DCU). From the economic burden described above then it is readily apparent that as a nation there is a significant under spend in research within these areas. Ireland does have specific expertise in certain areas, however, we do not have the capacity to effectively combat a problem of an epidemic proportion.

4.2 Gastro-Intestinal Inflammatory Disorders

The mucosal immune system of the gastrointestinal tract (GI tract) plays a key role in preventing pathogens from entering the body and maintaining the delicate balance with the gut micro-flora. Inappropriate activation of the mucosal immune system contributes to the development of a number of chronic inflammatory disorders, such Inflammatory Bowel Disease (IBD)

4.2.1Inflammatory Bowel Disease

Crohn’s Disease (CD) and Ulcerative Colitis (UC), collectively known as Inflammatory Bowel Disease (IBD), are chronic inflammatory disorders of the intestine resulting in symptoms such as abdominal pain, diarrhea, vomiting or weight loss (CD) or constant diarrhea mixed with blood, of gradual onset (UC). Treatment options are restricted to controlling symptoms, inducing remission and preventing relapse although UC can be cured by surgical removal of the colon. Years can elapse prior to accurate diagnosis of IBD and given increased risk of bowel obstruction, malnutrition and cancer, early detection is crucial.

The underlying pathophysiology of IBD remains to be elucidated. However, it is likely to involve a complex interplay between genetic, microbial, and environmental factors resulting in a sustained activation of the mucosal immune system and chronic inflammation/tissue damage. Genetic changes responsible for conferring susceptibility are currently under investigation. DNA variants in the NOD2/CARD15 gene, which has known functions in bacterial recognition, apoptosis and inflammatory signaling, look promising. Environmental triggers may include improved hygiene and reduced exposure to intestinal pathogens in addition to cigarette smoking, all of which may affect development of the humoral immune system. Indeed, it is believed that the fundamental defect in IBD is an overactive mucosal immune system which, in genetically susceptible individuals, inappropriately reacts to normal constituents of the mucosal microflora.

Why does IBD require a Joint Programming Approach?

IBD affects 15,000 people in Ireland, 130,000-140,000 people in the UK and millions worldwide. The incidence (annual diagnosis rate) of CD varies from 0.5-24.5/100,000 inhabitants with prevalence rates (estimated rate of population affected) as high as 396/100,000 inhabitants. IBD is an important public health problem as it afflicts young people, typically females in their child bearing years, and has a protracted and relapsing clinical course.

The prevalence of IBD has been steadily increasing in the US and Europe over the past 20-50 years (Juillerat et al. 2008, Armitage et al. 2001, Jacobsen et al. 2006) with rises as much as 30% reported. The rising prevalence of IBD may be a feature of developing nations or urbanisation and a recent report suggests that eastern European countries are now experiencing increasing incidence rates for both CD and UC (reviewed by Lakatos and Lakatos, 2009). In Europe, CD has now become one of the commonest chronic diseases. Since it mainly affects young adults and has a chronic and progressive course, this disease presents a significant social and economic burden. In terms of health care costs, a recent German study estimated mean 4-week costs per patient of €1425 and €1015 for CD and UC, respectively (Stark et al. 2006).The cost of IBD to the NHS has been estimated at about £720 million per annum, based on the prevalence and an average cost of £3,000 per year per patient. These lifelong healthcare costs are comparable to those for major chronic disorders such as cancer and diabetes. There is currently no cure for CD and early detection is critical to prevent further pathology, associated disorders, such as colorectal cancer, and increased mortality.

4.2.2 Celiac Disease

Celiac disease in an inherited autoimmune disorder triggered by the digestion of gluten resulting in an inappropriate immune response against the small intestine, resulting in chronic inflammation and inhibition of absorption of important nutrients. Patients typically present with chronic diarrhoea, weight loss and anaemia, in addition to extra-digestive symptoms, such as infertility and skin lesions. However, many patients are actually asymptomatic. Such a variable presentation has resulted in difficulties diagnosing this chronic disorder and it is estimated that only 10-20% of cases in Europe and the US have been diagnosed. Early diagnosis is essential to reduce patients’ risks of developing other autoimmune disorders, neurological problems, osteoporosis and cancer in addition to increased mortality. A gluten-free diet is currently the only form of treatment.

Celiac disease is a multi-organ inflammatory disorder of multi-factorial aetiology. Familial studies have revealed a genetic basis for this disorder and the human leukocyte antigen (HLA) class II DQA and DQB genes are the principal determinants of genetic susceptibility. These genes encode products that are responsible for presenting gluten (environmental trigger) to immune cells.

Why is celiac disease of significant concern?

An estimated 2.5 million Europeans suffer from celiac disease (approximate prevalence of 1%). However, this figure is on the rise. For example, a recent population-based cohort study in Finland reported a doubling in prevalence in the last two decades, which now stands at 2% (Lohi et al. 2007). This disorder is a major public health problem because of its high prevalence and long-term complications. Patients can be affected at any age, including during childhood, resulting in a considerable life long disease burden. Furthermore, patients are at an increased risk of developing other autoimmune disorders, such as Type I Diabetes, systemic lupus erythmatosus, and rheumatoid arthritis in addition to risk of seizures, short stature and cancer.