Blogger: Vibeke Videm

Twice as many of those who got rheumatoid arthritis between the HUNT2 population-based health survey in 1995-1997 and the next survey (HUNT3) in 2006-2008, reported previous cardiovascular disease at HUNT2. They either had angina or had suffered a myocardial infarction or stroke. The data indicate that there may be a causative link.

(…) chronic inflammation in one part of the body intensifies chronic inflammatory processes in other parts

Atherosclerosis, the most common cause of cardiovascular disease, is caused by chronic inflammation in the vessel walls. Rheumatoid arthritis is due to a gradual process with increasing dysregulation of the immune system that finally leads to inflammation in the joints. The inflammation due to atherosclerosis probably intensifies the process leading to rheumatoid arthritis. The study was recently published in the scientific journal  Arthritis Research and Therapy.

The findings are especially interesting because we already know that persons with established rheumatoid arthritis have an increased risk of cardiovascular disease. Our data indicate that the relationship between rheumatoid arthritis and cardiovascular disease may go both ways: if a person has one of these conditions, the risk of the other increases.

In other words: chronic inflammation in one part of the body intensifies chronic inflammatory processes in other parts. The joints and vessel walls are not independent sites, but influence each other.

In the HUNT surveys, the entire adult population in the county of North Trøndelag in Norway was invited to participate. In HUNT2, 70 % of those invited participated, and in HUNT2, 54 %. We studied 786 participants who reported having rheumatoid arthritis in HUNT3, but not in HUNT2. They were compared to more than 32,000 other HUNT participants. We found that 6.6 % of those who later got rheumatoid arthritis had previous cardiovascular disease, compared to 3.1 % of the other participants.

The risk was now 90 % larger for future rheumatoid arthritis in the participants who had cardiovascular disease at HUNT2.

The diagnosis of rheumatoid arthritis in HUNT is self-reported. This introduces some uncertainty because some of those who answer that they have rheumatoid arthritis may actually have another condition. We therefore repeated the analysis after investigating whether the participants reporting rheumatoid arthritis also had a diagnosis from one of the three hospitals in Trøndelag. When comparing these 201 persons with the remaining HUNT participants the connection became stronger: The risk was now 90 % larger for future rheumatoid arthritis in the participants who had cardiovascular disease at HUNT2.

Approximately 1 % of the population suffers from rheumatoid arthritis. Without treatment, the condition causes pain and gradual joint destruction, resulting in decreased function. To a large extent, this may be prevented by modern treatment. The most important risk factor is a genetic predisposition, and rheumatoid arthritis is more common in women. The risk also increases with advancing age. These are factors the individual cannot influence.

(…) our study confirms that lifestyle-related factors have an important impact on whether a person with a genetic predisposition actually develops rheumatoid arthritis

However, our study confirms that lifestyle-related factors have an important impact on whether a person with a genetic predisposition actually develops rheumatoid arthritis. Smoking, overweight, high blood pressure, too little physical activity and increased blood cholesterol are important risk factors for cardiovascular disease, which in turn is associated with increased risk of rheumatoid arthritis. Several of these factors also directly influence the risk of rheumatoid arthritis, without the “detour” via cardiovascular disease. It is well established that smoking at least doubles the risk of rheumatoid arthritis and that this effect remains for many years following cessation. In our study, the effect from previous cardiovascular disease was additive to the direct effect of smoking.

Which practical conclusions may be drawn from the study?

First, that a person with relatives having rheumatoid arthritis has very strong reasons to try to adopt a lifestyle that reduces the risk of cardiovascular disease: avoid smoking, eat a healthy diet and get enough exercise, and have his or her blood pressure and cholesterol checked from time to time. It is certainly a positive thing that it is possible to do something that reduces the risk of developing disease even if one has had back luck with respect to the genetic predisposition.

(…) a person with relatives having rheumatoid arthritis has very strong reasons to try to adopt a lifestyle that reduces the risk of cardiovascular disease

Second, that someone with cardiovascular disease who develops joint problems may actually have an early form of rheumatoid arthritis, and that the doctor needs to keep this diagnosis in mind during the diagnostic work-up. Joint problems have many causes. But if they turn out to be due to rheumatoid arthritis, it is important to start treatment as early as possible.

International collaboration

The study results from collaboration between researchers at the Medical Faculty at the Norwegian University of Science and Technology in Trondheim, Norway, and researchers at the University of Queensland in Brisbane, Australia. The HUNT study is very well suited for this kind of studies: There are a large number of participants, they represent the general population and not selected subgroups, and follow-up time is long.

We are grateful to the people in North Trøndelag who were willing to participate in several of the HUNT surveys. If not, the study would not have been feasible because it was based on comparison between responses in HUNT2 and HUNT3. The research group is now planning new studies on rheumatoid arthritis in a future HUNT4, where we hope that the inhabitants of North Trøndelag will once again contribute to helping us getting further knowledge about the causes and possible strategies to reduce the risk.

Early on a Friday morning in the middle of November, PhD student Anne Hokstad and I, headed towards Trondheim airport, Værnes, to catch the early flight to Copenhagen. We did not spend much time in bed that night as the airport taxi came at 4.20 am. However, there should be good opportunities for sleeping over the next 24 hours, although it had to be in a sitting position, either at Kastrup airport, or during the 13-hour flight to Singapore.

Sleeping in a sitting position on economy class is not easy, and we arrived for a stop-over in Singapore early Saturday morning after only two hours of interrupted sleep. It was tempting to take a short morning nap, but we decided to spend the day on walking along the streets of Singapore, and keep going throughout the day instead. After a good night sleep, in bed, we were ready for some more physical activity the next morning until the departure of our flight to Melbourne, Australia. Again we spent Sunday night in a sitting position on a plane with a few hours of interrupted sleep, again we arrived early in the morning, and again we spent the next day being active, settling in in Melbourne.

The purpose of this exhausting flight was to visit Associate Professor Julie Bernhardt and her colleagues at the Stroke Division at Florey Institutes of Neuroscience and Mental Health in Melbourne, Australia, and to continue our research collaboration on physical activity early after stroke.

So, why all this interest in time spent in bed, in sitting position and on physical activity? It is well known within the stroke society that acute treatment in a comprehensive stroke unit saves lives and reduces disability. Furthermore, from the stroke unit trial in Trondheim we know that early mobilisation and activity is the most significant factor for beneficial outcome, followed by stabilising diastolic blood pressure. It is therefore of great interest and importance to have a closer look at the activity levels offered to stroke patients admitted to stroke units across the world, and furthermore to analyse its association to outcome. 

Physical activity can be measured in different ways, both by observation and by use of body worn sensor systems. Julie Bernhardt has developed the Behavioural Mapping method which is a standard method of observation every 10-minute from 8 am to 5 pm over the course of a single day. At each observation, the patient’s location, who the patient interacts with, and which activity the patient is doing, is registered. Up to 10 patients can be observed at a time. At the Department of Neuroscience at NTNU, we have observed more than 500 patients, including a pilot study of 117 patients from the stroke unit at St. Olavs Hospital and a multisite study of 411 stroke patients admitted to 11 Norwegian stroke units, mainly in Central Norway but also in Bærum, Lillehammer and Tromsø. All behavioural mapping forms completed in these studies have been scanned and sent to Florey for processing and the initial analyses.

The primary aim of our visit this time was to help cleaning up the data and to bring a complete and tidy overview over the activity levels of the patients back home again. In the pilot study we found that an increased proportion of time spent in bed in the early phase after stroke was strongly associated with an increased risk of poor outcome (death or disability) three months later. While, to our surprise time spent on physical activity, like standing, walking and climbing the stairs, did not show the inverse association.

We are now very interested in the results from the 411 patients included in the Life Early After STroke – the LEAST study. Will the results from the pilot study be confirmed? And, will the activity levels provided by the 11 Norwegian hospitals differ significantly? That is what PhD student Anne Hokstad is going to figure out over the next 18 months.

We did not spend very much time in bed during our Melbourne trip. However, a great proportion of the time was spent in a sitting position, either at work at Florey, on the train to Heidelberg, on the plane to Alice springs, or on the 17-hour bus tour from Alice Springs to visit Ayers Rock (or Uluru as the Aboriginals call it) during the weekend in-between.

As we both are aware of the risk of spending too much time in sitting position, we tried to spend a significant proportion of the time also on physical activity like running on the treadmill at the hotel, walking along the Yarra River and also by walking along the streets of Melbourne.

The immune system has sensors that recognize invaders such as bacteria and viruses, but also damage to the cells in the body. When the immune system is activated, the result is inflammation, which is designed to remove invaders and repair cell damage. Inflammation is characterized by redness, heat, pain and swelling.

The body has to regulate inflammation carefully, because if the immune system overreacts, the response itself may cause more damage than the actual reason for the reaction. Chronic inflammation is linked to diseases such as atherosclerosis (hardening of the arteries), obesity, cancer, diabetes and dementia, among others.

Sugar + inflammation = true? Foto: istockphoto

Chronic inflammation is linked to diseases such as atherosclerosis (hardening of the arteries), obesity, cancer, diabetes and dementia, among others.

A key issue for us at the Centre of Molecular Inflammation Research (CEMIR) is how inflammation can be so closely associated with so many seemingly different chronic diseases.

The American Dr. Robert Lustig’s book “Fat Chance – The bitter truth about sugar,” is quite relevant here. Lustig blames high sugar consumption as the major culprit behind our generation’s greatest health challenge, metabolic syndrome¹. Dr. Lustig, who is a pediatric endocrinologist and works every day with overweight children, is perhaps best known for his lecture “Sugar: The bitter truth” on YouTube. This video is now been seen by more than 3.5 million people.

Lustig and others raise issues with the prevailing view that obesity is due solely to too much energy in, and too little energy out².

The World Health Organization’s definition of metabolic syndrome is insulin resistance, along with two or more of the following: hypertension (140/90), obesity (BMI> 30), high cholesterol (TG> 1.7), or increased excretion of protein into the urine (microalbuminuria). Metabolic syndrome results in enormous health care costs, and is more of a major public health problem worldwide than malnutrition.

Patients with metabolic syndrome are at higher risk of a number of different health problems, including heart attack and stroke. We have not been spared from this problem in Norway, and “Samhandlingsreformen” – the Coordination Reform – is an attempt by the Norwegian government to bring the issue to light through an increased focus on preventive health care.

When you consume sugar, your body must decide whether the energy should be used or stored. Sugar is an important source of energy – and it is therefore essential that we always have enough. Any surplus will mostly be stored, in a process that is managed by the liver and that results in a variety of wastes, including uric acid. Under normal conditions, the body can get rid of uric acid, but if it accumulates, it can form crystals.

In the first part of my doctoral research, we found a mechanism that explains how these crystals activate the immune system. The immune system tries to get rid of the crystals, but cannot (see video). The cells then send out a powerful cry for help, which activates the immune system further. This emergency signal is tightly regulated, because if the body overshoots its target, the result is chronic inflammation. If this inflammation manifests itself in a joint, we get redness, heat, pain, and swelling – all symptoms of a disease better known as gout.

The liver also converts sugar into fat for long-term storage. The fat is transported as LDL (better known as “bad cholesterol”) in the bloodstream and out to our fat cells. On the way, the cholesterol can stick to the walls of blood vessels and form the foundation for what we call atherosclerosis. Too much cholesterol in one place can also lead to the formation of crystals, cholesterol crystals.

We are currently completing a project where we have looked at whether cholesterol crystals activate the immune system in the same way. In this situation, the immune system overreacts, but the consequence may be that the vessel wall, and not the crystals, breaks down. This can cause a wound, which in turn can cause a blood clot. And depending on where the clot is located, it can cause a heart attack or a stroke.

The goal of our research is to improve our understanding of how the disease occurs. There are ongoing trials of immunosuppressive drugs to prevent heart attack and stroke. But it is also important from the patients’ perspective that we understand the mechanisms of disease as best we can.

But immunosuppressive drugs attack metabolic syndrome at the wrong end. If it really is correct that sugar + inflammation = true, then we can all approach this from the other end – namely by cutting our daily sugar intake.

1.     Lustig, R. Fat Chance: The bitter truth about sugar. (Fourth Estate, 2012).

2.     Taubes, G. The science of obesity: what do we really know about what makes us fat? An essay by Gary Taubes. BMJ 346, f1050 (2013).

The official opening of the Norwegian University of Science and Technology’s four new centres of excellence (CoE) will take place on Monday 10 June. CEMIR, the Centre of Molecular Inflammation Research, is one of these new centres. CEMIR researchers will study new mechanisms that set off inflammatory responses. We hope this will provide us with information that could help in the development of new treatment methods and the diagnosis of diseases in which inflammation plays a crucial role. You can read more about CEMIR at http://www.ntnu.edu/cemir

In June there will be more blogs from CEMIR researchers.

“There is a lot about the brain, and especially brain injury among newborns, that we don’t know about. Over the last 30 years, we have increased our knowledge significantly, but there are still many unanswered questions.”

When injury occurs among newborn children, it happens at a stage when the brain is still not fully developed. This means that hypoxic-ischemic brain injury, in addition to damaging the brain’s structure, also impacts the development of the brain. At the same time, however, it gives rise to the possibility of the brain repairing itself and finding alternative methods for solving various tasks.

Using MRI

In his thesis, “Magnetic Resonance Imaging of Hypoxic-Ischemic Brain Injury Development in the Newborn Rat – Manganese and Diffusion Contrast,” Widerøe finds that the hypoxic-ischemic brain injury process continues for a prolonged period of time after the initial incident, but that anti-inflammatories such as the antibiotic doxycycline can limit the damage.

To map the injury process and treatment effect, Widerøe has developed and adopted new techniques for magnetic resonance imaging (MRI) in newborn animals. The use of MRI means that repeated examinations can be performed without biopsies, and researchers can follow the development in individual animals over a longer period.

The research group he belongs to also uses MRI to assess how too much or too little oxygen affects normal brain development.

It is in connection with this that the researchers have concluded that treatment with an anti-inflammatory gives a more normal brain development after a hypoxic-ischemic brain injury, compared with those who did not receive the same treatment.

The results also confirm previous research which shows that administering pure oxygen can cause further damage and delay maturing-processes in the brain further after an incident of lack of oxygen.

The research using rats will continue, and one of the PhD students in the group will look further into the harmful effects of oxygen in connection with hypoxic-ischemic brain injury. Other PhD students will look at treatments using stem-cells. Using MRI, the researchers can look at the movements of stem-cells in the brain after they have been implanted, and how these can affect inflammation-reactions and the brain’s ability to repair itself. As part of this, the group will continue to study the brain’s development using MRI.

While Widerøe’s part of the group primarily has focused on animal testing, another part of the group, directed by professors Ann-Mari Brubakk and Jon Skranes, has followed children with low birth weight and premature children using MRI and mapped their brain activity into adulthood. Many of these children have had small and/or large brain injury during pregnancy or birth, and the goal has been to follow their brain development and map the long-term effects of impacts around birth.

Viva

Marius Widerøe will defend his thesis on 29 May. A lecture will be given at 09.00 in the Auditorium at Medisinsk teknisk forskningssenter at NTNU. The viva will take place at 11.00.

Hypoxic-ischemic brain injury

Hypoxic-ischemia is a combination of reduced oxygen and limited blood supply to the brain. It is one of the most common causes of brain injury among newborn children and increases mortality, as well as psychological and physiological problems later in life.

Publications:

• Doxycycline treatment in a neonatal rat model of hypoxia-ischemia reduces cerebral tissue and white matter injury: a longitudinal magnetic resonance imaging study. Widerøe M, et.al.
• Longitudinal manganese-enhanced magnetic resonance imaging of delayed brain damage after hypoxic-ischemic injury in the neonatal rat. Widerøe M, et.al.
• Manganese-enhanced magnetic resonance imaging of hypoxic-ischemic brain injury in the neonatal rat. Widerøe M, et.al.