Dr John Bowes and Dr Gisela Orozco reveal how genetic investigations will transform outcomes for people with psoriatic arthritis in the future
Scientists are always on the lookout for new psoriatic arthritis treatments. And the rapidly evolving field of genetics is throwing up some exciting new findings that could make a huge difference to the quality of life of people affected.
What is psoriatic arthritis?
Psoriatic arthritis is a type of arthritis that affects about one third of people with the skin condition psoriasis. It typically causes affected joints and tendons to become inflamed: swollen, stiff and painful. It can have other symptoms too such as fatigue, nail changes (pitting or separation from the nail bed) or redness and pain of the eye (uveitis).
A chronic disease or long-term condition, psoriatic arthritis can get worse over time if left untreated. When untreated, people experience a reduction in their quality of life caused by increasing disability and additional health complications.
The severity of psoriatic arthritis varies between individuals. Where some people may have severe problems affecting many joints, others might only notice mild symptoms in a couple of joints. At times symptoms may improve (remission) or get worse (flare-ups).
How is it psoriatic arthritis treated?
Although psoriatic arthritis has no definitive cure, treatments can alleviate symptoms, slow the condition’s progression and improve quality of life. People usually have to try a number of different medicines before finding one that helps.
Unfortunately, many people do not currently benefit from treatments as they are often not effective for controlling the disease. So the lack of treatment options for people with psoriatic arthritis is an important unmet clinical need.
Why do some people get psoriatic arthritis?
Psoriatic arthritis is what scientists call a complex disease. Its development is triggered by a combination of factors including a person’s genes, their lifestyle, and environmental issues such as diet, smoking or infections. Other examples of complex diseases are Alzheimer’s disease, asthma, Parkinson’s disease, multiple sclerosis and osteoporosis.
A particular combination of genetic factors that are correlated with disease predisposition can increase an individual’s risk for developing disease. But this does not mean that person is destined to develop the disease.
Instead, the development of disease will largely depend on the person’s exposure to environmental risk factors and their lifestyle.
What are we trying to do?
Expanding the treatment options available to people with psoriatic arthritis is one of the research priorities at the Centre for Genetics and Genomics Versus Arthritis. We know that we must learn more about the biological mechanisms that lead to disease. We need to understand what goes wrong in the body so we can find a drug that corrects it. Our knowledge about what causes psoriatic arthritis is limited, so this is a challenge.
How do genes come into it?
DNA is the cell’s instruction manual, and it is organised into genes, which contain the code for proteins, and non-coding regions. We all share a common genome, or set of instructions, that makes us human, but each person has a combination of DNA changes or variations that makes them unique. These DNA changes lead to visible inter individual variation for hair colour or height, for example. They can also influence predisposition to diseases such as psoriatic arthritis.
The identification of genes that are important to psoriatic arthritis can help us understand how these genes work together in biological processes. Genes and processes that we identify could become new targets for treatment. Conveniently, they may also already be targets for drugs used to treat other diseases so could be effective for treating psoriatic arthritis too. This is ideal as the drugs will have already gone through rigorous safety trials and a thorough approval process.
Identification
In addition, this knowledge can allow us to identify people with psoriasis who are at high risk of psoriatic arthritis. The result? Early treatment to reduce the impact of psoriatic arthritis.
For example, genetic studies discovered a link between the IL-23 pathway, a particular component of the immune response. The link suggested that drugs that target components of this pathway that are used to treat other diseases, could also be effective in psoriatic arthritis. These drugs are now used to treat psoriatic arthritis in the clinic. The identification of genetic factors that predispose people to psoriatic arthritis has huge potential in discovering other new therapeutic avenues.
Our on-going work, involving thousands of participants, has identified many DNA sequence changes that are found more frequently in psoriatic arthritis patients than in healthy people. These sequence changes that increase the chances of person developing psoriatic arthritis can help us understand the biological differences that lead to disease.
Most of the sequence changes that increase the chances of developing psoriatic arthritis actually lie in non-coding regions of DNA. We don’t fully understand the function of this non-coding DNA so it is difficult for researchers to work out how the sequence changes affect biological mechanisms in disease.
Cutting edge science
Modern experimental techniques reveal that non-coding DNA, which represents 98% of our genome, contains previously hidden switches and signals that play a critical role in regulating how genes are turned on and off. The sequence changes that increase the chances of psoriatic arthritis are thought to alter these gene regulating switches.
Identifying which genes are important is difficult because these sequence changes can be located a long way from the gene they control. We often picture DNA as a string of letters, or nucleotides, one after the other. But in reality, DNA is folded in the cells so regulatory switches in non-coding DNA can physically come into contact and regulate their target genes, although they may be separated by many nucleotides in the linear genome.
We think that genetic variants that increase the chance of developing psoriatic arthritis cause faulty connections between non-coding genetic switches and the genes they turn on and off. This would be one of the major causes of the disease.
So by studying how genetic variants affect the switches that turn genes on and off and how the DNA folds, we can identify the biological mechanisms that are altered in psoriatic arthritis. This information will help us pinpoint what biological mechanisms should be targeted to develop effective new treatments for psoriatic arthritis.
The end game
The answers to these questions will allow us to discover how genetic regions affect certain genes to cause psoriatic arthritis. The aim, of course, is the identification of new drugs that would be effective in the treatment of psoriatic arthritis… and to improve quality of life for people affected.
About the authors: Dr John Bowes and Dr Gisela Orozco are from the Centre for Genetics and Genomics Versus Arthritis at the University of Manchester
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