Summary

Behcet’s Disease is a rare disease that causes blood vessel inflammation throughout the body. An auto-inflammatory disease, it can also manifest in a myriad of symptoms including mouth and genital ulcers, rashes, and inflammation in the eye, bowels, large blood vessels and brain. Behcet’s Disease has no standard test; it is a ‘diagnosis of exclusion’ in which patients are subjected to a series of tests to rule out other diseases in a process of elimination. Professor Wilson’s research has identified an underlying genetic mutation in patients affected by this disease. The research team figured out what this genetic mutation does in immune cells, and identified the treatment most likely to work for patients with this mutation. This has led to a new subtype of disease, one that can now be diagnosed using a specific genetic test. This means that patients have a more definitive and faster diagnosis, and a first line of treatment based on evidence. Earlier diagnosis and treatment are better for patients, better for healthcare and better for clinical staff.

Research description

Professor Wilson’s research group has a long-established record of investigating the biological impact of genetic mutations in rheumatic diseases. Prior to this research, clinical colleagues at University Hospital Limerick identified a rare rheumatic disease, called Behcet’s disease, in a large Irish family who presented with a pattern of symptoms suggesting an underlying genetic cause. The team isolated the cells causing inflammation in the body and used technology called whole genome sequencing, which reads the order of the DNA code in a person’s cells, to examine these cells.

The team discovered a gene mutation that had never before been identified that is incredibly important for regulating immune responses. Each cell has two sets of chromosomes, which carry DNA. The team found the end section of the mutant gene was abnormal on one chromosome, but normal on the other. This change in DNA changed the function of an immune protein, resulting in the immune cells being less efficient at regulating the immune response.

Specifically, when an immune signal called TNF was trying to regulate the cells, the mutated protein acted incorrectly, leading to damage. There are highly specific drugs called TNF inhibitors that help stop inflammation in cases such as this and are already used to treat inflammatory conditions such as rheumatoid arthritis.

The identification of TNF signalling in this case, combined with the genetic mutation as drivers of the disease, led Professor Wilson to discover that the use of TNF inhibitors would be an effective treatment for this disease, which will have a direct impact on people suffering from Behcet’s Disease with similar mutations.

Research impact

Health impact

Rare diseases are uncommon to healthcare professionals who may only ever encounter one case in their working life. For this reason, rare diseases take longer to diagnose and therefore treat. Rare diseases that are ‘diagnoses of exclusion’ such as Behcet’s Disease, subject patients to a battery of tests to rule out diseases because they have no way to diagnose the actual condition.

This research, and the resulting definition of a new subtype of disease, has identified causative genetic mutations that can be used in diagnosis. This may have potential impact for those living with Behcet’s disease, particularly those with a family background of this condition.

Although rare in northwestern regions, such as Western Europe and the United States, Behcet’s Disease is common in populations along the historical Silk Road, with more than 350,000 people estimated to have Behcet’s Disease in Turkey alone. This research has also influenced the identification of additional cases in Japanese individuals.

Earlier diagnosis can lead to earlier treatment. TNF inhibitors target the underlying cause of the disease and can actually stop the disease from worsening. The information as to whether this occurs in Behcet’s disease has yet to be determined but is well established in other autoinflammatory diseases.

Symptoms of Behcet’s Disease include oral, genital, skin and eye ulcers, joint pain and other symptoms caused by inflammation of blood vessels. In the absence of treatment, the prognosis is severe due to potential blindness and the risk of lethal blood vessel rupture. Therefore, research that improves the ability to diagnose and identify the best treatment for the appropriate patient and provides access to earlier treatment has a potentially huge impact on those living with Behcet’s Disease. For example, the family at the centre of this research with the active disease were prescribed anti-TNFs and responded well. A child in the family had started showing symptoms and the team identified that they too had the mutation. As a result of this research, the first line of treatment for that child will now be anti-TNFs should these symptoms progress. This is particularly important as the alternative treatment is steroids, which has known developmental side effects for children.

This research will lead to earlier, more precise diagnoses for some families with Behcet’s Disease, saving health care professionals and patients time and allowing for the most appropriate treatment options. The identification of a causative mutation and the new subtype of disease by this research will improve the clinical pathway from patient presentation to diagnosis to treatment for all those suffering from Behcet’s disease.     

The research featured as a Research Impact Story for the 2022 Children’s Health Foundation’s annual report.