About one in forty people will sooner or later have to deal with it: psoriasis, the skin disease that is characterized by thick, scaly patches on the skin. The spots are usually on the elbows and knees, but can occur all over the body – including the face, for example. During periods when the disease flares up, the patches turn red and can become itchy and painful. “Psoriasis has a major impact on quality of life,” says dermatologist Elke de Jong. “People experience a lot of physical but also social discomfort. We have patients who hardly dare to go outside anymore.”
De Jong is a professor at Radboudumc in Nijmegen. There she supervised – in a large interdisciplinary team – three young researchers who all defended a thesis in October on different aspects of the disease.
“In the past, many doctors only saw psoriasis as a skin condition,” says De Jong. “Today we see it more as a systemic disease, in which the immune system plays a central role.” This shows an overreaction, whereby the production of skin cells in the overdrive and many local inflammations occur.
It is unclear what exactly causes the disease. It is also unclear what the relationship is with other disorders. “Many of our patients also have joint inflammation, diabetes, cardiovascular disease, obesity and depression,” says De Jong. “But we don’t know what exactly is cause and effect. That is why different specialisms work together in research and treatment.”
Trial and error
Psoriasis cannot be cured, but it can be treated, the dermatologist emphasizes. “There are already many medicines that people benefit from,” she says. “These substances suppress certain aspects of the immune system. Since 2005, a new group of drugs has been launched on the market, the biologics. They have revolutionized treatment.”
Biologics consist of animal or human proteins. Pharmaceutical companies use living cells – often from bacteria or animals – to make biologics. The complex molecules specifically target certain points in the immune system. This makes them more effective and gives fewer side effects than the synthetically made psoriasis medicines that have been around for some time. “But they are much more expensive,” says De Jong. “Sometimes up to tens of thousands of euros per patient per year. That is why traditional medicines still have a place in the treatment. There are patients who are very well helped by this.”
The search for the right medicine is often long and grueling. “It is a matter of trial and error”, says immunologist Hans Koenen, who also supervised a PhD student in the interdisciplinary team. “Of course, we would much rather know in advance who will benefit from which medicine. Then you can work in a much more targeted way and prevent many side effects.”
According to Koenen, the holy grail is therefore a blood test that shows abnormalities in the spectrum of immune cells, in the molecules they produce and in biological processes in these cells. “We are working on that in Nijmegen,” he says. “We are not there yet, but ultimately we want to be able to offer each patient a tailor-made treatment.”
Major studies
That is more complicated than it seems, says rheumatologist Mark Wenink of Radboudumc, the third supervisor of the cluster of PhD research. “Every patient’s immunological profile is different,” he explains. “That is why you often have too few patients in a study to be statistically strong. That is why we like to work together in large European projects: then you can merge patient groups.”
Biomarkers have already been found that appear to correlate with certain disease characteristics in small studies, Wenink continues, but this is rarely followed up. “That’s the tricky part in science,” he notes. “Repeating experiments isn’t as sexy as coming up with something new.”
“But it will absolutely happen, typing based on biomarker profiles,” predicts Koenen. In ten, fifteen years? “Oh, I think faster.”
“It won’t make much difference in terms of costs,” says Wenink. “But in the end you just want to give every patient really good treatment.”
Three PhDs in Nijmegen: state-of-the-art diagnosis and treatment
1. Mirjam Schaap charts psoriasis
How severe is this patient’s psoriasis? To answer that question, the doctor assigns a score based on the size, redness, scaling, and thickness of psoriasis patches. “But that is a subjective measure, which says nothing about the future course of the disease,” says Mirjam Schaap. “I investigated whether you can also assess psoriasis with innovative, non-invasive techniques, and whether you can predict the course of the disease with this. Hopefully this will allow doctors to treat their patients even more specifically.”
Schaap used a laser device, developed by the University of Twente, to visualize the blood flow in psoriasis spots. She investigated whether that information can predict whether psoriasis spots will spread. “We also looked at the blood circulation in the skin around the psoriasis site,” says Schaap. “Changes that you can’t see with the naked eye appear to be related to expansion of the site over a few weeks.”
With a relatively small dataset of about 1,500 photos, we already achieved very nice results
Mirjam Schaap
In addition, inflammatory proteins in the psoriasis site may provide valuable information. “You can collect those proteins with a skin biopsy,” says Schaap, “but that is quite drastic, especially in children.” There are also patches that you stick on the spot, and that absorb inflammatory proteins. You can then analyze it in the lab. “Unfortunately, we did not see a correlation between the concentrations of these proteins and the severity of the disease in individual patients. A major national study will soon start that will hopefully uncover proteins that can help with this.”
Schaap also investigated whether artificial intelligence can help determine the severity of psoriasis automatically based on photos. “We already achieved very good results with a relatively small dataset of about 1,500 photos,” she says. “Hopefully this will allow doctors to assess the disease more objectively in the future.”
2. Marloes van Muijen wants to optimize the medicine dose
For her PhD research, Marloes van Muijen extracted data from BioCapture. This is a network of twenty Dutch hospitals led by Radboudumc. Since 2005 they have been collecting data on psoriasis patients who are so-called biologics use: a relatively new and effective class of drugs. “Before a product is launched on the market, manufacturers conduct clinical research into its effectiveness and safety,” says Van Muijen. “That often happens in a relatively healthy group of patients, under controlled conditions. But it is also important to look at what a drug does in practice over a longer period of time: in a much larger, more diverse patient group.”
It would be ideal if you could determine the lowest effective dose for each patient
Marloes van Muijen
For her research, Van Muijen followed patients who have been using biologics successfully for a long time. “Many of these people have considerably fewer complaints than before,” she says. “Doctors may then think: this patient is doing well, we no longer have to keep an eye on him. I found out that’s not right. These patients do have specific needs. We also saw that some of these patients, despite low psoriasis activity, still develop psoriatic arthritis.”
If doctors keep a close eye on their psoriasis patients, they can try to taper off the medication where possible. “Basically, everyone gets the standard dose,” she says, “from an otherwise healthy 18-year-old girl to an older man who is overweight and diabetic. It would be ideal if you could determine the lowest effective dose for each patient, in order to optimize the balance between efficacy and side effects.”
Van Muijen discovered that many doctors are positive about dose reduction, but are sometimes hesitant to start. “That’s because few studies have been done on it, and no guidelines exist yet. Future research should therefore focus on that.”
3.Michelle Mulder wants to better predict the course of the disease
About a third of psoriasis patients also develop rheumatic inflammation over time. “We call this psoriatic arthritis,” says Michelle Mulder, who obtained her PhD at Radboud University but largely conducted her research at the Maartenskliniek in Nijmegen. “This condition takes many forms, including inflammation of joints and tendon attachments, skin and nail abnormalities, ‘sausage-shaped’ fingers and toes, and inflammation of the spine.”
The symptoms and severity of these can vary greatly from patient to patient, says Mulder. Some people have only mild symptoms, while for others the disease can be totally disabling. “Some patients no longer come up the stairs.”
Precisely because the disease is so heterogeneous, early detection is difficult. “While it is very important,” says Mulder, “to be able to treat people on time and effectively. For example, by seeing in time who could benefit from a referral to a rheumatologist.”
We looked at over a hundred different immune cell types in the blood
Michelle Mulder
So she and her supervisors worked on a way to identify these patients based on blood tests. “We looked at more than a hundred different immune cell types in the blood,” says Mulder. “On the basis of that overall picture, we were able to distinguish well between people with only psoriasis and people with psoriatic arthritis in addition. That is very promising.”
The researchers want to fine-tune this ‘fingerprint’ method in order to be able to predict the course of the disease at an early stage, to be able to characterize disease activity, and therefore also to be able to treat patients better. “With artificial intelligence, we are trying to teach computers to make this distinction,” she concludes. “We’re not that far yet, but it’s definitely going in that direction.”
What the clinic can do more quickly is another finding that Mulder made: many patients benefit from the combination of two ‘classic’, relatively cheap rheumatoid drugs. “That shows that it sometimes makes sense to revisit old resources.”