Flemish scientists find cure for rare immune disease

From Flanders Today:

A long wait

It may have taken them a decade, but researchers at the University of Leuven (KU Leuven) have finally determined the cause of a mysterious disease that has plagued one West Flemish family for three generations.

 

The disease – known as PAAND – causes severe skin lesions, muscle pain and general exhaustion. It first came to light about 10 years ago, when paediatric rheumatologist Carine Wouters (pictured right) was confronted with the case of a 13-year-old boy who was brought to the emergency department at Leuven University Hospital.

“Because of a cardiac muscle infection, the boy suffered from heart problems, but we quickly realised that the condition was part of a broader auto-inflammatory disease,” says Wouters.

To her amazement, the doctor soon discovered that other members of the young patient’s family were exhibiting similar symptoms. “But the cause remained unknown,” she says.

Unbearable pain

The boy’s father, who prefers to remain anonymous, has suffered from the same mysterious disease for most of his life. “Since I was five, I have had severe muscle pains, and I’ve suffered from extreme exhaustion,” he says. “Sometimes, I couldn’t even stand up and had to stay home from school for days, just to recover.”

He eventually finished school and found a job, but the condition made his career as a truck driver no less difficult. “The older I got, the more frequently I had to pull over to the side of the road and rest for a few hours,” he says.

The pain was so unbearable, he often couldn’t sleep through the night. As more health problems accumulated, the now 50-year-old man was forced to quit his job.

Sometimes, I couldn’t even stand up and had to stay from school for days, just to recover

- PAAND PATIENT

The disease also causes fever sensations and – most visibly –skin lesions. While the former truck driver has sores on his back, one of his brothers suffers from skin lesions on his face, some of which take the form of open wounds, as if the skin had been burned. During cold weather, the symptoms generally get worse.

Altogether, 12 members from three generations of the West Flemish family are afflicted with the disease. Until now, doctors could only ease their suffering with anti-inflammatory drugs and painkillers.

Genetic mutation

The breakthrough discovery of PAAND is the result of an extensive DNA comparison between the patients’ blood and that of their family members who are not affected by the disease.

The study was led by KU Leuven professor Adrian Liston, who also works at Flanders’ life sciences research institute VIB. Liston’s team collaborated with scientists from the Walter and Eliza Hall Institute in Melbourne, Australia.

The researchers traced the cause to a mutation of a gene known as MEFV. They determined that the mutation tricks the body into responding to a bacterial skin infection, even if there isn’t one. The response causes the skin to produce an inflammatory protein called interleukin-1 beta, which causes skin lesions, fevers and pain.

“If you have the flu, the fever and exhaustion you experience are the result of your immune system putting a lot of energy into battling the infection and not having enough energy left to allow you to function normally,” Liston explains.

With PAAND, he continues, “the immune system diverts much of that energy into fighting an infection that isn’t actually there, with disastrous consequences”.

Only one of the parents needs to carry the mutation for the disease to affect their children, though it isn’t necessarily passed on to every child.

The cure

“These insights were made possible because DNA analysis has become more innovative and affordable,” explains Liston. “We also couldn’t have done it without the collaboration with our colleagues abroad.”

Once they understood how the disease operates, the scientists started looking for a treatment. They found it in a drug called anakinra, also known under the brand name Kineret. While the drug is used in treating rheumatoid arthritis, Liston found it also has the ability to block the protein that causes PAAND.

We hope that the discovery will improve the quality of life for many other people in Flanders and abroad

- DR CARINE WOUTERS

In partnership with the University of Leeds in the UK, the drug was tested on a British patient who was diagnosed with PAAND. The results were striking; the patient’s skin lesions cleared rapidly, and the fevers and pain stopped entirely.

The medication is now being tested on five members of the family from West Flanders, including the father. “I hope the drug can make our lives more normal,” he says.

For the time being, his son is recovering from a second heart transplant and cannot take the medication. The scientists are planning to involve him and other patients at a later stage.

Dr Wouters, who has stood by the Flemish family over the past 10 years, is happy that their resilience has finally been rewarded. “We hope that the discovery will improve the quality of life for many other people in Flanders and abroad,” she says. Doctors in France and Lebanon have already indicated that they also have patients with PAAND.

The next steps

The treatment was first carried out in the UK because the country’s health-care system reimburses the drug anakinra. For the tests on Flemish patients, KU Leuven researchers negotiated directly with the drug’s manufacturer, the Swedish company Orphan Biovitrum.

We know about 6,000 rare diseases, and more innovative techniques could help us to identify new ones

- DR CARINE WOUTERS

To finance the project, Wouters and Liston used money from a research fund they set up in 2015 to finance the diagnosis and treatment of immune disorders in children, most of which are so rare, they are not covered by health insurance. According to the European categorisation of rare disorders, PAAND affects less than one in 2,000 people.

The two scientists have called on Belgium’s federal health minister Maggie De Block to focus more attention on diseases like PAAND. “Rare diseases are not rare,” Wouters says. “We know some 6,000 of them, and more innovative techniques could help us to identify new ones.”

According to Liston, more newborn babies should also be screened for immune system deficiencies. This, he says, could help prevent medical conditions later in life, which “not only affect the person’s overall health, but result in high costs to the social security system”.

Coauthors

All my coauthors from 110 publications. You can see the productivity of lab members, and also our most frequent collaborators - Michelle Linterman, Daniel Gray, Sylvie Lesage, Chris Goodnow, Carine Wouters

BioCentury Innovations

Our work was highlighted by BioCentury Innovations as a novel strategy to screen for anti-diabetic drugs:

Where we publish

Oh, it is nice to see Nature Immunology that prominent. JACI has sprung up a lot over the last few years with our move to translational immunology

How one lab challenged a grant rejection and won €5 million

A British scientist successfully appealed against an unfavourable grant review — but the road to victory can be paved with challenges.

Faced with a rejected grant application, scientists experience a range of emotions — shock, sadness, anger — before usually accepting the verdict and moving on. But when the European Commission rejected a €5-million (US$5.7-million) grant application from computational scientist Peter Coveney, he hired a lawyer and challenged the decision.

Read the full article

Personally, I wonder where the extra money came from to fund the appealed grant? Presumably they didn't cut someone else, so my guess is that the money probably comes from next-years budget, further reducing success rates.

What we work on

The titles of 110 publications. 

Nature research highlight

PAAND in the news

The write-ups range from the International Business Times to Nature Middle East to Science!

Decennia-oude, mysterieuze ziekte geïdentificeerd en mogelijke behandeling gevonden

Een mysterieuze ontstekingsziekte teistert al drie generaties lang een Vlaamse familie met ernstige huidletsels, koorts, pijn en uitputting. De ziekte, waarvoor men tot nu toe geen oorzaak of behandeling had gevonden, is nu geïdentificeerd als pyrine-geassocieerde auto-inflammatie met neutrofiele dermatose (Pyrin Associated Autoinflammation with Neutrophilic Dermatosis, afgekort PAAND), en werd ook vastgesteld bij families in Engeland en Frankrijk. In een nieuw onderzoek hebben Adrian Liston (VIB/KU Leuven) en Carine Wouters (UZ Leuven/KU Leuven) de genetische mutatie ontdekt die de ziekte veroorzaakt, en ook een doeltreffende behandeling gevonden. Hun onderzoek werd gepubliceerd in het internationale wetenschappelijke tijdschrift Science Translational Medicine.

Al decennia lang kampen families in België, Engeland en Frankrijk met een mysterieuze ziekte die huidletsels, koorts, pijn en uitputting veroorzaakt. Elke generatie krijgt de helft van de kinderen van personen die de ziekte hebben, dezelfde symptomen. Artsen waren er niet in geslaagd de ziekte te identificeren of een doeltreffende behandeling te vinden. Nu is de identificatie eindelijk een feit en is dankzij een internationaal onderzoeksteam ook een behandeling gevonden. 

Prof. Adrian Liston (VIB/KU Leuven, hoofd van het wetenschappelijk onderzoeksteam): “Dankzij het nauwgezette werk van de artsen weten we nu dat we te maken hebben met een erfelijke aandoening. Dankzij de vooruitgang in de DNA-sequentietechnologie konden we het genoom van deze patiënten bepalen en de mutatie opsporen die de ziekte veroorzaakt.”

Het gaat om een mutatie in het MEFV-gen. Mensen die van hun beide ouders een MEFV-gen met een mutatie overgeërfd hebben, lijden aan de ontstekingsziekte familiaire mediterrane koorts (FMF), een ontstekingsziekte. Bij PAAND-patiënten gaat het echter om een andere mutatie in het MEFV-gen én is één enkele kopie van de mutatie voldoende om de ziekte door te geven. Dit betekent dat de helft van de kinderen van de patiënten de ziekte overerven, in tegenstelling tot de mutaties die FMF veroorzaken (die vaak een generatie overslaan). De PAAND-mutatie zorgt ervoor dat het lichaam reageert alsof er een bacteriële huidinfectie plaatsvindt. Daardoor gaat de huid het ontstekingseiwit interleukin-1β produceren, dat huidletsels, koorts en pijn veroorzaakt. 

Een behandeling voor de nieuwe ziekte?
Dankzij het opsporen van de biologische oorzaak van deze ziekte kon men ook een nieuwe behandeling bepalen. De onderzoekers hergebruikten anakinra (Kineret ®), een middel tegen artritis dat zich richt tegen interleukin-1β, dat ook bij PAAND een belangrijke rol speelt. De resultaten bij een eerste patiënt, uit een Engels gezin, waren opvallend positief. De huidletsels verdwenen snel en de patiënt herstelde helemaal van de koorts en de pijn. Op dit moment wordt een uitgebreidere test uitgevoerd bij Vlaamse patiënten, om te zien of deze gerichte behandeling tot een volledige genezing kan leiden.

Prof. Carine Wouters (KU Leuven/UZ Leuven, hoofd van het klinische onderzoeksteam): “Dit is het resultaat van een intense samenwerking tussen artsen en wetenschappers die al bijna tien jaar de ziekte trachten te begrijpen. Ik ben verheugd vast te stellen dat we deze zeldzame mutatie nu beter begrijpen en dat we voor deze patiënten de weg hebben geopend naar een doeltreffende therapie.”

Citaat van een patiënt: “We zijn blij en heel dankbaar dat de artsen en wetenschappers hun zoektocht naar de oorzaak van de ziekte die onze familie al zo lang treft, nooit hebben gestaakt. We hopen dat de nieuwe behandeling gunstig zal zijn voor onze familie. En we beseffen ook dat de bevindingen andere patiënten zullen helpen om een correcte diagnose en behandeling te krijgen.”

Prof. Adrian Liston (VIB/KU Leuven, hoofd van het wetenschappelijk onderzoeksteam): “Dit is een uitzonderlijke periode voor het onderzoek rond erfelijke aandoeningen. We helderen elke maand klinische gevallen op die enkele jaren geleden nog niet op te lossen waren. We ontdekken nieuwe mutaties en beschrijven nieuwe ziektebeelden en ziektemechanismen waarvoor ook nieuwe werkzame geneesmiddelen kunnen worden voorgeschreven. Patiënten komen daardoor soms in moeilijke situaties terecht, waarbij de wetenschap een oplossing kan bieden, maar de ziekteverzekeringen de kosten voor geavanceerde diagnosetests of nieuwe behandelingen nog niet kunnen terugbetalen. Dit vormt dan ook een uitdaging voor zowel de farmaceutische industrie als de overheid. Zowel nieuwe medicijnen als bestaande medicijnen voor nieuwe indicaties dienen ter beschikking worden gesteld van patiënten die – op basis van genetische testen – zeer goed kunnen gedefinieerd worden. 

Prof. Carine Wouters en prof. Adrian Liston hebben het Leuven Universiteitsfonds Ped IMID (Pediatrische Immuun-inflammatoire aandoeningen) opgericht, een waarmee ze middelen willen werven om onderzoek, diagnose en behandeling mogelijk te maken voor personen die lijden aan zeldzame immuunziekten die momenteel niet door de ziekteverzekeringen worden gedekt.

Ook gelezen: De Staandard, Het Laatste Nieuws, Het Nieuwsblad, De Morgan

Decades-old mystery disease identified and potential cure found

A mysterious inflammatory disease has been afflicting a Flemish family for three generations, causing severe skin lesions, fevers, pain and exhaustion. This disease, which previously had no known cause or cure, has now been identified as Pyrin Associated Autoinflammation with Neutrophilic Dermatosis (PAAND), and has also been found in families in England and France. New research by Adrian Liston (VIB/University of Leuven, Belgium), Seth Masters (Walter and Elisa Hall Institute, Australia), Carine Wouters (University of Leuven, Belgium) has found the genetic mutation causing the disease and also identified an effective treatment. This research was published in the international scientific journal Science Translational Medicine.

For decades, families in Belgium, England, and France have been living with a mysterious disease that results in skin lesions, fevers, pain and exhaustion. Every generation, half of the children of the people with this disease develop the same symptoms. Doctors had been previously unable to identify the disease or find any effective treatment. For the first time, this disease has been identified and a treatment found due to an international research team.

Professor Adrian Liston (VIB/University Leuven): “Detailed work by clinicians told us that we were dealing with a genetic disease. Thanks to advances in DNA sequencing technology we were able to sequence the genome of these patients and find the mutation causing the disease”.

The mutation is in the gene called MEFV. This gene was known to cause an inflammatory disease called Familial Mediterranean Fever (FMF) in patients who inherit mutated copies from both mother and father. However, the mutation found in the PAAND patients is different. Only a single copy of the mutation is needed to cause disease, meaning it affects half the children of patients, unlike the mutations that cause FMF, which often skip generations.

Professor Seth Masters (Walter and Elisa Hall Institute): “The PAAND mutation causes the body to as if there is a bacterial skin infection. This leads to the skin making the inflammatory protein interleukin-1β, which causes skin lesions, fevers and pain”.

A cure for the new disease?

Understanding the biological basis for this new disease allowed the rational selection of a new treatment. The researchers repurposed an anti-arthritis drug, anakinra, which targets the same protein that causes PAAND, interleukin-1β. The results in the first volunteer, from an English family, were striking, with a rapid clearance of skin lesions and a complete recovery from fevers and pain. A larger trial is now beginning in the Flemish patients to see if this targeted treatment will act as a complete cure.

Professor Carine Wouters (KU Leuven/UZ Leuven, lead clinical researcher): “This is the synthesis of an intense collaboration between clinicians and scientists trying to understand this disease for almost 10 years.  I am delighted to see how it has increased our understanding of rare mutations, and especially has opened a therapeutic perspective for these patients.”

Quote from one of the patients: “We are happy and very grateful to the doctors and scientists who never gave up their search to understand the disease that affected members of our family for so many years. We are very hopeful that the new treatment will be beneficial to our family. Also we realize that the findings will help other patients to get a correct diagnosis and therapy.”

Professor Adrian Liston (VIB/KU Leuven, lead scientific researcher): “This is an amazing time to be working on genetic diseases. Every month we are solving clinical cases that would have been too hard to work out just a few years ago. Actually, to be honest the research is moving much faster than the healthcare system – we are finding new mutations, new diseases and trialling new treatments faster than the healthcare system is adapting. It creates a difficult situation for patients where the science is in, but the health insurance funds are not ready to reimburse the costs of the advanced diagnostic tests we use or novel treatments that we discover. This is a challenge, but also an opportunity – medical improvements could be rolled out quite quickly with political will.”

Professors Carine Wouters and Adrian Liston have established the charity Ped IMID to seek funding for research, diagnosis, and treatment of people living with rare immune disorders not currently covered by the health insurance funds. 

To read more, go to our article in Science Translational Medicine:

Masters, Lagou, Jéru, Baker, Van Eyck, Parry, Lawless, De Nardo, Garcia-Perez, Dagley, Holley, Dooley, Moghaddas, Pasciuto, Jeandel, Sciot, Lyras, Webb, Nicholson, De Somer, van Nieuwenhove, Ruuth-Praz, Copin, Cochet, Medlej-Hashim, Megarbane, Schroder, Savic, Goris, Amselem, Wouters* and Liston*. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Science Translational Medicine. 2016 in press.