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Rare fever syndromes provide insights into the anti-inflammatory effect of therapies

Quite a few people suffer lifelong regularly occurring fever and inflammation attacks with no apparent reason. For a long time, doctors were unable to decipher the reasons for such periodic fever syndromes. However, the identification of the genetic causes of the syndromes has in the meantime led to the identification of the metabolic pathway involved as well as to targeted therapies. Effective treatment has greatly improved sufferers’ quality of life. In addition, insights into the development and treatment of periodic fever syndromes have also led to the development of new strategies for the treatment of diabetes mellitus and gout.

Dr. med. Jasmin Kümmerle-Deschner, senior physician in the Department of Paediatric Medicine at the University Hospital of Tübingen, recalls only too well the first patient that she diagnosed with Muckle-Wells syndrome (MWS), a rare autosomal dominant disease. The girl was suffering from recurrent fever attacks, skin rashes, conjunctivitis and painful joints. The initial diagnosis of rheumatic fever could not be confirmed. The fact that the patient, along with numerous other members of her family, suffered from pronounced deafness, eventually put the head of the paediatric rheumatology outpatient department on the right track.

Dr. Jasmin Kümmerle-Deschner is the head of the Paediatric Rheumatolgy Outpatient Clinic at Tübingen University Hospital © private

"Molecular genetic methods were used to ascertain that the girl had Muckle-Wells syndrome, and we then went on to identify the same disorder in twelve of the girl's relatives," said Kümmerle-Deschner. MWS belongs to the group of periodic autoinflammatory fever syndromes and is an autosomal-dominant disease, which is why it also occurs in family members that happen to carry the same defective gene. This discovery ended years of suffering for the patients in question as the fever and inflammatory attacks, which in the case of MWS are triggered by unspecific factors such as cold and stress, typically start during childhood. "The patients feel as if they constantly have a cold," said Kümmerle-Deschner going on to add, "this considerably reduces quality of life". As the disease progresses, many patients develop sensorineural deafness and reduced kidney function. "Many MWS patients need to undergo dialysis very young because the kidneys are unable to remove waste from the body," said Kümmerle-Deschner.

Genetics provides a decisive clue

The NALP3 inflammasome is crucial in the development of cryopyrin-associated periodic syndromes (CAPS) © Dr. Jasmin Kümmerle-Deschner
A novel therapy has for quite some time been used to successfully prevent the fever attacks as well as the long-term consequences of inflammation. The therapy is the result of the identification of the genetic causes of MWS. In 2001, a group of American researchers and doctors discovered that a mutation in the CIAS1 (cold-induced autoinflammatory syndrome 1) gene was responsible for the disease. A mutation in the CIAS1 gene leads to increased activity of the protein cryopyrin, which is part of an intracellular protein complex known as NALP3 inflammasome that is involved in the regulation of interleukin (IL) 1β. “This is a messenger substance in the human body that promotes inflammatory reactions,” said Kümmerle-Deschner. Inflammasomes, which are part of the innate immune system, are normally activated by bacteria or cellular waste products. However, a mutation in the CIAS1 gene leads to the activation of the NALP3 inflammasomes upon environmental cues such as a cold shower, at which point excess IL-1β is produced, which leads to inflammation throughout the entire body in MWS sufferers. A therapy that targets IL-1β leads to the rapid and permanent disappearance of MWS symptoms. “We have found the human monoclonal antibody canakinumab to be extremely effective,” said Kümmerle-Deschner who was involved in the drug’s marketing authorisation study. Canakinumab therapy leads to the almost complete disappearance of fever attacks and joint pain without any noteworthy side effects. “In some patients, the antibody even leads to an improvement in hearing,” said Kümmerle-Deschner going on to add, “the antibody also seems to stabilise kidney function.” In addition to the antibody canakinumab, other IL-1β antagonists (e.g. the IL-1 receptor antagonist anakinra, which is however not yet approved for MWS treatment, and rilonacept, a fusion protein consisting of parts of the human IL-1 receptor, which is not yet commercialised in Europe) have proved their value in the treatment of MWS.

Complex disease symptoms

Disorders known as cryopyrin-associated periodic syndrome (CAPS) © Dr. Jasmin Kümmerle-Deschner
Besides MWS itself, there are two other syndromes related to mutations in the CIAS1 gene with similar symptoms to MWS. All three diseases, which are categorised as cryopyrin-associated periodic syndromes (CAPS), can be successfully treated with IL-1 antagonists. The mildest form of CAPS is familial cold urticaria (also known as familial cold autoinflammatory syndrome, FCAS) causes flu-like symptoms with fever, chills and painful joints a few hours after exposure to cold. “The symptoms usually disappear quite quickly, which makes it quite difficult to diagnose the disease. The symptoms are often no longer present by the time the patient goes to a doctor,” said Kümmerle-Deschner. The most severe type of CAPS is the NOMID/CINCA syndrome (neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome) characterised by the onset of disease shortly after birth. The disease is characterised by periodic fever associated with uncontrolled inflammation in multiple parts of the body. Other symptoms are neurologic damage associated with epileptic seizures, progressive deafness and inflammatory eye changes that can lead to blindness. “FCAS, MWS and NOMID/CINCA syndrome were originally regarded as three different diseases,” said Kümmerle-Deschner. This changed once the genetic basis (i.e. mutation of the CIAS1 gene) of the diseases was identified, and the three diseases are now subsumed as CAPS. However, the diseases are not as rare as was originally believed. Around 50 CAPS patients are treated every year in Tübingen alone. “As the genetic basis of the diseases is now known, we frequently identify patients who had not previously been correctly diagnosed,” says the paediatric rheumatologist from Tübingen, talking from personal experience. It often takes several years before symptoms are correctly interpreted, even in cases where sufferers have regular medical treatment. “This clearly shows that is important for doctors to always take the entire clinical picture into account; it is not enough to make a diagnosis based on known symptoms from one’s own medical discipline,” said Kümmerle-Deschner.

Interleukin-1 plays a key role in inflammatory diseases

Interleukin-1β-mediated inflammatory reactions also seem to play a key role in many other diseases, including gout and type 2 diabetes mellitus. “It appears that uric acid crystals or elevated blood glucose levels also induce the production of larger quantities of IL-1,” said Kümmerle-Deschner. Initial investigations have shown that the blockage of IL-1β in people with severe gout leads to a considerable improvement in their condition. New drugs have been shown to have a positive effect on the regulation of the blood glucose level in diabetics as well as on the secretory function of insulin-producing cells. It can therefore be assumed that the anti-inflammatory IL-1 antagonists are likely to lead to promising outcomes in the treatment of such classical common diseases in the not-too-distant future.

Further information:
Dr. med. Jasmin Kümmerle-Deschner
University Children's Hospital Tübingen
Outpatient Department of Rheumatology and Autoimmune Diseases
Department of General Paediatrics, Haematology/Oncology (I)
Hoppe-Seyler-Str. 1
72076 Tübingen
Tel.: +49 (7071) 29-80901
Fax: +49 (7071) 29-4157
E-mail: Jasmin.Kuemmerle-Deschner(at)med.uni-tuebingen.de

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