Autoinflammatory syndromes

In people with auto-inflammatory syndrome, the innate immune system reacts excessively and triggers inflammatory processes. The cause is often the alteration of a single gene, but non-hereditary forms also occur. These diseases are very difficult for doctors to diagnose because they are so rare, diverse and varied. Once the diagnosis has been made, auto-inflammatory syndromes can usually be treated well with various medications. Severe complications and courses are rare, but possible.

What are auto-inflammatory syndromes?

Autoinflammatory syndromes comprise a large group of diseases that are associated with fever attacks and other signs of inflammation that also occur in episodes. There are many different diseases that doctors now classify as auto-inflammatory syndromes. Examples include familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS) and TNF receptor-associated periodic syndrome (TRAPS). Due to the recurring episodes of fever, these diseases used to be called recurrent fever syndromes.

Autoinflammatory syndromes are rare diseases that are inherited in many cases. But non-hereditary forms also occur. The exact mechanism of development has not yet been clarified. However, the basis seems to be a dysregulation of the immune system, which leads to an excessive inflammatory reaction of the body.

In addition to the fever attacks and increased inflammation levels in the blood, those affected suffer from other symptoms and organ manifestations. Skin changes, abdominal, muscle and joint pain and neurological problems can occur.

Diagnosis is usually a challenge for doctors. In the case of hereditary causes, the genetic alteration can be detected using molecular genetic tests. The treatment depends on the type of auto-inflammatory syndrome. Doctors try to reduce the number and severity of fever episodes and reduce inflammatory activity. This is usually achieved with the help of various medications.

Autoinflammatory syndromes – frequency and age

Autoinflammatory syndromes are among the rare diseases. The disease often begins in childhood, but it is not uncommon for it to start in adulthood. The group of autoinflammatory syndromes includes a large number of different clinical pictures that occur with varying frequency. It is not possible to put an exact figure on how many people are affected. But there are estimates.

Some examples:

• Familial Mediterranean fever (FMF): Affects approximately 1 to 5 out of every 10,000 inhabitants. FMF is particularly common among Mediterranean nationals, Armenians and Iraqis. Familial Mediterranean fever usually begins before the age of 30.
• Cryopyrin-associated periodic syndrome (CAPS): This in turn includes three different syndromes with varying degrees of severity: Muckle-Wells syndrome (MWS), familial cold-induced autoinflammatory syndrome (FCAS) and chronic infantile neurologic-cutaneous-articular syndrome (CINCA) or Neonatal-Onset Multisystem Inflammatory Disease (NOMID). CAPS is a very rare disease, with only around 1,000 cases recorded worldwide to date. It can start in children, but also in adults. Both sexes can become ill.
• TNF receptor-associated periodic syndrome (TRAPS): The disease occurs worldwide, but is more common in Northern Europe, Japan and the Arabian Peninsula. Doctors estimate that only around 1 in 1 million people fall ill. TRAPS usually manifests itself in children from the age of three, sometimes not until adulthood.
• Hyper-IgD syndrome (HIDS): The disease usually begins in the first year of life. It occurs about equally often in boys and girls, especially in people of northern European descent.
• Still’s syndrome: The disease occurs worldwide and affects around 0.16 to 0.4 in 100,000 people. Still’s syndrome affects children and adolescents (systemic juvenile idiopathic arthritis = SJIA), but also adults (adult-onset Still’s disease = AOSD). Males and females are equally affected, but some data suggest that women are slightly more likely to develop the disease (60:40).

• PFAPA syndrome(periodic fever, aphthae, pharyngitis, (lymph) adenopathy syndrome): It is the most common periodic fever syndrome in children (under five years of age), but the exact incidence is unknown. It can also appear for the first time in adults. Both sexes are affected about equally often.

Other diseases are also known that doctors classify as auto-inflammatory syndromes. They occur with varying frequency, but are also very rare overall. Examples are:

• Schnitzler syndrome
• Blue syndrome
• CRIA syndrome
• CANDLE syndrome
• Majeed syndrome
• DIRA syndrome (interleukin 1 receptor antagonist deficiency)
• DITRA syndrome (interleukin 36 receptor antagonist deficiency)
• Cyclic neutropenia

Autoinflammatory syndromes: often caused by altered genes

People with auto-inflammatory syndrome have a disorder of the innate immune system, which reacts excessively. The causes often lie in a single altered gene (monogenetic). Other family members are then usually also affected. However, non-hereditary causes are also possible in auto-inflammatory syndromes.

Depending on the clinical picture, different genes are altered (mutated), which in turn result in the production of defective proteins. These are involved in the formation of the so-called inflammasome. These are protein complexes that are designed to recognize danger signals in the body and control inflammatory processes in the body.

The mutation in autoinflammatory syndromes causes this inflammasome to be increasingly activated. The consequence of this is an excessive production and release of inflammatory messengers – cytokines. A particularly important player is interleukin-1 (IL-1- β). However, the organism can also release increased amounts of other substances that promote inflammation.

Some examples of the causes of autoinflammatory syndromes:

• Familial Mediterranean fever: The mutations (more than 300 changes have been described) affect the Mediterranean fever gene (MEFV gene). This is located on chromosome 16 and codes for the protein pyrin. In those affected, the inflammasome is inadequately activated by pyrin and too many cytokines are produced, particularly from the IL-1 family. The inheritance is autosomal recessive. This means that it only occurs if the gene mutation is located on both chromosomes 16. The probability of developing the disease is 25 percent if both parents are carriers of the mutation.
• Cryopyrin-associated periodic syndrome (CAPS): A mutation in the so-called NLRP3 gene is detectable in all three forms of CAPS. It is responsible for the production of a protein called cryopyrin – and this is an important part of the inflammasome.
• TNF receptor-associated periodic syndrome (TRAPS): The mutations affect the so-called TNFRSF1A gene. The mode of inheritance is autosomal dominant. This means that the change only has to be present on one chromosome. Children have a 50 percent chance of inheriting the defective gene and also developing the disease. With TRAPS, the body also releases an increased amount of cytokines.
• Hyper-IgD syndrome: The mutation is located on the so-called mevalonic acid kinase gene (MVK gene). Inheritance is autosomal recessive. The production of cytokines is also increased here.
• Still’s syndrome: The causes are not yet fully understood, but several gene mutations probably play a role. The overproduction particularly affects the cytokines IL-1, IL-6 and IL-18. Various triggers can play a role, such as previous infections.
• PFAPA syndrome: Doctors have not yet found a genetic predisposition and the causes are still unclear. However, PFAPA syndrome occurs more frequently in some families.

Symptoms: Autoinflammatory syndromes cause fever attacks

Autoinflammatory syndromes are very different clinical pictures that often cause unspecific symptoms. The symptoms can also occur in many other diseases, which is why auto-inflammatory syndromes are so difficult to diagnose.

What they all have in common, however, are recurring bouts of fever for which no cause can be found – such as an infection with bacteria or viruses. The fever usually lasts for a few days and then subsides. This is followed by fever-free intervals, which can vary in length. Fever episodes can occur with varying frequency – from once a year to once a week.

Elevated inflammation levels can also be detected in the blood, such as C-reactive protein (CRP) or serum amyloid A (SAA).

The symptoms can also affect the skin, mucous membranes, the musculoskeletal system or the central nervous system (CNS). Depending on the clinical picture, those affected may also develop the following symptoms:

• Skin changes: Skin rash on arms, legs or the trunk of the body, reddening of the skin, hives (urticaria), acne
• Swelling of the face
• Eye inflammation, e.g. conjunctivitis or inflammation of the skin of the eye (uveitis)
• Abdominal pain
• Muscle pain and joint pain
• Chest pain
• Headache
• Tiredness, feeling ill
• Failure to thrive in children, short stature
• Reduced hearing ability, hearing loss
• Deposition of proteins inside and outside the cells (amyloidosis)

The symptoms do not all have to occur together. Which symptoms occur depends on the respective clinical picture. The intensity can also vary. The signs of the disease can start from birth or only become apparent in adulthood.

Autoinflammatory syndromes: diagnosis with us

The diagnosis of auto-inflammatory syndromes is a challenge for doctors. The symptoms are often so unspecific that we do not immediately associate them with auto-inflammatory syndrome. For example, fever is a symptom of many infectious diseases. In addition, autoinflammatory syndromes are very rare and doctors rarely come into contact with them in their everyday work. And: It was a group of very different clinical pictures that are difficult to classify.

All in all, the diagnosis is difficult, requires some experience and doctors must always rule out other illnesses as causes for the symptoms. As a result, many sufferers only receive the correct diagnosis at a late stage. Treatment therefore often only begins years after the onset of the first symptoms. By then, complications and consequential damage have sometimes already set in.

In principle, specialist (pediatric) doctors in the field of immunology are responsible for the diagnosis of auto-inflammatory syndromes. As the symptoms affect different organs and tissues, patients are often treated on an interdisciplinary basis.

The first step is always to discuss the patient’s medical history, the anamnesis. We first ask questions about the type, severity, time of first occurrence, duration and location of the complaints. Any underlying illnesses and (hereditary) diseases in the family also help us. In the case of auto-inflammatory syndromes, several family members often already have the disease.

This is usually followed by a physical examination, in which we examine the skin, for example. Listening to the heart and lungs and palpating various parts of the body are also part of the physical examination. Determining the body temperature (fever) also provides important information.

A blood test shows whether the inflammation values are elevated, for example the C-reactive protein (CRP) or serum amyloid A (SAA). In addition – other blood values are important, such as the white blood cells (leukocytes). If hyper-IgD syndrome is suspected, we measure the immunoglobulins in the blood.

Depending on the suspected clinical picture, further examinations are carried out. Examples are:

• Tissue sample from the skin (biopsy): A pathologist then analyzes the cells under a microscope.
• Hearing test, hearing tests
• Imaging procedures, e.g. computer tomography (CT) or magnetic resonance imaging (MRI = magnetic resonance imaging)

In hereditary auto-inflammatory syndromes, a specific gene is often altered. This mutation can be detected by molecular genetic testing (genetic test).

Autoinflammatory syndromes: prevention, early detection, prognosis

You cannot prevent autoinflammatory syndromes because in many cases the causes lie in the genes. And you cannot influence this. Prevention of non-hereditary autoinflammatory syndromes is also virtually impossible because the causes are still largely unknown. Specific measures for early detection are also not known.

The general advice is therefore: always consult a doctor if you notice unusual symptoms in yourself or your child. This applies in particular to recurring bouts of fever that cannot be explained by pathogenic germs such as bacteria or viruses.

Course and prognosis of auto-inflammatory syndromes

The course and prognosis of auto-inflammatory syndromes cannot be generally predicted. The clinical pictures and courses of the disease vary greatly and a generally valid prognosis cannot be derived.

It is important to diagnose the disease in good time. This enables doctors to treat autoinflammatory syndromes at an early stage and prevent complications and consequential damage. These include, for example, amyloidosis, in which proteins are increasingly deposited in the body. They damage the organs, especially the heart and kidneys. Hearing loss, deafness, joint damage and physical disabilities are also possible.

However, it is not possible to prevent such damage in all cases because these diseases are so difficult to diagnose. Very severe courses of autoinflammatory syndromes can also be fatal, for example due to amyloidosis. However, doctors can often keep the disease well under control with adequate therapy.

Autoinflammatory syndromes: treatment with medication

The treatment of auto-inflammatory syndromes belongs in the hands of doctors who have sufficient experience with these complex clinical pictures.

To date, there is no treatment that addresses the cause of the disease (the altered genes), but the symptoms can be effectively treated with medication. The aim of treatment is to lower the fever, reduce inflammation, reduce the number and severity of fever and inflammatory episodes and prevent complications.

Autoinflammatory syndromes: overview of medication

The following treatment options are available – depending on the clinical picture:

• Antipyretic and pain-relieving medication: Drugs from the group of non-steroidal anti-inflammatory drugs (NSAIDs) are usually used, such as the active ingredients ibuprofen, diclofenac or acetylsalicylic acid (ASA)
• Colchicine, for example in familial Mediterranean fever.
• Anti-inflammatory medication: Glucocorticoids (“cortisone”) suppress the immune system. Prednisolone is a frequently used active ingredient.
• Immunosuppressants, e.g. methotrexate (MTX) or azathioprine, to reduce the dose of glucocorticoids
• Cytokine-blocking drugs (e.g. IL-1, IL-6 or TNF antagonists): These relatively new drugs are very effective. They inhibit interleukin-1 (IL-1), IL-6, TNF-alpha and other inflammatory cytokines – the symptoms usually diminish quickly. Examples of IL-1 blockers are Canakinumab, Anakinra and Rilonacept. Serious secondary damage can also be avoided in many cases with the medication.