Autoinflammation of unknown cause

Content last updated on: January 18, 2015


Summary of autoinflammation of unknown cause

If someone has symptoms of autoinflammation, but these are not compatible with one of the known autoinflammatory diseases, we say this patients has autoinflammation of unknown cause. Autoinflammation of unknown cause is diagnosed by excluding other causes for the symptoms and by proving that treatment with the anti-inflammatory drug anakinra is effective.


Several autoinflammatory diseases are known

Several autoinflammatory diseases are known. Examples are: familial Mediterranean fever (FMF), Cryopyrin associated periodic syndrome (CAPS), Hyperimmunoglobulin D and periodic fever syndrome (HIDS), TNF-receptor associated periodic syndrome (TRAPS), Schnitzler syndrome, Adult onset Still's disease, Behcet's disease, periodic fever, aphtous ulcers, pharyngitis and adenitis (PFAPA) syndrome and pyoderma gangrenosum, pyogenic arthritis and acne (PAPA) syndrome. You can find more information on some of these diseases elsewere on this website.

Some people suffer from signs and symptoms of an autoinflammatory disease, although one of the known autoinflammatory diseases cannot be found. This is called autoinflammation of unknown cause.


Autoinflammation of unknown cause is an undiscovered disease

A disease is defined as a combination of signs and symptoms that appear together an share the same cause. Two random examples of this are

1. The disease flu: patients with flue suffer from fever, mucle pain and chills (and some other things). This is caused by infection with an influenza virus.

2. The disease diabetes is characterized by weight loss, increased thirst and a high blood sugar level. This is caused by a lack of insulin (a hormone that lowers the blood sugar level).

New diseases are discovered when the same combination of signs and symptoms is observed in several patients. Someone has to write this down in a scientific paper and give this combination of signs and symptoms a name. Knowledge on the cause of the symptoms is preferred, but not necessary for discovering a new disease.

Someone who suffers from autoinflammation with unknown cause has a disease that was not named before, because only few people suffer from this disease. This makes it difficult to note the same combination of signs and symptoms in several people and to write a scientific paper on it ( as to prove something scientifically, it has to be observed in as many people possible, otherwise it can be a coincidental finding).


Autoinflammation of unknown cause can present with many symptoms

Many symptoms can be present in autoinflammation of unknown cause. Common symptoms are:

- fever

- skin rash

- muscle pain

- joint pain or inflammation of one or more joints with redness, swelling and warmth

- abdominal pain

- diarrhea

- nausea

- chest pain (caused by inflammation of the pleura or pericardium)

- enlarged lymph nodes

- enlarged liver or spleen

- red eyes

- aphtous ulcers in the mouth or on the genitals

Most patients with autoinflammation of unknown cause suffer from one or more of these symptoms. They often present episodically (these episodes are called attacks). Attacks can last from hours to weeks, after which symptoms resolve spontaneously. In most cases they reappear later. In some patients symptoms may be present continuously.


How to recognize possible autoinflammation of unknown cause

Because autoinflammation of unknown cause is caused by an undiscovered disease, it can be difficult to recognize. All known autoinflammatory diseases are very rare, and autoinflammation of unknown cause is even rarer. Therefore, many doctors will not consider it as a cause of symptoms easily.

Patients with autoinflammation of unknown cause often tell the same story: they have been suffing from attacks with fever and other symptoms for years. They have visited several doctors and often multiple hospitals, but a cause for these attacks was never found. Patients often have been admitted several times. Treatment with antibiotics for suspected infection is common, but does not change the symptoms (sometimes it may seem it does, especially when given at the end of an attack. Symptoms disappear spontaneously, but it seems the antibiotics cure the disease).

Besides a story like this, autoinflammation of unknown cause has the following characteristics:

- marked inflammatory response. This can be measured in the blood. Increased inflammatory markers, such as erythrocyte sedimentation rate (ESR), CRP and white blood cell count will be present during an attack. Outside an attack, these values will be normal.

- no other cause for the symptoms is found (for instance infection, autoimmune disorder or a known autoinflammatory disease). To known for sure no other disease causes the symptoms, extensive investigation has to be performed prior to the diagnosis. Blood tests, X-rays an scans may all have to be done.


Autoinflammation of unknown cause is caused by inflammation

The cause of autoinflammation of unknown cause is excess inflammation. This is caused by changes in the innate immune system. Why these changes appear and where they are located is unknown in autoinflammation of unknown cause.

Changes in the innate immune system lead to overproduction of the inflammatory mediator interleukin-1 (IL-1). When this is produced, it causes fever and other symptoms of autoinflammation.


Diagnosis equals treatment in autoinflammation of unknown cause

The anti-inflammatory drug anakinra is an inhibitor of the effects of the inflammatory mediator IL-1. As this mediator causes inflammation in autoinflammation of unknown cause, the use of anakinra will reduce symptoms. People with an autoinflammatory disease notice a decrease or even disappearance of their symptoms in one or two days after the start of anakinra therapy. Inflammatory markers in the blood will also decrease. In some cases it is necessary to use anakinra for several weeks to evaluate its effect. If anakinra is not effective after several weeks of daily use, autoinflammation does not cause the symptoms.

When it is proben that anakinra reduces signs and symptoms, it can be used as treatment for the autoinflammatory disease. If the disease is episodical, anakinra can be used only during an episode (on demand treatment). If signs and symptoms are continuous, anakinra has to be injected on a daily basis for a longer time. You can find more information on anakinra on the page on this drug on this website.


The discovery of new autoinflammatory diseases by autoinflammation of unknown cause

Patients with autoinflammation of unknown cause are mostly glad a cause for their symptoms has finally been found and that they can be treated. However, many patients remain curious for the cause of the disease (and their doctors too!). To discover this, patients with autoinflammation of unknown cause may participate in research projects.

An example of this kind of research is the Dutch 300-gene panel. At the department of medical genetics in the university hospital in Utrecht, The Netherlands,  300 autoinflammation-related genes can be tested at the same time to see if one of these genes is altered (mutation) in patients with autoinflammation of unknown cause. For many of these 300 genes it is not known if and how mutations will cause inflammation, but when a mutation is found, this can be studied further. This way, new autoinflammatory diseases can be discovered in patients with autoinflammation of unknown cause.

In other countries, other research projects for the discovery of new autoinflammatory diseases in patients with autoinflammation of unknown cause may be available. You can talk to your doctor about this. He or she wil be able to tell you more about local research projects.