DIRA

Deficiency of IL-1 Receptor Antagonist

DIRA is short for Deficiency of the Interleukin-1 Receptor Antagonist. DIRA is a rare (autosomal recessive) genetic autoinflammatory disease. Affected children suffer from severe inflammation of the skin and skeleton. Other organs, such as the lungs, may also be affected. Without treatment, the disease may lead to disability and even death.

Causes
Affected children have dira autoinflammatory syndromes from birth because it is a gene abnormality. The responsible gene is called IL1RN. The gene produces a protein, IL-1 Receptor antagonist (IL-1RA), that plays a role in the natural resolution of inflammation. IL-1RA neutralises the effect of another protein, interleukin-1 (IL-1), which is a powerful inflammatory messenger in the human body. If the IL1RN-gene carries a mutation, the body cannot produce effective IL-1RA. As a result, IL-1 is no longer controlled and the patient develops inflammation.

Inheritance
The disorder is inherited as an autosomal recessive disease, which means that both parents have the mutated gene. They are both carriers, which means that they don’t have the disease themselves, and there is a 25% chance that their child will get the disease. To date only cases of the disease are known in which both parents come from the same population group.

Symptoms
The main symptoms of the disease are skin inflammation and bone inflammation. The skin inflammation is characterised by redness, pustules and scaling. The skin disorder can affect any part of the body. The skin abnormalities occur spontaneously, but can be exacerbated by local injury. For instance, IVs often lead to local inflammation, as do areas of mechanical friction such as under the diaper or under plasters.

The bone inflammation is characterised by painful swelling of the bones, with the skin over the affected areas often becoming red and warm. Many bones can be involved, including the limbs, ribs, vertebrae and the skull. Usually, the periosteum is also inflamed at the site of the affected area. The periosteum is very sensitive to pain. Therefore, affected children are often irritable and miserable. Because of the pain and inflammation, DIRA patients don’t grow well. Affected vertebrae can collapse and damage the spinal cord. Nails of DIRA patients can become inflamed and even separate and fall off.

Diagnosis

First there must be a suspicion of DIRA based on the symptoms. Genetic testing can then confirm this suspicion.DIRA can only be proven by genetic analysis. The diagnosis of DIRA is confirmed if the patient carries two mutations in ILRN; one from each parent. Genetic analysis is not available in every hospital.

Treatment

DIRA cannot be adequately controlled with anti-inflammatory drugs. High doses of corticosteroids can partially control disease symptoms, but usually at the expense of unwanted side effects. Pain killers are needed to control bone pain until treatment with anakinra has taken effect. Anakinra (brand name Kineret®) is a form of IL-1RA that is artificially produced in bacteria. Anakinra is the protein that DIRA patients lack. Daily injections with anakinra have so far proven to be the only effective treatment of DIRA. In this way, the shortage of natural IL-1RA is corrected and the disease can be brought under control. This prevents the disease symptoms from recurring. The patient will have to take this medicine for the rest of his/her life. If administered daily, the symptoms will disappear. The dose should not be modified without consulting the physician. If the medicine is not taken anymore, the disease will return in full. Since this is a life-threatening disease, this must be avoided at all cost. Anakinra is very expensive. It is therefore not available in all countries.

Anakinra has side-effects. The most unpleasant side effect is the reaction at the site of injection, comparable to an insect sting. Especially in the first weeks of treatment, this can cause a lot of pain. In patients treated with anakinra for other diseases, an increase in infections is seen. It is not known (and not likely) that this is the case for patients with DIRA. Some children who are given anakinra for other diseases, are gaining too much weight. Again, we do not know whether this also the case with DIRA. The difference is that with these other diseases, an excess of IL-1Ra is administered in the form of anakinra. For patients with DIRA, IL-1RA deficiency is only normalised. Anakinra has only been given to children since the beginning of the century. No one knows yet if there will be any side effects in the very long term. It is unknown whether anakinra is safe for pregnant women and their unborn child.

Long-term prognosis
The child and family face major problems before the diagnosis is made. After the diagnosis is made and treatment has been instituted, many children will lead an almost normal life. They can participate in society and there are no obstacles with activities such as sports and playing. It’s very important that they take the medication correctly throughout their lives, otherwise the disease will return.

Some children will have bone deformities that can seriously interfere with their normal activities. The daily injections may be a burden, not only because of the pain, but also because travel may be difficult due to the storage requirements of anakinra.

The child can be vaccinated. With most vaccines, there is no problem at all. Inoculation with live viruses (mumps-measles-rubella, chicken pox) is only allowed after the treating specialist has given explicit instructions and permission for this. Always consult your physician.

DIRA is short for Deficiency of the Interleukin-1 Receptor Antagonist. DIRA is a rare (autosomal recessive) genetic autoinflammatory disease. Affected children suffer from severe inflammation of the skin and skeleton. Other organs, such as the lungs, may also be affected. Without treatment, the disease may lead to disability and even death.

Causes
Affected children have dira autoinflammatory syndromes from birth because it is a gene abnormality. The responsible gene is called IL1RN. The gene produces a protein, IL-1 Receptor antagonist (IL-1RA), that plays a role in the natural resolution of inflammation. IL-1RA neutralises the effect of another protein, interleukin-1 (IL-1), which is a powerful inflammatory messenger in the human body. If the IL1RN-gene carries a mutation, the body cannot produce effective IL-1RA. As a result, IL-1 is no longer controlled and the patient develops inflammation.

Inheritance
The disorder is inherited as an autosomal recessive disease, which means that both parents have the mutated gene. They are both carriers, which means that they don’t have the disease themselves, and there is a 25% chance that their child will get the disease. To date only cases of the disease are known in which both parents come from the same population group.

Symptoms
The main symptoms of the disease are skin inflammation and bone inflammation. The skin inflammation is characterised by redness, pustules and scaling. The skin disorder can affect any part of the body. The skin abnormalities occur spontaneously, but can be exacerbated by local injury. For instance, IVs often lead to local inflammation, as do areas of mechanical friction such as under the diaper or under plasters.

The bone inflammation is characterised by painful swelling of the bones, with the skin over the affected areas often becoming red and warm. Many bones can be involved, including the limbs, ribs, vertebrae and the skull. Usually, the periosteum is also inflamed at the site of the affected area. The periosteum is very sensitive to pain. Therefore, affected children are often irritable and miserable. Because of the pain and inflammation, DIRA patients don’t grow well. Affected vertebrae can collapse and damage the spinal cord. Nails of DIRA patients can become inflamed and even separate and fall off.

Diagnosis

First there must be a suspicion of DIRA based on the symptoms. Genetic testing can then confirm this suspicion.DIRA can only be proven by genetic analysis. The diagnosis of DIRA is confirmed if the patient carries two mutations in ILRN; one from each parent. Genetic analysis is not available in every hospital.

Treatment

DIRA cannot be adequately controlled with anti-inflammatory drugs. High doses of corticosteroids can partially control disease symptoms, but usually at the expense of unwanted side effects. Pain killers are needed to control bone pain until treatment with anakinra has taken effect. Anakinra (brand name Kineret®) is a form of IL-1RA that is artificially produced in bacteria. Anakinra is the protein that DIRA patients lack. Daily injections with anakinra have so far proven to be the only effective treatment of DIRA. In this way, the shortage of natural IL-1RA is corrected and the disease can be brought under control. This prevents the disease symptoms from recurring. The patient will have to take this medicine for the rest of his/her life. If administered daily, the symptoms will disappear. The dose should not be modified without consulting the physician. If the medicine is not taken anymore, the disease will return in full. Since this is a life-threatening disease, this must be avoided at all cost. Anakinra is very expensive. It is therefore not available in all countries.

Anakinra has side-effects. The most unpleasant side effect is the reaction at the site of injection, comparable to an insect sting. Especially in the first weeks of treatment, this can cause a lot of pain. In patients treated with anakinra for other diseases, an increase in infections is seen. It is not known (and not likely) that this is the case for patients with DIRA. Some children who are given anakinra for other diseases, are gaining too much weight. Again, we do not know whether this also the case with DIRA. The difference is that with these other diseases, an excess of IL-1Ra is administered in the form of anakinra. For patients with DIRA, IL-1RA deficiency is only normalised. Anakinra has only been given to children since the beginning of the century. No one knows yet if there will be any side effects in the very long term. It is unknown whether anakinra is safe for pregnant women and their unborn child.

Long-term prognosis
The child and family face major problems before the diagnosis is made. After the diagnosis is made and treatment has been instituted, many children will lead an almost normal life. They can participate in society and there are no obstacles with activities such as sports and playing. It’s very important that they take the medication correctly throughout their lives, otherwise the disease will return.

Some children will have bone deformities that can seriously interfere with their normal activities. The daily injections may be a burden, not only because of the pain, but also because travel may be difficult due to the storage requirements of anakinra.

The child can be vaccinated. With most vaccines, there is no problem at all. Inoculation with live viruses (mumps-measles-rubella, chicken pox) is only allowed after the treating specialist has given explicit instructions and permission for this. Always consult your physician.

DIRA is short for Deficiency of the Interleukin-1 Receptor Antagonist. DIRA is a rare (autosomal recessive) genetic autoinflammatory disease. Affected children suffer from severe inflammation of the skin and skeleton. Other organs, such as the lungs, may also be affected. Without treatment, the disease may lead to disability and even death.

Causes
Affected children have dira autoinflammatory syndromes from birth because it is a gene abnormality. The responsible gene is called IL1RN. The gene produces a protein, IL-1 Receptor antagonist (IL-1RA), that plays a role in the natural resolution of inflammation. IL-1RA neutralises the effect of another protein, interleukin-1 (IL-1), which is a powerful inflammatory messenger in the human body. If the IL1RN-gene carries a mutation, the body cannot produce effective IL-1RA. As a result, IL-1 is no longer controlled and the patient develops inflammation.

Inheritance
The disorder is inherited as an autosomal recessive disease, which means that both parents have the mutated gene. They are both carriers, which means that they don’t have the disease themselves, and there is a 25% chance that their child will get the disease. To date only cases of the disease are known in which both parents come from the same population group.

Symptoms
The main symptoms of the disease are skin inflammation and bone inflammation. The skin inflammation is characterised by redness, pustules and scaling. The skin disorder can affect any part of the body. The skin abnormalities occur spontaneously, but can be exacerbated by local injury. For instance, IVs often lead to local inflammation, as do areas of mechanical friction such as under the diaper or under plasters.

The bone inflammation is characterised by painful swelling of the bones, with the skin over the affected areas often becoming red and warm. Many bones can be involved, including the limbs, ribs, vertebrae and the skull. Usually, the periosteum is also inflamed at the site of the affected area. The periosteum is very sensitive to pain. Therefore, affected children are often irritable and miserable. Because of the pain and inflammation, DIRA patients don’t grow well. Affected vertebrae can collapse and damage the spinal cord. Nails of DIRA patients can become inflamed and even separate and fall off.

Diagnosis

First there must be a suspicion of DIRA based on the symptoms. Genetic testing can then confirm this suspicion.DIRA can only be proven by genetic analysis. The diagnosis of DIRA is confirmed if the patient carries two mutations in ILRN; one from each parent. Genetic analysis is not available in every hospital.

Treatment

DIRA cannot be adequately controlled with anti-inflammatory drugs. High doses of corticosteroids can partially control disease symptoms, but usually at the expense of unwanted side effects. Pain killers are needed to control bone pain until treatment with anakinra has taken effect. Anakinra (brand name Kineret®) is a form of IL-1RA that is artificially produced in bacteria. Anakinra is the protein that DIRA patients lack. Daily injections with anakinra have so far proven to be the only effective treatment of DIRA. In this way, the shortage of natural IL-1RA is corrected and the disease can be brought under control. This prevents the disease symptoms from recurring. The patient will have to take this medicine for the rest of his/her life. If administered daily, the symptoms will disappear. The dose should not be modified without consulting the physician. If the medicine is not taken anymore, the disease will return in full. Since this is a life-threatening disease, this must be avoided at all cost. Anakinra is very expensive. It is therefore not available in all countries.

Anakinra has side-effects. The most unpleasant side effect is the reaction at the site of injection, comparable to an insect sting. Especially in the first weeks of treatment, this can cause a lot of pain. In patients treated with anakinra for other diseases, an increase in infections is seen. It is not known (and not likely) that this is the case for patients with DIRA. Some children who are given anakinra for other diseases, are gaining too much weight. Again, we do not know whether this also the case with DIRA. The difference is that with these other diseases, an excess of IL-1Ra is administered in the form of anakinra. For patients with DIRA, IL-1RA deficiency is only normalised. Anakinra has only been given to children since the beginning of the century. No one knows yet if there will be any side effects in the very long term. It is unknown whether anakinra is safe for pregnant women and their unborn child.

Long-term prognosis
The child and family face major problems before the diagnosis is made. After the diagnosis is made and treatment has been instituted, many children will lead an almost normal life. They can participate in society and there are no obstacles with activities such as sports and playing. It’s very important that they take the medication correctly throughout their lives, otherwise the disease will return.

Some children will have bone deformities that can seriously interfere with their normal activities. The daily injections may be a burden, not only because of the pain, but also because travel may be difficult due to the storage requirements of anakinra.

The child can be vaccinated. With most vaccines, there is no problem at all. Inoculation with live viruses (mumps-measles-rubella, chicken pox) is only allowed after the treating specialist has given explicit instructions and permission for this. Always consult your physician.