Pres European Union Printo

Blau’s disease/Juvenile Sarcoidosis

What is it?
Blau syndrome is a genetic disease. Patients will suffer from a combination of skin rash, arthritis and  uveitis. Other organs can be affected too and intermittent fever can be associated as well. Blau syndrome is the term used for familial forms of the disease, sporadic forms can occur as well and are known as Early Onset Sardoidosis (EOS).

How common is it?
The frequency is unknown. It is a very rare disease that affects patients in early childhood (mostly before 5 years of age) and will become worse if left untreated. Since the discovery of the associated gene  it is being diagnosed more frequently which will allow for a better knowledge of its prevalence and natural history.

What are the causes of the disease?
Blau syndrome is a genetic disease. The responsible gene is called   NOD2  (synonymous with CARD15 ) which encodes a protein with a role in the immune-inflammatory response. If this gene carries a mutation, as in Blau syndrome, the protein doesn’t function properly and the patients experience chronic inflammation with granulomas in various tissues and organs of the body. Granulomas are characteristic long-lived clusters of inflammatory cells that are associated with inflammation and may disrupt the normal structure and functioning of various tissues and organs.

Is it inherited?
It is inherited as an autosomal dominant disease (which means that it is not linked to the gender and that at least one parent needs to show symptoms of the disease). This type of transmission means that to have Blau syndrome one needs only one mutated gene, either from the mother or the father. In EOS, the sporadic form of the disease, the mutation emerged in the patient him/herself and both parents will be healthy. If a patient carries the gene, he or she will suffer from the disease. If one parent has Blau syndrome, there is a 50% chance that his/her child will suffer from it as well.

Why has my child got this disease? Can it be prevented?
The child has the disease because of the genes that cause Blau syndrome. Currently, the disease cannot be prevented but the symptoms can be treated.

Is it contagious?                                                                                     
No, it is not.

What are the main symptoms?
The main symptoms of the disease are a clinical triad of arthritis, dermatitis and uveitis. The initial symptoms comprise a typical exanthema, with tiny round lesions that vary in color from pale pink to tan or intense erythema. Over the course of the years the rash waxes and wanes. Arthritis is the most common manifestation, starting in the first decade of life. There is important joint swelling with preserved mobility at onset. With time, limitation of movement deformities and erosions may develop. Uveitis (inflammation of the iris) is the most threatening manifestation, since it often is associated with complications (cataract, increased intraocular pressure) and may cause decreased vision if left untreated.
In addition, granulomatous inflammation may affect a wide spectrum of other organs, causing other symptoms as well such as decreased lung or kidney functioning, increased blood pressure, persistent fever.

Is the disease the same in every child?
It is not the same in every child. Moreover, the type,   and severity of symptoms may change as the child grows older. The disease progresses if left untreated and the symptoms will evolve accordingly.

How is it diagnosed?
Generally, for the diagnosis of Blau syndrome, the following approach is followed:
a) Clinical suspicion: It is possible to consider Blau syndrome when a child presents a combination of symptoms (joint, skin, eye) out of the typical clinical triad. A detailed investigation into the family history should be considered, because this disease is very rare and inherited in an autosomal dominant fashion.                                                              
b) Demonstration of granulomas: to make the diagnosis of Blau syndrome/EOS, the presence of typical granulomas in affected tissue is essential. Granulomas can be seen on a biopsy of a skin lesion, or of an inflamed joint. Other causes of granulomatous inflammation (such as tuberculosis, immune deficiency, other inflammatory diseases such as some vasculitides) need to be excluded by thorough clinical examination, a tuberculin skin test and blood tests.
c) Genetic analysis: For the last couple of years, it has been possible to perform a genetic analysis of patients to ascertain the presence of mutations that are thought to be responsible for the development of Blau syndrome/EOS.

What is the importance of tests?
a) Skin biopsy: a skin biopsy is a removal of a tiny piece of tissue from the skin and it is very easy to perform. If the skin biopsy shows granulomas, the diagnosis of Blau syndrome is done after exclusion of all other diseases that are associated with granuloma formation.
b) Blood test: blood tests are important to exclude other diseases that can be associated with granulomatous inflammation (such as immune deficiency, Crohn’s disease..). They are important as well to see the extent of inflammation and to evaluate the involvement of other organs (such as kidney, liver).
b) Genetic test: the only test that unambiguously confirms the diagnosis of Blau syndrome is a genetic test that shows the presence of a mutation in the NOD2 gene.

Can it be treated or cured?
It cannot be cured, but it can be treated with drugs that control inflammation in the joints, the eyes and any involved organ. The drug treatment aims to control symptoms and to halt the progression of the disease.

What are the treatments?
At present, there is no evidence concerning the optimal treatment for Blau syndrome/EOS. Joint problems often can be treated with anti-inflammatory nonsteroidal drugs and methotrexate. Methotrexate is known for its capacity to control arthritis in many children with juvenile chronic arthritis; its effectiveness in Blau syndrome may be less marked.           Uveitis is very difficult to control; local therapies (steroid eye drops, or local steroid injection) may not be sufficient for many patients. The efficacy of methotrexate to control uveitis is not  always sufficient, and patients may need to take corticosteroids by mouth in order to controle severe eye inflammation.                                                           
In patients with difficult-to-control inflammation of eyes and/or joints, and in patients with involvement of internal organs, the use of cytokine-inhibitors, notable of TNF-α inhibitors (Infliximab, Adalimumab) may be effective.

What are the side effects of drug therapy?
The most frequent adverse effects seen with methotrexate are nausea and abdominal distress the day of intake. Blood tests are needed to monitor liver function and the number of white blood cells. Corticosteroids are associated with possible side effects such as weight gain, swelling of the face, acne, and mood swings. If the steroids are prescribed for a prolonged period, they can cause suppression of growth and osteoporosis.
TNF-α inhibitors are recent drugs, they can be associated with an increased risk of infections, activation of tuberculosis, and possible development of neurological or other immune diseases. A potential risk of development of malignancies has been discussed; at present there are no statistical data proving an increased risk for malignancies with these drugs.

How long should treatment last for?
There are no data at present that allow to decide on the optimal duration of treatment. It is essential to control and continue to control inflammation in order to prevent joint damage, visual loss or damage to other organs.

What about unconventional or complementary therapies?
There is no such therapy.

What kind of periodic check-ups are necessary?
Children should be seen regularly (at least 3 times yearly) by their pediatric rheumatologist to monitor the control of the disease and adjust the medical treatment. It is important to have regular visits with the ophthalmologist – with a frequency depending on the severity and evolution of eye inflammation – as well. Children being treated should have blood and urine tests for at least twice yearly.

How long will the disease last for?
It is a life-long disease. The activity of the disease however may fluctuate over time.

What is the long term prognosis (predicted outcome and course) of the disease?
There exist very limited data concerning the prognosis in the long term. Some children have been followed for more than 20 years and have attained almost normal growth, normal psychomotor development and a good quality of life with well-adjusted medical treatment.

Is it possible to recover completely?
No, because it is a genetic disease. However, good medical follow-up and treatment will give the majority of patients a good quality of life. There are differences in the severity and progression of the disease among patients with Blau syndrome, at this moment it is impossible to predict the disease course for the individual patient.


Everyday life

How could the disease affect the child and family’s daily life?
The child and the family may experience various problems before the disease is diagnosed. Once the diagnosis has been made, they have to take the child to the doctor (pediatric rheumatologist and ophtalmologist) regularly to monitor disease activity and adjust the medical treatment. Children with difficult joint disease may need physiotherapy. There may be the psychological burden of a life-long disease and long-term treatment.

What about school?
Active joint and eye disease, visits to the doctor can cause problems with school attendance. The teachers should be informed about the disease and its effects on the child.

What about sports?
Patients with Blau syndrome can do any sport they wish if the disease is well controlled.

What about diet?
There is no specific diet.

Can climate influence the course of the disease?
No, it cannot.

Can the child be vaccinated?
The child can be vaccinated except with live vaccines when under treatment with methotrexate of TNF- inhibitors.

What about sexual life, pregnancy, birth control?
Patients with Blau syndrome don’t have fertility problems before treatment, but methotrexate is a drug with teratogenic side effects. There are no safety data concerning TNF- inhibitors and pregnancy, so patients must stop these when they wish to become pregnant.