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Autoinflammatory syndromes


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Autoinflammatory syndromes are a group of rare diseases caused by a, excessive activation of the immune system, in particular the innate immunity. Innate immunity is our first line of defense against external agents. The exaggerated and disproportionate activation of the innate immunity in absence of identifiable triggers or with minimal stimuli is called autoinflammation. In most cases, the dysregulation is due to mutations or polymorphisms in genes that code for proteins involved in the regulation of the innate immunity, which is amplified to the point of damaging the organism instead of protecting it

In most cases, the onset of symptoms occurs in pediatric age, as in the case of Familial Mediterranean Fever (FMF) and Tumor necrosis factor Receptor Associated Periodic Syndrome (TRAPS). However, there are also adult-onset diseases such as adult onset Still's disease (AOSD) and the recently identified VEXAS syndrome. The hallmarks of hereditary autoinflammatory disorders are recurrent attacks of fever and organ inflammation with associated increase in inflammation indices (CRP, ESR, ferritin, serum amyloid protein).
Symptoms can last for hours, days, weeks or, rarely, be subcontinuous. Among the most frequent, in addition to fever (which in some cases has a cyclical course), there are skin rashes, arthralgia, arthritis, myalgia, abdominal pain, ocular manifestations, lymphadenopathy and serositis. The periods between attacks are often characterized by clinical well-being and normalization of inflammation indices. However, the recurrence of inflammatory episodes, especially in cases of lack of treatment of late diagnosis, constitutes a risk for the development of organ damage and long-term complications such as renal amyloidosis.
The diagnosis of autoinflammatory diseases is usually made by exclusion. This means that before being able to confirm the diagnosis it is necessary to exclude the presence of other causes that may explain the symptoms described. In particular, the presence of infections, solid and haematologic neoplasms, immunodeficiencies and autoimmune diseases must be excluded. In case of suspicion of an autoinflammatory syndrome, a molecular investigation is usually carried out (search for mutations in the DNA). This approach is useful for syndromes with a known molecular pathogenesis (including FMF, TRAPS and VEXAS). However, many classification criteria are used, in particular for those syndromes whose molecular characterization is still in the process of being defined (as for AOSD).

There are rare diseases with a prevalence of between 1-5 / 10,000, which generally occur in the pediatric age. TRAPS and FMF generally arise before the age of 20, the latter is widespread above all in Mediterranean populations (Armenians, Turks, Jews and Arabs), whose carrier frequency is high (1/5-1/10). AOSD can affect people older than 16 years of age and in 60% of cases it affects women. VEXAS syndrome has currently only been described in male subjects with a mean age beyond the sixth decade of age.

The therapy of auto-inflammatory diseases is based on drugs that can modulate the activity of the innate immune system. In particular, FMF responds well to colchicine, while TRAPS responds better to steroid treatment and in some cases to anti-monoclonal antibodies such as anti-TNF (Etanercept) or anti-IL-1 receptor. Monoclonal antibodies blocking the activity of IL-1 such as Canakinumab (anti IL-1) and Anakinra (anti IL-1 receptor) and anti-IL-6-receptor (Tocilizumab) have been proven to be very effective for the treatment of AOSD. Moreover, other immunosuppressive drugs such as methotrexate and cyclosporin A are used for the treatment of AOSD patients.

REFERRING DOCTORS for this desease
at Ospedale San Raffaele

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