Uncommon Chronic Systemic Inflammatory Disorders Periodic Fever Syndromes

Hereditary periodic fever syndromes are a group of rare inherited disorders defined by recurrent attacks of self limited inflammation for which no infections or autoimmune cause can be identified. The membranous synovial and serosal linings are particular targets resulting in articular and abdominal pain. A family history is useful but often lacking. A useful indication of hereditary periodic fever syndrome as opposed to persistent inflammation is the presence of normal inflammatory markers between episodes with normal growth and development. There are clinical similarities between diseases in this category, but also clear distinctions between mode of inheritance and characteristic features. Life threatening amyloidosis can occur in a percentage of cases of periodic fever syndromes, and despite improved diagnostic methods and therapeutic interventions, it remains the most frequent cause of death (124,125). Familial Mediterranean fever (FMF) is the most prevalent periodic fever syndrome worldwide. It frequently presents in adolescence, and will hence be covered. Syndromes that tend to present earlier in childhood will not be covered, e.g., muckle-wells syndrome; familial cold autoinflammatory syndrome (FCAS); chronic neurologic and cutaneous articular syndrome (CINCA); tumor necrosis factor receptor associated periodic syndrome (TRAPS); and hyperimmu-noglobulinemia D periodic fever syndrome.

Familial Mediterranean Fever

Familial Mediterranean fever is defined by recurrent febrile episodes accompanied by abdominal pain (95%), serositis (25-80%), synovitis (75%), and an erysipelas-like rash (7-40%) and splenomegaly (126). Each attack lasts for 12 to 72 hours at intervals of days to months. Between attacks, children or adolescents are asymptomatic and their inflammatory markers are normal. Onset of symptoms occurs within the first decade of life in 50% of individuals (126). It is common in countries surrounding the eastern Mediterranean sea (particularly in Sephardic and Iraqi Jews, Armenians, and Levantine Arabs) and rare in North America and Northern Europeans. A more severe form is seen in North African Jews correlated with homozygosity for M694V (126). FMF has a favorable response to treatment with colchicine, with reduction in the frequency of attacks or preventing them completely. Treatment should be continued for life, but without treatment or with inadequate treatment, amyloidosis is frequent. Early diagnosis using genetic analysis, followed by early treatment with colchicines, will reduce the risk of renal failure secondary to amyloidosis. TNF receptor inhibitors such as etanercept also provide a rational approach to treatment.

Castleman's Disease (Angiofollicular Lymph Node Hyperplasia)

Castleman's disease is a rare atypical lymphoproliferative disorder characterized by enlarged lymph nodes with striking vascular proliferations. It is separated into localized disease, usually observed in young patients, and multicentric disease, more common in older patients. Localized disease has a good prognosis with surgery. Multicentric disease can be associated with other systemic disorders such as HIV, AIDS, malignant lymphoma, and rheumatoid arthritis. Diagnosis depends on biopsy. Treatment options include surgery, chemotherapy, anti-herpetic treatments, antiretroviral therapy and monoclonal antibodies against IL-6 and CD20 (127). Prognosis depends on the underlying disorder.

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