• Autoinflammatory diseases called periodic fever syndromes are generally monogenic inherited diseases characterized by recurrent fever, serositis, arthritis and cutaneous inflammation that develop without any microorganism warning.
• In these diseases, there is a primary dysfunction of the innate immune response.
• Neutrophil infiltration, increase in inflammatory cytokines and dysregulation of the receptors of these cytokines (IL-1ᵝ) are observed in the blood and affected tissues, and IL-1 is overproduced.
Differential diagnosis of periodic fever
Hereditary autoinflammatory syndromes
Familial Mediterranean Fever (FMF = AAA)
• Familial Mediterranean Fever (FMF) is an autosomal recessive inherited disease that is seen in races living in the Mediterranean region.
• This disease is characterized by recurrent, self-limiting attacks of fever and serositis.
pathogenesis
• As a result of mutations in the MEFV gene located on the short arm of chromosome 16, the pyrin (also known as marenostin) protein cannot be encoded.
• Due to this pyrin protein defect, the inflammatory response due to C5a inhibitor deficiency increases.
• In cases where Pyrin is mutated, it cannot show its regulatory effect on caspase-1, apoptosis is delayed and an uncontrolled IL-1 response occurs.
• The most common mutation is M694V.
• 90% of patients present clinical signs before the age of 20.
Clinic:
• The most common symptom of the disease is febrile abdominal pain. Attacks usually last for 12 hours-3 days.
• Serositis findings are most commonly in the form of peritonitis.
• There may also be chest pains due to pleural involvement (unilateral) and recurrent pericarditis attacks due to pericardial involvement. Depending on the involvement of the tunica vaginalis, pain may be seen around the testis.
• Approximately half of the patients have joint involvement and patients present with recurrent isolated arthritis attacks. Joint involvement is seen as arthritis in 70% of cases and arthralgia in 30% of cases. Arthritis in AAA is a non-migratory, nonerosive, acute monoarthritis that mostly localizes to the lower extremities, does not leave sequelae, and mostly involves the knee and ankle.
• The only cutaneous finding is erysipelas-like erythema. It is usually seen on the ankle and back of the foot.
• HSP (Henoch-Schonlein purpura )is seen in 5% of patients.
Familial Mediterranean Fever (FMF) diagnostic criteria:
Major
1. Typical attacks with peritonitis (generalized)
2. Typical attacks with pleuritis (unilateral) or pericarditis
3. Typical attacks with motorarthritis (ankle, knee, hip)
4. Typical attacks with fever only
5. Incomplete abdominal attack
minor
1. Incomplete attacks with chest pain
2. Incomplete attacks with monoarthritis
3. Leg pain with exercise
4. Good response to colchicine treatment
Diagnosis: made by ≥1 major criteria or ≥2 minor criteria
Typical attack: ≥3 recurrent attacks, fever ≥38°C, short duration (12 hours-3 days)
Incomplete attack: Painful and recurrent attacks that do not meet the criteria for a typical attack.
• Fibrinogen elevation has no specificity in diagnosis and prognosis. However, it is as valuable as other acute phase reactants.
Treatment
• Colchicine is used for life (no alternative treatment). Colchicine inhibits the development of amyloid. Even if amyloid has developed, it can provide partial regression. It is not harmful to mother or baby during pregnancy.
• The IL-1 receptor antagonist anakinra or the IL-1 inhibitor rilonacept can be used in patients who do not respond to colchicine.
Complications
• The most important complication in patients is the development of AA type amyloidosis and most commonly it starts with proteinuria. The picture may progress to nephrotic syndrome and chronic renal failure. Amyloid deposition may be seen in the GI tract, heart, and spleen.
• Macroglossia and neuropathy are not expected in FMF-induced amyloidosis.
Risk Factors for Development of Amyloidosis in FMF:
1. Family history of AA type amyloid
2. Homozygous positivity of M694V mutation
3. Polymorphism in the serum AA gene
4. Male gender
5. Non-compliance with colchicine therapy
Amyloid risk is high in patients with excessive serum AA protein and acute phase reactants during an attack.
Hyperimmunoglobulin D Syndrome IgD
• It is an autosomal recessive, autoinflammatory disease.
• It occurs as a result of mutations in the MVK gene in the chromosome that encodes the mevalonate kinase (MVK) enzyme, which plays a role in cholesterol biosynthesis.
• In hyperimmunoglobulin D syndrome, although the enzyme activity decreases markedly as a result of mutation in the mevalonate kinase gene, the enzyme activity remains about 5%.
• If the enzyme activity is completely absent as a result of the mutation in the mevalonate kinase gene, a metabolic disease called "mevalonic aciduria", characterized by dysmorphic facial appearance, progressive cerebellar ataxia, psychomotor retardation and growth retardation, develops.
• It is characterized by recurrent fever, lymphadenopathy, abdominal pain and rash attacks.
Clinic:
• The average age of onset is six months. The first attacks of 63% of the patients are after vaccination.
• Recurrent fever that starts in infancy (lasts 3-7 days)
• Lymphadenopathy (The most common finding is lymphadenopathy and is usually cervical)
• Stomach ache
• Arthralgia and arthritis
• Morbiliform rash
• It is characterized by recurrent oral aphthae and genital ulcers.
Laboratory Findings:
• Increase in acute phase reactants, high IgD (>100 mg/dl)
• Serum IgA elevation (≥2.6 g/L)
• Mevalonic acid increase is detected in organic acid analysis in urine.
Hyperimmunoglobulin D syndrome should be considered in patients with recurrent fever, cervical lymphadenopathy, rash and unresponsive to colchicine starting in infancy.
Treatment:
• The most important difference from FMF is that the response to colchicine is very low and amyloidosis is not expected.
• There is no proven treatment. Steroid, colchicine and nonsteroidal anti-inflammatory drugs, etanercept and anakinra can be used in the treatment.
PFAPA Syndrome
• It is the most common recurrent fever syndrome in children.
• Unlike other hereditary autoinflammatory diseases, its etiology is not yet clear.
• It is associated with periodic fever, aphthous stomatitis, pharyngitis , adenitis (cervical).
• Other findings are headache, abdominal pain and arthralgia.
• Regular attacks (every 3-6 weeks) and negative throat culture play an important role in the differential diagnosis.
• The majority of patients respond to a single dose of oral prednisolone (1-2 mg/kg).
• This syndrome usually develops between the ages of 2-5. It heals spontaneously in 4-8 years.
• To prevent attacks, tonsillectomy, use of cimetidine or colchicine (response is around 30%) can be tried.
• Studies on the use of anakinra during an attack are promising.
Adenosine Deaminase 2 Deficiency
This disease, also called Sneddon syndrome or childhood-onset PAN, is a genetic disease characterized by uncontrolled inflammation in various tissues, especially in vessels, resulting from OR transitional mutations in the ADA2 gene.
The skin, gastrointestinal tract, kidneys and central nervous system are the main tissues involved. The disease is a systemic vasculitis. Some patients may have mild immune system disorders, but the frequency of infection does not increase.
Livedo reticularis, livedo racemosa, thrombotic vasculitis of small and medium vessels in the skin, and focal neurological deficits are the main findings.
Main symptoms and signs
• Recurrent intermittent fever
• Hepatosplenomegaly
• Livedo reticularis
• Hypertension
• Recurrent stroke attacks
• Eye and heart involvement
• Decrease in kidney functions
Antibodies detected in rheumatic diseases
• ANA: SLE (screening test)
• Anti ds DNA: SLE (specific)
• Anti Smith (anti-SM): SLE (specific)
• RF: JIA, primary biliary cirrhosis, endocarditis, tbc, syphilis, hepatitis B-C, parvovirus B19 and
mycoplasma infections, 10% of healthy children
• Anti Ro: Sjögren and neonatal lupus
• Anti La: Sjogren and neonatal lupus
• Anti-SCL70 (topoisomerase 1): Scleroderma
• Anti-Centromeric antibodies: CREST syndrome
• Anti-JO-1: Polymyositis/dermatomyositis
• Anti Pm-Scl: Seclerodermatomyositis
• c-ANCA (PR3 antigen): Wegener
• ANCA (BPI antigen): Cystic fibrosis
• p-ANCA: (MPO antigen): Microscopic polyangiitis, Churg-Strauss, ulcerative colitis, Crohn's disease, sclerosing cholangitis
• p-ANCA (Actin antigen): Autoimmune hepatitis type 1
• Anti-Histone antibodies: Drug-induced lupus
• Anti-RNP: Mixed connective tissue disease, SLE
• Anticardiolipin antibody IgM and IgG: Antiphospholipid antibody syndrome
• Lupus anticoagulant: Antiphospholipid antibody syndrome
• Anti-glomerular basement membrane antibody: Goodpasture syndrome, rapidly progressive glomerulonephritis
• Anti CCP: RF positive JIA
