A. Introduction

1. Collection of poorly understood syndromes
2. Most have clear familial pattern of inheritance
3. Cytokine overproduction plays a role in these diseases
   1. Interleukin 1 (IL1) is major mediator of fever
   2. IL1 stimulates IL6 and TNFa production
   3. Most of these diseases are considered "autoinflammatory"
   4. Macrophages and endothelium play significant role
   5. High doses of IL1 blockers may be very effective

B. Familial Mediterranean Fever (FMF) [2,5,9]

1. Occurs in patients with Sephardic Jewish, Turks, Armenian, Arab ancestry
2. Symptoms begin between ages 5 and 15
3. Recurrent, self-limited episodes of fever and polyserositis
   1. Episodic (high) fever, usually <72 hours duration
   2. Peritonitis
   3. Pleuritis
   4. Arthritis
   5. Vomiting
   6. Erysipelas-like skin lesions (less common)
   7. Amyloidosis (AA type) occurs in many patients over time without treatment
   8. Renal disease
4. Molecular Genetics
   1. Autosomal recessive with carier frequency is ~1:5 in affected populations
   2. Mutations in Gene MEFV on chromosome (chr) 16p cause FMF [6]
   3. MEFV codes for pyrin or marenostrin
   4. Expressed in granulocytes, monocytes, dendritic cells, fibroblasts
   5. Wild type marinostrin is cytoplasmic and colocalizes with microtubules
   6. Likely regulates inflammatory responses at level of cytoskelaton
   7. May also be localized to nucleus and regulate IL1ß and/or nuclear factor kappa B (NFkB)
   8. Four missense mutations (of 28 known) in MEFV account for most cases
   9. Homozygote mutant MEFV persons are always symptomatic
   10. Heterozygotes may be symptomatic (including M694V mutations)
5. Pathophysiology of Serositis
   1. Characterized by chronic inflammation and acute flares with neutrophilia
   2. Inflammation of joints, pleural and peritoneal cavity, and somtimes the skin
   3. Patients with FMF lack a specific protease in serosal fluids
   4. This protease degrades interleukin 8 and chemotactic complement factor 5a
   5. Therefore, this protease is called the IL8/C5a inhibitor
   6. Likely that pyrin controls the expression IL8/C5a inhibitor
   7. Absence or reduction of IL8/C5a inhibitor leads to inflamed serosa
6. Diagnosis
   1. High suspicion
   2. Clinical criteria: acute reversible serosal attack
   3. Clinical history
   4. Demonstration of mutations in MEFV gene
   5. Absence of serosal protease currently demonstrable only in research setting
7. Laboratory
   1. Leukocytosis with neutrophilia 10-30K/µL during attacks
   2. ESR elevated only during attacks
   3. Fibrinogen and serum amyloid A elevated as well
   4. C5a inhibitor deficiency in serosal or synovial fluid
   5. Urinary protein excretion >0.5gm/24 hours suggests renal amyloidosis
   6. Renal disease may progress to nephrotic syndrome
   7. Molecular genetic confirmation of diagnosis is cost effective and rapid [5]
8. Nephropathy is major morbidity
   1. Divided into 4 stages
   2. Preclinical Stage
   3. Proteinuria
   4. Nephrotic Syndrome
   5. Renal Failure (uremia)
9. Treatment
   1. Colchicine in high doses may prevent or retard progression to renal failure
   2. Doses >1.8mg/day should probably be given before creatinine >1.5mg/dL
   3. Colchicine can prevent deposition of amyloid
   4. Anakinra (Kineret®), an IL1-receptor antagonist, can reduce fever, other symptoms
10. Prognosis
    1. Normal in absence of amyloidosis (AA type)
    2. In presence of AA amyloidosis, reduced life expectancy (mainly due to renal disease)
    3. Arabs with FMF appear to have lower frequency of amyloidosis [2]

C. TNF-Receptor Associated Periodic Syndrome [3]

1. Formerly called Familial Hibernian Fever (FHF)
2. Affects Scottish and Irish
3. Onset age <20
4. Symptoms
   1. Episodic fever attacks typically last >14 days
   2. Myalgia and oligoarticular arthralgia
   3. Painful erythematous macules
   4. Conjunctivitis
   5. Abdominal pain
   6. Unilateral periorbital edema
   7. Chest pain less common
5. Other Characteristics
   1. Inguinal hernia very common in affected males
   2. Secondary amyloidosis reported in one patient
   3. Amyloidosis (AA type) develops in ~25% of affected families
6. Molecular Genetics
   1. Autosomal pattern of inheritance linked to chr 12
   2. Missense mutations in gene for Type 1 tumor necrosis factor (TNF) receptor
   3. This is the 55K TNF-Receptor whose ligand is TNF alpha
   4. Over 16 mutations have been documented to cause syndrome
   5. These mutations prevent TNFalpha-TNF-R from being shed from cell surface
   6. Thus, these mutations block "shedase" functions and maintain TNFalpha signalling
7. Diagnosis
   1. During attack, neutrophilia and inflammatory markers elevated
   2. C-reactive protein increased
   3. Complement activation mild
   4. Polyclonal immunoglobulin levels (particularly IgA) increased
   5. Low serum level of soluble type 1 TNF-R is most definitive test
   6. Urine should be screened for protein (may be due to renal amyloid)
   7. Molecular analysis is best method for definitive diagnosis
8. Treatment
   1. Prednisone >20mg/day started early in course is very effective
   2. Etanercept (soluble TNF-R - Fc fusion) 25mg twice weekly sc recommended
   3. Etanercept 25mg qd x 3 days induced remission for 6 months
   4. Cyclosphosphamide has been used to stabilize amyloidosis in one patient
9. Prognosis
   1. Depends on presence or absence of amyloidosis
   2. Amyloid deposits associated with renal (or hepatic) failure
   3. Lack of amyloid associated with normal lifespan

D. Hyper-IgD Syndrome (HIDS) [4]

1. Affects primarily (60%) Dutch and French; others are White from Western Europe
2. Onset age <1 year
3. Symptoms
   1. Episodic fever attacks typically last 4-6 days
   2. Prominent cervical lymphadenopathy
   3. Erythematous macules
   4. Abdominal pain and vomiting
   5. Arthralgia
   6. Uncommon: painful aphthous ulcers in mouth or vagina
4. Attacks generally recur every 4-6 weeks
5. Molecular Genetics
   1. Autosomal recessive pattern of inheritance linked to long arm chr 12
   2. Missense mutations in gene for mevalonate kinase (MK)
   3. Mutation V377I (Valine to Isoleucine) is present in >80% of patients
   4. MK is key enzyme in cholesterol synthesis following HMG-CoA reductase
   5. MK levels in hyper-IgD syndrome reduced to 5-15% of normal
   6. Serum cholesterol levels are slightly reduced during attacks
   7. How defects in MK enzyme are linked to elevated IgD and inflammation not yet known
   8. MK mutations also responsible for autosomal recessive mevalonic aciduria, with fevers, developmental delay, ataxia, dysmorphic features, cataracts, retinal dystrophy [15]
6. Diagnosis
   1. During attack, neutrophilia and inflammatory markers elevated
   2. C-reactive protein and serum amyloid A increased
   3. Serum IgD levels uniformly elevated (>100IU/mL)
   4. Serum IgA levels elevated in 80% of patients
   5. Elevated urinary excretion of neopterin reflects disease activity
   6. Urine should be screened for protein (may be due to renal amyloid)
   7. Molecular analysis is best method for definitive diagnosis
7. Treatment
   1. Unclear benefits of any therapy
   2. Thalidomide did not improve symptoms
   3. Simvastatin and other statins have shown good activity
   4. TNFa blockers are being evaluated
   5. Interleukin 1 receptor antagonist (anakinra) has shown some activity [4]
8. Prognosis
   1. Frequency of attacks usually decrease after adolescence
   2. Amyloidosis has not been reported in associated with hyper-IgD syndrome
   3. Joint or organ destruction is rare

E. Malignant Hyperthermia (MH) [7,8]

1. MH is an autosomal dominant disease manifesting with anesthesia
2. Occurs in about 1 case per 50,000 adults
3. Occurs 1 in 15,000 children (usually familial)
4. With careful observation and supportive therapy, mortality is now <10%
5. Genetics
   1. Due to mutations in the sarcolemmal calcium release channel (CRC)
   2. CRC is also called the ryanodine receptor
   3. At least 16 different mutations in skeletal CRC gene Ryr1 linked to MH
6. Pathogenesis
   1. CRC controls muscle calcium (Ca2+) flux
   2. Anesthetics inducing MH cause massive unregulated Ca2+ release
   3. Increased uptake of Ca2+ by mitochondria leads to increased CO2 production, O2 use
   4. Results are manifestations of MH
7. Symptoms
   1. Muscle rigidity
   2. Hyperthermia
   3. Hypercapnea
   4. Hyperkalemia
   5. Cardiac arrhythmias
   6. Acidosis
   7. Rhabdomyolysis with myoglobinemia, renal failure
   8. DIC can occur
8. Treatment
   1. Dantrolene, which closes CRC, is major treatment modality for MH
   2. Supportive care with intensive monitoring is required

F. Neonatal Onset Multisystem Inflammatory Disease (NOMID) [10]

1. Hereditary systemic autinflammatory disorder
   1. Most cases (~60%) due to mutations in gene for cold-induced autoinflammatory syndrome 1 (CIAS1) gene which codes for crypyrin (NALP3)
   2. Similar phenotypes in those patients without these mutations
2. Inflammation in this syndrome due to activaiton of "inflammasome"
   1. Inflammasome assembly leads to activation of caspase 1
   2. Activated caspase 1 cleaves pro-IL1ß into biologically active form
   3. May also activated NF-kB
3. Syndrome develops within first 6 weeks of life
4. Characteristics
   1. Fever
   2. Urticarial rash
   3. Aspetic meningitis and other CNS manifestations
   4. Deforming arhthropathy
   5. Hearing Loss
   6. Mental retardation
   7. Leukocytosis
   8. Hepatosplenomegaly
   9. Elevated serum amyloid A and C-reactive protein (CRP)
5. Marked improvement with IL1 Blockade
   1. Essentially all symptoms improved with anakinra (Kineret®), an IL1-receptor antagonist
   2. Discontinuation of the IL1-R antagonist lead to symptom recurrence within days

G. Macrophage Activation Syndrome (MAS)

1. Genetic component not yet identified
2. Also called reactive hemophagocytic syndrome
3. Rare, potentially fatal complication of rheumatic and autoinflammatory diseases
   1. Usually associated with juvenile chronic arthritis (JCA, systemic onset, Still's Disease) [11]
   2. May accompany hyper-IgD syndrome or other periodic fever syndromes [12]
   3. Reported associated with ankylosing spondylitis [13]
4. Pathogenesis [14]
   1. Uncontrolled activation of T-helper type 1 lymphocytes
   2. Usually secondary to inciting factors associated with inflammation
   3. These include rheumatologic disease flare, viral or other nfection, ymphoma, or other cancer
   4. Interleukin 18 (IL18), strong inducer of Th1, is highly elevated
   5. Other Th1 cytokines highly elevated, and macrophages are nonspecifically activated
5. Characteristics
   1. Fever is very common, usually with systemic illness and anemia or pancytopenia
   2. Systemic illness with significantly upregulated IL1 and other monokine production
   3. Bone marrow aspiration is generally required for diagnosis
   4. Well differentiated macrophages phagocytosing hematpoietic elements are diagnostic
   5. CNS dysfunction and hemorrhages most common clinical discriminators [11]
   6. Elevated aspartate aminotransferase, presence of leukopenia, hypofibrinogenemia
   7. Hypertriglyceridemia and hyperferritinemia often found
   8. May erupt following withdrawal of TNFa blockade
6. Treatment
   1. Anakinra (IL1 receptor antagonist) at high doses, usually intravenous, very effective
   2. Cyclosporine A (CsA) also active
   3. Intravenous immunoglobulin (IVIg) has reported activity
   4. Generally poor responses to high dose glucocorticoids
   5. TNFa blockade generally not effective

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