Hereditary periodic fevers syndromes

Definition: recurrent attacks of inflammation with genetic molecular basis for which no infectious or

auto-immune cause can be identified

Familial Mediterranean Fever (FMF) 88%

TNF-R-associated periodic syndrome (TRAPS) (55-kd TNFRSF1A gene mutation: C70R, P46L)

Hyper IgD periodic fever syndrome (HIDS) (MVK gene mutation--> mevalonate kinase deficiency)

Muckle-Wells syndrome (MWS)

Familial cold urticaria (FCU)

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Familial Mediterranean Fever (FMF)

Autosomal recessive inherited periodic disease Sephardic, North African Jews, Armenians, Arabs, Druze and Turks are affected

Major criteria: Fever attacks >38

Serositis (peritoneum, pleura, pericardium)

Monoarthritis (hip, knee, ankle)

Minor criteria: Incomplete attacks:

Exertional leg pain

Colchicine efficiency (1-2mg/day)

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12-72hr typical

incomplete wk6hr

FMF. Supportive criteria:

1. Family history of FMF / parents consanguinity

2. Appropriate ethnic origin

3. Age <20 years at disease onset

4. Severe, requiring bed rest

5. Spontaneous remission

6. Acute phase reaction: ESR, SAP, fibrinogen

7. Appendectomy

8. Episodic proteinuria / hematuria

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FMF. The requirements for diagnosis:

•= or > 1 major criteria

•= or > 2 minor criteria

•1 minor plus 5 supportive criteria

1 minor plus 4 of the first 5 supportive criteria

Typical attacks:

recurrent: = or > 3 of the same type

febrile >38

short (12hr-3 days)

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Familial Mediterranean Fever

Genetic

FMF gene is mapped to short arm of chromosome 16p (The International FMF Consortium. Cell 1997. The French FMF consortium. Nat Genet 1997)

FMF gene mutations (25) ---> transcription factor deficit (pyrin) -----> cytoskeleton mobility----> granulocyte activation ----> inflammation

Common FMF mutations:

M694V(3/52%), M680I(5/9%), V726A(2/3%), M694I(0/0.4%), E148Q(1.2/4%)

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Familial Mediterranean FeverCommon MEFV (FMF gene) mutations among Jewish ethnic groups in Israel:M694V, 726A, M680I, E148QCarrier frequency of at least two mutations: Ashkenazi 14%, Iraqi 29%, Moroccan Jews 21%Ashkenazi carrier / non-carrier : no difference in morbidityV726A or E148Q: excess of febrile episodesThe frequency of MEFV mutation exceeds overt FMF rate (phenotype III) by 40-240 fold.Conclusions (MEFV mutations in Israel): high carrier rate among Jews most subjects are unaffected

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Familial Mediterranean Fever

Elevated pro-inflammatory cytokine expression in circulating leukocytes:

TNF-alpha

IL-1beta

IL-6

IL-8

is found during attacks and in attack-free FMF patients and supports subclinical inflammation between attacks.

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Familial Mediterranean Fever

Corticosteroid failure

Colchicine:

Daily administration

Life-long treatment

Dose:1-2mg/day

Reduces the frequency of attacks

Reduces the severity of attacks

Prevents amyloidosis

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Amyloidosis

•Amyloid - extracellular fibrillar insoluble protein deposition affecting organ structure and function.

•Amyloid has blue staining with iodine (Virchow 1854). Cellulose (amylum) has the same staining.

•Diagnose is established by demonstration of amyloid in tissue:

Congo red staining in polarized light(apple-green birefringence): + in 1/3 AL and 2/3 AA

Tissue biopsy is positive: abdominal fat 85% AL, gingival, rectal 1/3-2/3, kidney,bone 30%,CTS 90%

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Amyloidosis. Light-Chain Amyloid (AL)

Primary (non-tumor type): derived from small population of non-tumor plasma cells

Multiple myeloma (MM) (tumor-type): derived from malignant clone of plasma cells

Pathology: monoclonal Ig light-chain deposits

Bence-Jones (light-chains) proteinuria is common

1/3 of light-chain amyloidosis show MM

15% of MM are complicated with Amyloidosis

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Amyloidosis AL. Clinical features:

•One organ shows predominant involvement

•Cardiovascular - in almost all cases, CHF 25%

•Proteinuria and azotemia - in most cases. AL should be ruled out:>30 yrs+nephrotic syndrome

•Tongue enlargement (macroglossia) 20%

•Peripheral neuropathy 16%. CNS is not involved

•Carpal tunnel syndrome 20%

•GI tract: malabsorbtion, hepatomegaly, diarrhea

•Autonomic dysfunction: ortostatism, constipation..

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Amyloidosis AL. Clinical features:

• Rare splenomegaly. Functional hyposplenism (Howell-Jolly bodies: blood cells remnants, CBC)

•Cutaneous echymoses (periorbital: “raccoon eye”)

•Nail dystrophy

•Alopecia

•Arthropathy: cold non-inflammatory effusion, pad-like shoulders enlargement, DD hypothyroid

•Lung AL is usual. Decreased function is rare.

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Amyloidosis AL. Laboratory abnormalities.

1. Serum protein electrophoresis: Ig monoclonal spike 45%, hypogammaglobulinemia 25%

2. Immunoelectrophoresis/immunofixation: monoclonal protein 90%, Bence-Jones proteinemia (Light chain) 25%. Lambda light chains 65%. kappa 35% (in contrast to MM).

3. Urine: Bence-Jones 75%. Low level<200mg/24hr - occult malignancy:LY,CLL,MM, may be N serum

4. Monoclonality is not found in other amyloidosis

5. Renal failure 50%, Cr > 1.3 - shorter survival

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Amyloidosis AL. Laboratory abnormalities.

6. Anemia 50%

7.Thrombocytosis 10%, functional hyposplenism

8. Leucocytosis

9. Increased ESR

10. Bone marrow: >5% plasma cells in 50% cases

7. Multiple myeloma laboratory abnormalities due to infections, pancytopenia, hypercalcemia, hypoIg, hypoalbuminemia

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Amyloidosis AL. Treatment.

Survival of AL without treatment -few months only

Multiple myeloma - VAD

Primary AL:

1. Cyclic oral therapy -mild efficacy. Melphalan 0.2 mg/d + prednison 1mg/kg for 4 days every 6 weeks

2. High dose of melphalan (200mg/m2+prednison 1mg/kg for 2 days) + autologic stem cells + GCSF harvesting. Normal cardiac function is requested. Efficacy 50 %. Heart, liver, kidney disease reverse.

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Amyloidosis AL. Treatment.

Primary AL:

3. Intermediate melphalan+autologic stem cells are given at compromise cardio-renal function patients with response 25%.

4. Organ transplantation + aggressive 2 schedule

5. IDOX (resorbtion of amyloid) +dexamethasone+alkalating agent

6. Supportive: nutrition, pacemaker, dialysis, transplantation

7. Contraindicated: digitalis, beta-, Ca-blockade

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Amyloidosis AA Reactive Systemic (secondary)

Amyloid A Protein (acute phase reactant) deposits

Bence Jones proteinuria is absent. Signs resemble AL. Better survival: 10 years, less due to infection.

Due To: Autoimmune dis.:RA, JRA, AS, IBD

Neoplasm: Hodgkin dis., adenocarcinoma

Chronic infections: osteomyelitis, TB

Heredofamilial: FMF

Neuropathic I-IV types

Diagnosis: tissue immuno-staining for AA protein

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Amyloidosis AA. Treatment.

Therapy for underlying disease: RA, TB, FMF

Colchicine 1.5-2mg/d, Chlorambucyle 2-8mg/d 2yrs

Other amyloidosis types ( no Bence Jones protein)

SSA senile cardiac amyloid: 24% >70yrs old, CHF

AF or ATTR familial: heart, renal, neuropathic

CAA cerebral, CNS plaques of Alzheimer disease

Beta 2-microglobulinemic amyloid due to dialysis

IAPP islet polypeptid amyloid of DM type II

AE amyloid:thyroid medullary cancer (Calcitonin)

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FMF. ARTHRITIS.

THREE FORMS OF ARTHRITIS IN FMF:

1. Asymmetrical non-destructive acute (75%). Knees, ankle, wrist. One-two joints. Large effusion. Resolution.

2. Chronic destructive including sacroiliitis (2-5%). Hips, knees. One protracted.Repeated short attacks Sacroiliitis 0.4%. HLA B27neg. Free lumbar spine.

3. Migratory, rheumatic fever-like.

Erysipelas-like erythema (7-40%). Unilateral. Dorsum of ankle or foot. Fades away within 2-3ds

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FMF.

RARE MANIFESTATIONS

Mollaret’s meningitis

Fundoscopy: retinal colloid bodies

Splenomegaly, 30-50%. Nonamyloid.

Acute orchitis

Phenotype II: renal family amyloidosis+non history of FMF + positive genetic for FMF

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