חזרה לדף הבית

תקציר שיקופיות הרצאה (טבריה 03/01/2003)

Autoimmune hereditary fever

TNF RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS)

•Familial Hibernian Fever (FHF)

•Benign autosomal dominant familial periodic fever (FPF)

•Autosomal dominant periodic fever with amyloidosis

TRAPS

• a dominantly inherited disorder

• Irish or Scottish ancestry

• episodic attacks of fever

• severe localized inflammation

• systemic amyloidosis

TRAPS

• episodes much longer than in FMF, lasting longer >1 week sometimes for 4-6 weeks

• conjunctival inflammation

• periorbital edema

• migratory myalgia and rash

• erysipelas like erythema

• corticosteroids >> effective than colchicines

mutations in TNFRSF1 A
on chromosome 12p13

gene encodes the 55 kDa TNF receptor

(p55, TNFR1, CD120a)

_________________________________________________________________________________________________________________

TRAPS

14 TNFRSF1 A mutations:

• 7 - missense changes that disrupt conserved extracellular disulfide bonds

• 1- a missense mutation that abolishes a conserved hydrogen bond in CRD1

• 1 is a splicing mutation causing the insertion of 4 amino acids in CRD1,

• and the remainder are missense substitutions of residues closely adjacent to cysteines.

_________________________________________________________________________________________________________________

TRAPS

• Inflammatory from impaired cleavage of TNFRSF1 A ectodomain upon cellular activation

• Normally, cleavage or TNFR has a negative homeostatic effect, (reducing the number of receptors on the cell surface, and creating a pool of potentially antagonistic soluble receptor.)

• Reduced levels of soluble p55 TNF receptor

• Soluble p55 levels in TRAPS patients show a minimal increase during inflammatory episodes.

_________________________________________________________________________________________________________________

A pilot study of anti-TNF therapy
in TRAPS:

• Patients have been treated etanercept (Enbrel) (recombinant p75 TNFR:Fc fusion protein) at the standard dosage for adult or juvenile rheumatoid arthritis.

• F/U 2 -10 mo, clinical and laboratory responses have been encouraging

• D L Kastner, I Aksentijevich, J Galon, and J J O'Shea,
Arthritis and Rheumatism Branch, NIAMS/NIH, Bethesda.

• Petechiae and Purpura on the Lower Right Leg during a Febrile Attack in a Patient with the Hyper-IgD Syndrome.

• The skin lesions disappeared a week after the end of the attack. The clinical findings in this patient (Patient 30 in the hyper-IgD syndrome

Familial Hibernian fever

• In the year 409 AD Irish tribes of Hibernia liberate Britain from the Romans and settle in Northwest Britain and Wales.

• By 410 AD the kingdom of powys is founded. A major rebuilding of the city of Virconium begins.

• Vortigern assumes control of central and southern Britain. Vortigern offers friendship to the Irish kingdoms of western wales and northwest Britain.

• There is peace in Britain.

HIDS criteria

• CONSTANTLY

• High IgD (100 U/mL) measured at 2 occasions with at least one month apart

HIDS

• 1984, Van der Meer and colleagues (6 patients with periodic fever and a constantly elevated polyclonal IgD

• Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome (called here HIDS)

HIDS

• Nijmegen HIDS registry: 144 cases of this new syndrome

• Most patients stem from (West) European countries

• Clear preponderance for the Netherlands or the north of France

HIDS

• long history of episodic attacks of fever

• The majority has attacks before the end of their first year of life

• Attacks occur every 4-8 weeks

• Last 3-7 days

• Attacks persist throughout life although patients experience a reduction in intensity and frequency of attacks after adolescence.

_________________________________________________________________HIDS: Clinical symptoms

• Lymphadenopathy

• abdominal pain and diarrhoea

• Headache

• hepato/splenomegaly

• arthralgia/ arthritis

• skin lesions

• In some - aphtous mouth or vaginal ulcers.

• In most patients - no apparent symptoms between attacks

_________________________________________________________________________________________________________________

HIDS: Laboratory analysis

• Acute phase response with high C-reactive

• Leukocytosis

• Increased TNFa , IL-6 and IFN-g

• Also anti-inflammatory compounds: IL-1ra, sTNFr p55 and sTNFr p75)

• Most typical: serum IgD (> 100 U/mL comparable to 141 mg/l)

• Majority has also elevated serum IgA levels.

HIDS: Treatment

• Largely supportive since various standard anti-inflammatory drugs (including colchicine and steroids) failed to suppress the attacks.

• Currently there are trials underway judging the effect of thalidomide and simvastatine in HIDS

_________________________________________________________________

HIDS: genetic disorder

• 15 families with 34 affected members

• Hereditary trait being autosomal recessive.

• Highly homogenic genetical disorder with complete penetrance.

• Linkage analysis: long arm of chromosome 12 (12q24).

• Mevalonate kinase is the HIDS gene.

HIDS: Mevalonate kinase (MVK)

• a homodimeric enzyme presents in the peroxisomes of every mammalian cell

• Follows 3-hydroxy-3-methylglutaryl-CoA reductase in the cholesterol synthesis

• Converts mevalonate into 5-phosphomevalonate.

HIDS: Mevalonate kinase (MVK)

• 4 missense mutations and a 92bp deletion in the MVK encoding gene,

• V377I being the most frequent mutation

• A moderate (5-15%) functional defect of MVK as tested in cultured fibroblasts or lymphocytes.

• As yet it is unclear why a disorder in the cholesterol metabolism can cause a disorder of periodic inflammatory attacks

_________________________________________________________________________________________________________________

HIDS criteria

AT ATTACKS

• Elevated ESR and leukocytosis

• Abrupt onset of fever (38.5°C)

• Recurrent attacks

• Elevated IgA (2.6 g/L)

• Lymphadenopathy (cervical)

• Abdominal distress: vomiting, diarrhoea, pain

• Skin manifestations (erythematous macules and papules)

• Arthralgias / Arthritis

• Splenomegaly

_______________________________________________________________________________________

PAPA syndrome

**PYOGENIC STERILE ARTHRITIS, PYODERMA GANGRENOSUM, AND ACNE *604416**

Alternative titles; symbols

PAPA SYNDROME; PAPAS

Gene map locus 15q24-q26.1

_______________________________________________________________________________________

PAPA syndrome

Pyogenic Arthritis, Pyoderma gangrenosum, and severe cystic Acne. (Lindor et al. 1997)

An autosomal dominant inheritance

Family members (10) variable expression of pauciarticular, nonaxial, destructive, corticosteroid-responsive arthritis that began in childhood;

• pyoderma gangrenosum

• severe cystic acne in adolescence and beyond

_______________________________________________________________________________________

PAPA syndrome

• Lindor et al. (1997)

• a multigeneration family: autosomal dominant

• pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne.

• Ten affected family members manifested variable expression of pauciarticular, nonaxial, destructive, corticosteroid-responsive arthritis that began in childhood;

• pyoderma gangrenosum;

• severe cystic acne in adolescence and beyond.

PAPA syndrome

Less commonly

• adult-onset insulin-dependent diabetes mellitus

• proteinuria

• abscess formation at the site of injections

• cytopenias attributable to sulfonamide medications

• no HLA linkage

___________________________________________________________________________________________________________________

Yeon HB, Lindor NM, Seidman JG, Seidman CE.

Am J Hum Genet 2000 Apr;66(4):1443-8

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q.

(maximum two-point LOD score, 5.83; recombination fraction [straight theta] 0 at locus D15S206).
Department of Medicine and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, USA.

____________________________________________________________________________________

CINCA SYNDROME; CINCA

Alternative titles; symbols:

CINCA syndrome

CHRONIC NEUROLOGIC CUTANEOUS AND ARTICULAR SYNDROME

NOMID syndrome

NEONATAL ONSET MULTISYSTEM INFLAMMATORY DISEASE

• Gene map locus 1q44

____________________________________________________________________________________

Cryopyrin

• Cold-induced autoinflammatory syndrome, familial

• Muckle-Wells syndrome

• CINCA syndrome

• CIAS1, C1orf7, FCU, FCAS

• Location: 1q44

_________________________________________________________________

CIAS1 gene

• encodes a pyrin-like protein expressed predominantly in peripheral blood leukocytes.

• It is mutant in familial cold autoinflammatory syndrome (FCAS)

• Muckle-Wells syndrome (MWS)

• CINCA (NOMID) syndrome.

__________________________________________________________________________________________________________________

MOLECULAR GENETICS

• Hoffman et al. (2001) 4 different missense mutations in exon 3 of the CIAS1 gene in 3 families with FCAS and 1 with MWS

• Dode et al. (2002) CIAS1 mutations, all located in exon 3, in 9 unrelated families with MWS and in 3 unrelated families with familial cold urticaria (FCU),

• originating from France, England, and Algeria. Five mutations were novel.

MOLECULAR GENETICS

• Feldmann et al. (2002) identified heterozygous missense mutations in the CIAS1 gene in the affected members of each of 7 families with CINCA syndrome.

• Severe cartilage overgrowth observed in some patients with CINCA syndrome

• A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes

_________________________________________________________________

PAPA syndrome

Less commonly

• included adult-onset insulin-dependent diabetes mellitus

• Proteinuria

• abscess formation at the site of parenteral injections,

• cytopenias attributable to sulfonamide medications

• Genetic studies excluded linkage to the major histocompatibility complex

____________________________________________________________________________________

BLAU SYNDROME

SYNOVITIS, GRANULOMATOUS, WITH UVEITIS AND CRANIAL NEUROPATHIES

Alternative titles; symbols

ARTHROCUTANEOUVEAL GRANULOMATOSIS;
JABS SYNDROME
BLAU SYNDROME
GRANULOMATOUS INFLAMMATORY ARTHRITIS, DERMATITIS, AND UVEITIS, FAMILIAL
GRANULOMATOSIS, FAMILIAL, BLAU TYPE

____________________________________________________________________________________

Blau syndrome

• Jabs et al. (1985) presumably 'new' syndrome: granulomatous synovitis: symmetric, boggy polysynovitis of the hands and wrists, resulting boutonniere deformities. Hand radiographs showed no erosions or joint destruction despite > 20 years of disease

• Nongranulomatous uveitis and cranial neuropathies (corticosteroid-responsive hearing loss and sixth nerve palsy).

• Blau (1985) found granulomatous arthritis, iritis, and skin involvement in 11 members of 4 generations of a family.

____________________________________________________________________________________

Yeon HB, Lindor NM, Seidman JG, Seidman CE.

Am J Hum Genet 2000 Apr;66(4):1443-8

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q.

Department of Medicine and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, USA.

Yeon HB, Lindor NM, Seidman JG, Seidman CE.

Mapping of a disease locus for familial pyoderma gangrenosum-acne-arthritis to the long arm of chromosome 15 (maximum two-point LOD score, 5.83; recombination fraction [straight theta] 0 at locus D15S206).

חזרה לדף הבית

תקציר שיקופיות הרצאה (טבריה 03/01/2003)

Autoimmune hereditary fever

TNF RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS)

•Familial Hibernian Fever (FHF)

•Benign autosomal dominant familial periodic fever (FPF)

•Autosomal dominant periodic fever with amyloidosis

TRAPS

• a dominantly inherited disorder

• Irish or Scottish ancestry

• episodic attacks of fever

• severe localized inflammation

• systemic amyloidosis

TRAPS

• episodes much longer than in FMF, lasting longer >1 week sometimes for 4-6 weeks

• conjunctival inflammation

• periorbital edema

• migratory myalgia and rash

• erysipelas like erythema

• corticosteroids >> effective than colchicines

mutations in TNFRSF1 A on chromosome 12p13

gene encodes the 55 kDa TNF receptor

(p55, TNFR1, CD120a)

TRAPS

14 TNFRSF1 A mutations:

• 7 - missense changes that disrupt conserved extracellular disulfide bonds

• 1- a missense mutation that abolishes a conserved hydrogen bond in CRD1

• 1 is a splicing mutation causing the insertion of 4 amino acids in CRD1,

• and the remainder are missense substitutions of residues closely adjacent to cysteines.

_________________________________________________________________________________________________________________

TRAPS

• Inflammatory from impaired cleavage of TNFRSF1 A ectodomain upon cellular activation

• Normally, cleavage or TNFR has a negative homeostatic effect, (reducing the number of receptors on the cell surface, and creating a pool of potentially antagonistic soluble receptor.)

• Reduced levels of soluble p55 TNF receptor

• Soluble p55 levels in TRAPS patients show a minimal increase during inflammatory episodes.

_________________________________________________________________________________________________________________

A pilot study of anti-TNF therapy in TRAPS:

• Patients have been treated etanercept (Enbrel) (recombinant p75 TNFR:Fc fusion protein) at the standard dosage for adult or juvenile rheumatoid arthritis.

• F/U 2 -10 mo, clinical and laboratory responses have been encouraging

• D L Kastner, I Aksentijevich, J Galon, and J J O'Shea, Arthritis and Rheumatism Branch, NIAMS/NIH, Bethesda.

• Petechiae and Purpura on the Lower Right Leg during a Febrile Attack in a Patient with the Hyper-IgD Syndrome.

• The skin lesions disappeared a week after the end of the attack. The clinical findings in this patient (Patient 30 in the hyper-IgD syndrome

Familial Hibernian fever

• In the year 409 AD Irish tribes of Hibernia liberate Britain from the Romans and settle in Northwest Britain and Wales.

• By 410 AD the kingdom of powys is founded. A major rebuilding of the city of Virconium begins.

• Vortigern assumes control of central and southern Britain. Vortigern offers friendship to the Irish kingdoms of western wales and northwest Britain.

• There is peace in Britain.

HIDS criteria

• CONSTANTLY

• High IgD (100 U/mL) measured at 2 occasions with at least one month apart

HIDS

• 1984, Van der Meer and colleagues (6 patients with periodic fever and a constantly elevated polyclonal IgD

• Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome (called here HIDS)

HIDS

• Nijmegen HIDS registry: 144 cases of this new syndrome

• Most patients stem from (West) European countries

• Clear preponderance for the Netherlands or the north of France

HIDS

• long history of episodic attacks of fever

• The majority has attacks before the end of their first year of life

• Attacks occur every 4-8 weeks

• Last 3-7 days

• Attacks persist throughout life although patients experience a reduction in intensity and frequency of attacks after adolescence.

_________________________________________________________________HIDS: Clinical symptoms

• Lymphadenopathy

• abdominal pain and diarrhoea

• Headache

• hepato/splenomegaly

• arthralgia/ arthritis

• skin lesions

• In some - aphtous mouth or vaginal ulcers.

• In most patients - no apparent symptoms between attacks

HIDS: Laboratory analysis

• Acute phase response with high C-reactive

• Leukocytosis

• Increased TNFa , IL-6 and IFN-g

• Also anti-inflammatory compounds: IL-1ra, sTNFr p55 and sTNFr p75)

• Most typical: serum IgD (> 100 U/mL comparable to 141 mg/l)

• Majority has also elevated serum IgA levels.

HIDS: Treatment

mutations in TNFRSF1 A
on chromosome 12p13

A pilot study of anti-TNF therapy
in TRAPS:

• D L Kastner, I Aksentijevich, J Galon, and J J O'Shea,
Arthritis and Rheumatism Branch, NIAMS/NIH, Bethesda.

**PYOGENIC STERILE ARTHRITIS, PYODERMA GANGRENOSUM, AND ACNE *604416**