AUTOINFLAMMATORY DISORDERS

PERIODIC FEVER SYNDROMES

GINO TANN

Figure 5 Overview of the pattern-recognition receptor system of phagocytes, including the TLR
family

Dale, D. C. et al. Blood 2008;112:935-945

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Temporal Patterns of Fever and Associated Clinical Findings in a Patient with Familial
Mediterranean Fever (Panel A), a Patient with the Hyper-IgD Syndrome (Panel B), and a Patient
with the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (Panel C)

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

Distinctive Features of Familial Mediterranean Fever, the Hyper-IgD Syndrome, and the Tumor
Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

Contrast-enhanced chest CT scan showing a left-sided pleural effusion.

Katsenos S et al. Chest 2008;133:999-1001

2008 by American College of Chest Physicians

Tel-Hashomer Criteria for Diagnosis of FMF

Major criteria
Recurrent febrile episodes accompanied by serositis
or synovitis
Amyloid A amyloidosis without a predisposing cause
Response to continuous colchicine prophylaxis
Minor criteria
Recurrent febrile episodes
Erysipelas-like erythema
FMF in a first-degree relative
Definite diagnosis
Two major or one major and two minor criteria
Probable diagnosis
One major and one minor criteria

Structure of the Gene for Familial Mediterranean Fever (MEFV )

PYRIN

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

MEFV (MEditerranean FeVer)

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

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

CEREBELLAR ATROPHY HYPER IgD syndrome

Fig 1. MRI of patient 3 at the age of 6 years, showing the severe cerebellar atrophy

Prietsch, V. et al. Pediatrics 2003;111:258-261

Copyright 2003 American Academy of Pediatrics

Metabolism of Mevalonate and Biosynthesis of Cholesterol in Mammalian Cells

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

Hypothesized Pathogenesis of the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic

Syndrome

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

Fig. 1. Synthesis and secretion of IL-1beta and formation of the cryopyrin inflammasome

Simon, A. et al. Am J Physiol Regul Integr Comp Physiol 292: R86-R98 2007;
doi:10.1152/ajpregu.00504.2006

Copyright 2007 American Physiological Society

The Cryopyrin Inflammasome

Drenth J and van der Meer J. N Engl J Med 2006;355:730-732

NLRs and relevant proteins

Journal of Leukocyte Biology. 2008;83:13-30

PYRIN domain and related proteins

Stehlik, Reed Journal of Experimental Medicine

2008:200:551-558
2008 Stehlik et.al.

Potential molecular mechanisms underlying PFSs

Stehlik, Reed Journal of Experimental Medicine

2009:200:551-558
2009 Stehlik et.al.

Fig. 2. Two current hypotheses on the mechanism of pyrin action

Simon, A. et al. Am J Physiol Regul Integr Comp Physiol 292: R86-R98 2007;
doi:10.1152/ajpregu.00504.2006
Copyright 2007 American Physiological Society

Figure 1. Steps in the processing and secretion of IL-1

LL37

Dinarello Journal of Experimental Medicine 2008:201:13551359

2008 Dinarello

Figure 2. Systemic manifestations of IL-1

Dinarello Journal of Experimental Medicine 2008:201:13551359

2008 Dinarello

Fig. 1. Pathway of fever development in response to infection, inflammation, or trauma

Leon, L. R. J Appl Physiol 92: 2648-2655 2002;

doi:10.1152/japplphysiol.01005.2001
Copyright 2002 American Physiological Society

HEREDITARY PERIODIC-FEVER SYNDROMES

Hereditary Systemic Autoinflammatory Disorde
Familial cold autoinflammatory syndrome
Muckle-Wells syndrome
Episodes of urticarial rash and systemic inflammation
No bony overgrowth
No CNS abnormalities
Mutations in CIAS1 gene encodes cryopyrin (NALP3)
CIAS1-associated diseases

FCAS

MWS

Serial Measurements of Plasma Concentrations of Serum Amyloid A Protein in Two Patients

with the Muckle -Wells Syndrome

Hawkins P et al. N Engl J Med 2003;348:2583-2584

Neonatal-onset multisystem inflammatory disease (NOMID)

Chronic infantile neurologic, cutaneous, articular syndrome
(CINCA)
Urticaria-like rash in 1st 6 weeks of life
Bony overgrowth in knees
Chronic aseptic meningitis
Increased intracranial pressure
Cerebral atrophy
Ventriculomegaly
Chronic papilledema
Optic nerve atrophy with loss of vision
Mental retardation
Seizures
Sensorineural hearing loss
Short stature
Hepatosplenomegaly
Leukocytosis
Increased serum amyloid A, CRP and ESR
20 % mortality before adulthood
Systemic amyloidosis in 25 % cases
Goldbach-Mansky R et al. N Engl J Med 2006, 355: 583-592

Inflammatory Organ Manifestations in Neonatal-Onset Multisystem Inflammatory Disease

before (Panels A, C, E, and G) and after (Panels B, D, F, and H) Treatment with Anakinra

Goldbach-Mansky R et al. N Engl J Med 2006;355:581-592

Glomerular Amyloid Deposition in a Renal-Biopsy Specimen (Congo Red, x400)

Hull K et al. N Engl J Med 2002;346:1415-1416

Mutations in CIAS1

Blood, 1 April 2004, Vol. 103, No. 7, pp. 2809-2815

TABLE 1. Criteria for the diagnosis of adult onset Still's disease

(Yamaguchi et al. 1992 [28]).
Five or more criteria (including two major) required for diagnosis

Major criteria

Minor
criteria

Fever >39C

Sore throat

Arthralgias

Lymphadenopathy or splenomegaly

Still's rash

Hepatic dysfunction

Neutrophilic leucocytosis

Negative RF and ANA

ANA, antinuclear antibody; RF, rheumatoid factor.

Rheumatology 2002; 41: 216-222

NON EROSIVE CARPAL FUSION

Rheumatology 2002; 41: 216-222

TABLE 2. Positive/abnormal tests

VARIABLE

Value

Erythrocyte sedimentation rate (mm/h)

120

(020)

C-reactive protein (mg/dl)

21.6

00.8

Haemoglobin (g/dl)

7.9

1215

White blood cell count (x10/mm3)

25.6

3.410

Aspartate transaminase (U/L)

88

1132

Alanine transaminase (U/L)

65

530

Lactate dehydrogenase (U/L)

317

110205

Ferritin (ng/ml)

9846

12250

Rheumatology 2002; 41: 216-

TABLE 3. Negative/normal tests

Antinuclear antibodies

Angiotensin converting enzyme concentration

Anti-double-stranded DNA antibodies

Anti-cardiolipin antibody

Anti-Smith

Familial Mediterranean fever genetic test

Anti-Ro
Anti-La

Lyme antibody

Anti-RNP

VDRL test

C3

Purified protein derivative

C4

Cytomegalovirus (buffy coat, urine)

Rheumatoid factor
ANCA
Serum protein electrophoresis

Human immunodeficiency virus antibody

Cultures: blood, urine, cerebrospinal fluid, bone marrow, broncho-alveolar lavag

Creatine kinase

Rheumatology 2002; 41: 216-222

TABLE 4. Pathology
reports
Bone marrow

Marked granulocytic hyperplasia; no dysplasia

Liver

Patchy periportal inflammation; moderate steatosis

Cervical

Non-specific reactive histology

lymph node

Lacrimal gland

Normal histology with no lymphoid infiltrate or

evidence of epithelial malignancy

Spleen

Follicular hyperplasia; negative for lymphoma

Small intestine

Mild villous atrophy; Congo Red stain negative for amyloid

Rheumatology 2002; 41: 216-222

Acute rash at the onset of SJIA Expression of S100A9 by keratinocytes

Rheumatology 2008 47(2):121-125

Figure 3. Values of (a) temperature; (b) active joint count; (c) white blood cells (WBC); (d)
hemoglobin; (e) platelet count; and (f) ESR in 9 SoJIA patients

Pascual et al. Journal of Experimental Medicine

2009:201:1479-1486
2009 Pascual et.al.

SWEETS SYNDROME ( Acute Febrile Neutrophilic Dermatosis)

Moderate to high fever

Pink eye (conjunctivitis) or sore eyes
Tiredness
Aching joints and headache
Mouth ulcers

PAPA syndrome
Syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne

proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1),

Rheumatology 2005 44(3):406-408

also known as CD2-binding protein 1

PYODERMA GANGRENOSUM

Ecthyma-like

Peristomal-UC

Post-surgical

Severe

Ulceration Resembling Pyoderma Gangrenosum but Due to Antiphospholipid-Antibody

Syndrome

Weenig R et al. N Engl J Med 2002;347:1412-1418

DD: PYODERMA GANGRENOSUM

Frequency of Diagnostic Findings on Initial or Repeated Biopsy

Weenig R et al. N Engl J Med 2002;347:1412-1418

The Actions of Interleukin-1 (IL-1) and Interleukin-1-Receptor Antagonist (IL-1Ra)

Dinarello C. N Engl J Med 2000;343:732-734

Inflammatory Skin and Bone Manifestations in Patients with Deficiency of Interleukin-1Receptor Antagonist

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437

Mutations in the IL1RN Gene Encoding Interleukin-1-Receptor Antagonist and a Genomic

Deletion in the Study Patients

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437

Functional Consequences of Deficiency of Interleukin-1-Receptor Antagonist

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437

Clinical and Laboratory Response of Patients with Deficiency of Interleukin-1-Receptor

Antagonist to Treatment with Anakinra

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437

THANK YOU

GT05122009