Auto-inflammatory Syndromes Questions and Answers. Dr. med. Bruno Strebel

Transcription

1 Auto-inflammatory Syndromes Questions and Answers Dr. med. Bruno Strebel

2 Question 1 Definition of autoinflammatory syndromes in general? Auto-inflammatory Syndromes Questions and answers 2

3 Question 1 Definition of autoinflammatory syndromes in general? Mutations of genes coding for proteins responsible for the regulation of the inflammatory response Auto-inflammatory Syndromes Questions and answers 3

4 Question 2 Clinical characterization of autoinflammatory syndromes in general? Auto-inflammatory Syndromes Questions and answers 4

5 Question 2 Clinical characterization of autoinflammatory syndromes in general? Flares of systemic inflammation: - sudden fever episodes associated with elevation of acute phase reactants - rash, serositis, lymphadenopathy and arthritis Symptom-free intervals are characterised by complete wellbeing Auto-inflammatory Syndromes Questions and answers 5

6 Question 3 Which is the most frequent among hereditary recurrent inflammatory disorders? Auto-inflammatory Syndromes Questions and answers 6

7 Question 3 Which is the most frequent among hereditary recurrent inflammatory disorders? Familial Mediterranean fever (FMF) Auto-inflammatory Syndromes Questions and answers 7

8 Question 4 Presentation of FMF (who, how)? Auto-inflammatory Syndromes Questions and answers 8

9 Question 4 Presentation of FMF (who, how)? Arabs, Armenians, Turks, non-ashkenazi Jews (north-african Jews), Druzes, Lebanese, Italians, and Greeks Clinical picture: ⅔ disease onset before 5 years with - fever attacks (few hours to 3-4 days) - serosal inflammation (peritonitis 90%, pleuritis 40%) severe abdominal pain and chest pain - arthritis 50% - erysipela-like erythema of the lower limbs Long term sequelae if untreated: secondary amyloid nephropathy (AA) Auto-inflammatory Syndromes Questions and answers 9

10 Question 5 Mutation in FMF (gene, mechanism)? Auto-inflammatory Syndromes Questions and answers 10

11 Question 5 Mutation in FMF (gene, mechanism)? Recessive, short arm of chromosome 16 (gene: MEFV for MEditerranean FeVer ) responsible protein: pyrin/marenostrin Auto-inflammatory Syndromes Questions and answers 11

12 Question 6 Treatment of FMF? Auto-inflammatory Syndromes Questions and answers 12

13 Question 6 Treatment of FMF? Colchicine, 1 mg/day Auto-inflammatory Syndromes Questions and answers 13

14 Question 6 Treatment of FMF? Colchicine, 1 mg/day Auto-inflammatory Syndromes Questions and answers 14

15 Question 7 Presentation of periodic fever associated with mevalonate kinase deficiency (MKD, hyper IgD-Syndrome)? Auto-inflammatory Syndromes Questions and answers 15

16 Question 7 Presentation of MKD, hyper IgD- Syndrome)? Dutch ancestry, mediterranean basin, and Asia Clinical picture: almost all patients onset within first decade of life - Fever with abrupt onset (last 4-6 days) - Severe abdominal pain, accompanied by vomiting and/or diarrhoea - Cervical lymphadenopathy and splenomegaly is common - Mucocutaneous manifestations: erythematous macules, urticaria-like lesions and, less commonly, oral aphthous lesions - Articular involvement occurs in the majority of patients Long term sequelae: mostly without amyloidosis, tend to become less pronounced with time Auto-inflammatory Syndromes Questions and answers 16

17 Question 8 Mutation in MKD (gene, mechanism)? Auto-inflammatory Syndromes Questions and answers 17

18 Question 8 Mutation in MKD (gene, mechanism)? Recessive, chromosome 12q24, mutations in the mevalonate kinase (MVK) enzyme in isoprenoid synthesis shortage of nonsterol isoprenoid end products Auto-inflammatory Syndromes Questions and answers 18

19 Question 9 Treatment of MKD? Auto-inflammatory Syndromes Questions and answers 19

20 Question 9 Treatment of MKD? Prednisone 1 mg/kg/day (single dose or short course of 3-5 days) Recently, IL-1 receptor antagonist (anakinra) was found to promising Auto-inflammatory Syndromes Questions and answers 20

21 Question 10 Presentation TNF-receptor associated autoinflammatory syndrome (TRAPS)? Auto-inflammatory Syndromes Questions and answers 21

22 Question 10 Presentation TNF-receptor associated autoinflammatory syndrome (TRAPS)? Initially described in scandinavian families, allthough also present in Black Americans, Japanese, and patients with mediterranean ancestry Clinical Picture: attacks last longer than five days and up to three weeks - Abdominal pain can simulate a surgical event - wide spectrum of skin rashes (urticaria-like, plaques and patches) with a migratory course from the root to the extremity of the limbs - painful myalgias, the other most distinctive manifestation Long term sequelae: secondary amyloidosis possible, except in R92Q mutation, which shows a milder course of disease Auto-inflammatory Syndromes Questions and answers 22

23 Question 11 Mutation in TRAPS (gene, mechanism)? Auto-inflammatory Syndromes Questions and answers 23

24 Question 11 Mutation in TRAPS (gene, mechanism)? Dominant, mutations in the p55 TNF receptor (or TNFR1A), encoded by the TNF super family receptor 1A gene (TNFRSF1A). Missense mutations in the cysteine rich domains (CRD), CRD1, CRD2, or CRD3 of the ectodomain of the mature TNFR1 Reduced shedding of TNFR reduced pool of soluble receptors which may scavenge circulating TNF reduced clearance of TNF Auto-inflammatory Syndromes Questions and answers 24

25 Question 12 Treatment of TRAPS? Auto-inflammatory Syndromes Questions and answers 25

26 Question 12 Treatment of TRAPS? When given at onset of attack, corticosteroids can attenuate its length and severity. Most severe forms of TRAPS require daily use of corticosteroids Colchicine does not seem to prevent recurrences TNF inhibitors seem designed as treatment of TRAPS: - Etanercept, a TNFRSF1B receptor-immunoglobulin fusion molecule, mimics the effect of the normal soluble TNF receptor and thus compensates its deficit in TRAPS - Exacerbation of the inflammatory signs observed after administration of anti-tnf antibody (infliximab), thus this drug should not be used Anti-IL-1 inhibitors (anakinra) can have a better effect Auto-inflammatory Syndromes Questions and answers 26

27 Question 13 Which are the 3 subgroups of Cryopyrinassociated periodic syndromes (CAPS)? Auto-inflammatory Syndromes Questions and answers 27

28 Question 13 Which are the 3 subgroups of Cryopyrinassociated periodic syndromes (CAPS)? Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome (MWS) Chronic infantile neurological cutaneous and articular syndrome (CINCA) Auto-inflammatory Syndromes Questions and answers 28

29 Question 14 Presentation of Cryopyrin-associated periodic syndromes (CAPS)? Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome (MWS) Chronic infantile neurological cutaneous and articular syndrome (CINCA) Auto-inflammatory Syndromes Questions and answers 29

30 Question 14 Presentation of Cryopyrin-associated periodic syndromes (CAPS)? Familial cold autoinflammatory syndrome (FCAS) - urticarial rash and fever spikes of short duration (<24 h) induced by cold exposure, Arthralgia and conjunctivitis Muckle-Wells syndrome (MWS) - Urticaria and fever develop in early infancy, not triggered by cold exposure. Acute phase reactants are elevated - Long term sequelae: Neurosensorial deafness, polyarthritis, AAamyloidosis Chronic infantile neurological cutaneous and articular syndrome (CINCA) - Most severe phenotype with urticaria-like rash during first weeks of life Auto-inflammatory Syndromes Questions and answers 30

31 Question 15 Mutation in CAPS (gene, mechanism)? Auto-inflammatory Syndromes Questions and answers 31

32 Question 15 Mutation in MKD (gene, mechanism)? Dominant, gain of function mutation of NLRP3 (NOD-like receptor 3, syn. cold-induced autoinflammatory syndrome 1, CIAS1) cryopyrin Auto-inflammatory Syndromes Questions and answers 32

33 Question 16 Treatment of Cryopyrin-associated periodic syndromes (CAPS)? Auto-inflammatory Syndromes Questions and answers 33

34 Question 16 Treatment of Cryopyrin-associated periodic syndromes (CAPS)? Pivotal role of massive secretion of IL-1β suggested anti-il-1-treatment Recombinant IL-1 receptor antagonist anakinra at a starting dosage of 1 mg/kg per day s.c. rapid decrease in acute phase reactants with complete normalisation in the majority of patients. Same excellent results observed using other IL-1 blockers such as IL-1 Trap (rilonacept) and anti-il-1 monoclonal antibodies (canakinumab) Auto-inflammatory Syndromes Questions and answers 34

35 Question 17 Presentation of Periodic fever syndrome and mutations in NLRP12? Auto-inflammatory Syndromes Questions and answers 35

36 Question 17 Presentation of Periodic fever syndrome and mutations in NLRP12? Recurrent fever Cold sensitivity Neuronal hearing loss Aphthous ulcers Lymphadenopathy Abdominal pain Acute phase response Long term course mostly benign Auto-inflammatory Syndromes Questions and answers 36

37 Question 17 Presentation of Periodic fever syndrome and mutations in NLRP12? Recurrent fever Cold sensitivity Neuronal hearing loss Aphthous ulcers Lymphadenopathy Abdominal pain Acute phase response Long term course mostly benign Auto-inflammatory Syndromes Questions and answers 37

38 Question 18 Presentation and pathophysiology of Blau syndrome (familial juvenile systemic granulomatosis)? Auto-inflammatory Syndromes Questions and answers 38

39 Question 18 Presentation and pathophysiology of Blau syndrome (familial juvenile systemic granulomatosis)? Noncaseating granulomatous inflammation - Triad of arthritis, dermatitis, and uveitis Associated with mutations of the NACHT domain of the gene CARD15 (or NOD2) of note is that mutations in this same gene have been associated with Crohn s disease Auto-inflammatory Syndromes Questions and answers 39

40 Question 19 Presentation and pathophysiology of PAPA syndrome? Auto-inflammatory Syndromes Questions and answers 40

41 Question 19 Presentation and pathophysiology of PAPA syndrome? Pyogenic sterile Arthritis Pyoderma gangrenosum Acne = PAPA Long term sequelae: synovial and cartilage destruction Pathophysiology: mis-sense mutations within the CD2BP1 gene, that binds pyrin lower pyrin levels see FMF cascade Auto-inflammatory Syndromes Questions and answers 41

42 Question 20 Presentation and pathophysiology of Majeed s syndrome/chronic recurrent multifocal osteomyelitis (CRMO)? Auto-inflammatory Syndromes Questions and answers 42

43 Question 20 Presentation and pathophysiology of Majeed s syndrome/chronic recurrent multifocal osteomyelitis (CRMO)? Congenital dyserythropoietic anaemia with microcytosis Inflammatory dermatosis (vary from Sweet syndrome to chronic pustulosis) Recurrent fever episodes Growth failure Auto-inflammatory Syndromes Questions and answers 43