auto-inflammatory syndromes – questions and answers...auto-inflammatory syndromes – questions...

Auto-inflammatory Syndromes – Questions and Answers

Dr. med. Bruno Strebel

Auto-inflammatory Syndromes – Questions and answers 2

Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital

Question 1 Definition of autoinflammatory syndromes in general?



Question 1 Definition of autoinflammatory syndromes in general?

Mutations of genes coding for proteins responsible for the regulation of the inflammatory response



Question 2 Clinical characterization of autoinflammatory syndromes in general?



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



Question 3 Which is the most frequent among hereditary recurrent inflammatory disorders?



Question 3 Which is the most frequent among hereditary recurrent inflammatory disorders?

Familial Mediterranean fever (FMF)



Question 4 Presentation of FMF (who, how)?



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)



Question 5 Mutation in FMF (gene, mechanism)?



Question 5 Mutation in FMF (gene, mechanism)? Recessive, short arm of chromosome 16 (gene: MEFV for

MEditerranean FeVer ) responsible protein: pyrin/marenostrin

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Question 6 Treatment of FMF?




Colchicine, 1 mg/day



Question 7 Presentation of periodic fever associated with mevalonate kinase deficiency (MKD, hyper IgD-Syndrome)?



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



Question 8 Mutation in MKD (gene, mechanism)?



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

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Question 9 Treatment of MKD?



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



Question 10 Presentation TNF-receptor associated autoinflammatory syndrome (TRAPS)?



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



Question 11 Mutation in TRAPS (gene, mechanism)?



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



Question 12 Treatment of TRAPS?



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



Question 13 Which are the 3 subgroups of Cryopyrin-associated periodic syndromes (CAPS)?



Question 13 Which are the 3 subgroups of Cryopyrin-associated periodic syndromes (CAPS)?

Familial cold autoinflammatory syndrome (FCAS)

Muckle-Wells syndrome (MWS)

Chronic infantile neurological cutaneous and articular syndrome (CINCA)



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)



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, AA-amyloidosis

Chronic infantile neurological cutaneous and articular syndrome (CINCA) - Most severe phenotype with urticaria-like rash during first weeks of life



Question 15 Mutation in CAPS (gene, mechanism)?



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 +++

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Question 16 Treatment of Cryopyrin-associated periodic syndromes (CAPS)?



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)



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



Question 18 Presentation and pathophysiology of Blau syndrome (familial juvenile systemic granulomatosis)?



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



Question 19 Presentation and pathophysiology of PAPA syndrome?



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



Question 20 Presentation and pathophysiology of Majeed’s syndrome/chronic recurrent multifocal osteomyelitis (CRMO)?



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...auto-inflammatory syndromes – questions...

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