A new passenger on the Autoinflammatory Autobus, Line A20 Nataa - - PowerPoint PPT Presentation

A new passenger on the Autoinflammatory Autobus, Line A20

Nataša Toplak 1,2

1Department of Allergology, Rheumatology and Clinical Immunology, University

Children’s Hospital Ljubljana, Slovenia

2Medical faculty, University of Ljubljana, Slovenia

The Israeli Society of Rheumatology, 2019, December 12th, Jerusalem

University Children‘s Hospital, UKC, Ljubljana

Outline of presentation

• A new disease Haplo-insufficiency A20
• Genetics
• Mechanism- the disturbance of ubiquitination
• Other diseases with similar mechanism
• Clinical presentation
• Treatment

A20 Haploinsufficiency

• Haploinsufficiency A20- a newly described AD

autoinflammatory disease

• First described in 2016
• Patients may present with:
• dominantly inherited, early-onset systemic inflammation and

a Behcet-like disease, or a variety of

• autoinflammatory and autoimmune features

Aeshlimann et al. Ann Rheum dis 2018, Aeschlimann&Laxer. Curr Opin Rheumatol 2018.

Zhou et al. Nat gene 2016; Aeshlimann et al. Ann Rheum dis 2018.

Genetics

• Chromosome 6 / Gene TNFAIP3 / protein A20, also called

TNFα Induced Protein 3 (TNF/AIP3) / 790 amino acids

• Gene / 9 exons
• Currently 39 variants (infever data base)

TNFAIP3 (NM_006290.3) sequence variants (A20, AISBL, OTUD7C, TNFA1P2)/ Editor(s): Ivona AKSENTIJEVICH

https://infevers.umai-montpellier.fr/web/

Mechanism

• Protein A20 / TNFα Induced Protein 3 (TNF/AIP3) is NF-κB

regulatory protein

• loss-of-function mutations in TNFAIP3 result in the activation
• f the nuclear factor (NF)-κB pathway

Dysregulation of ubiquitin pathway-

• decreased deubiquitination of NF-κB inhibitor (mutated A20)
• increased degradation of NF-κB inhibitor

Aeshlimann et al. Ann Rheum dis 2018, Aeschlimann&Laxer. Curr Opin Rheumatol 2018.

Mechanism / Ubiquitin

• Ubikvitin- small regulatory protein, which is added to substrat

protein- proces of ubiquitination / post-translational modification

• Ubiqutination affects proteins in several proceses
• Label the protein for degradation in proteasom
• Repair of DNA
• Activation of protein kinases / regulatory role
• Highly dynamic pocess- reversable by deubiqutination

Nassif et al. IUBMB life 2016.

Aeschlimann&Laxer. Curr Opin Rheumatol 2018.

Aeschlimann&Laxer. Curr Opin Rheumatol 2018.

Increased degradation

• f kB inhibitor (IkB)

Activation of a NF-kB pathway

Other diseases / dysregulated ubiquitination

Disease Clinical presentation haploinsufficiency of A20 (HA20) 61 cases / 26 families

a disease phenotype mimicking BD or other more common, multifactorial diseases, particularly those presenting with mucosal inflammation, an early disease onset and a positive FH; AD dis.

OTULIN deficiencies (otulipenia) 4 cases

signs and symptoms usually begin within the first few weeks of life: recurring episodes of fever; diarrhoea; painful, swollen joints; and skin rashes. The skin rashes- due to inflammation

• f the fatty tissue- panniculitis- causes painful red bumps.

Lipodystrophy / Failure to thrive. AR dis.

linear ubiquitin chain assembly complex (LUBAC) 3 cases

chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis- a muscular deficiency that can affect the cardiac muscles in particular. AR dis. Aksentijevich & Zhou. Front Immunol 2017 Yu et al. World Journal of Pediatrics 2019

Clinical presentation

• First described in 2016
• Clinical picture form first 16 patients (13 F) from 7 unrelated families recently

published- 2018

• Manifested in early childhood (range- first week of life- 29 y of age)
• The main clinical symptoms:
• Recurrent oral, genital and/or GIT ulcers 16/16
• Musculoskeletal complaints 9/16
• GIT complaints 9/16
• Cutaneous lesions 8/16
• Episodic fever 7/16
• Recurrent infections 7/16
• ANA pos in 4/10, anti-DNA pos 2/5
• Biopsy- nonspecific chronic inflammation

Zhou et al. Nat gene 2016; Aeshliman et al. Ann Rheum dis 2018.

Clinical presentation

• Review of published cases – 2019
• first described patients Caucasian, 29 Japanese patients reported later
• 61 patients from 26 families, 62% female
• Highly variabile clinical manifestations- patients had been diagnosed with Behcet’s

dis, RA, RF, JIA, PFAPA, Crohns disease, SLE and even adult-onset Stills’ disease

• Initial symptoms occurred early, at a mean age of 14 years (5 d to 29 y), 73% of

patients (n = 45) experienced their first symptoms before 10 years of age

• 64% of patients reported oral and/or genital ulcers
• nly 5 patients with ocular manifestations (typical for Behcet!)
• 44% recurrent fever
• 44% GIT complaint
• 43% skin changes
• 33% musculosceletal complaints

Yu et al. World Journal of Pediatrics 2019

Treatment

• Nearly half of the patients responded to cholchicine
• GCS, mesalazine, cyclosporine, Mtx, azatioprine
• Anakinra, rituximab, tocilizumab, infliximab

Zhou et al. Nat gene 2016; Aeshlimann et al. Ann Rheum dis 2018. Yu et al. World Journal of Pediatrics 2019

Conclusion

• Fever is the most common sign of the most common diseases
• Recurrent/ periodic fever could be a sign of a rare disease
• Concept of autoinflammation is changing / new mechanisms…
• AI are rare, even more rare are diseases of disturbed ubiquitination
• Spectrum of clinical presentation
• Importance of genetic diagnosis

when you run out of ideas for diagnosis- think about AUTOINFLAMMATION New bus line A 20