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Aberrant activation of the innate immune system leads to systemic and organ specific inflammation in the absence of pathogens or autoimmunity. This system is genetically encoded and mutations stimulating those pathways or impacting cellular homeostasis cause auto-inflammatory diseases (AIDs). Monogenic and complex (for which other genetic factors and the environment play a role) AIDs share phenotypic features and physiopathologic mechanisms. Only about 15-40% of patients suspected of monogenic AIDs will receive a specific molecular diagnosis. The Australian Autoinflammatory Diseases RegistrY (AADRY) gathers undiagnosed patients and provides whole exome sequencing to patients and families in search of new mechanisms explaining their diseases. In this thesis, we functionally validate the polymorphism E148Q in pyrin showing its functional effect in vitro. In patients with familial Mediterranean fever (FMF), it potentiates pathogenic mutations in cis and therefore could have a role in disease presentation and severity. I also assess a new mutation in CDC42 found in a family with members presenting an AID over three generation. A phenotypic and mechanistic hypothesis based approach shows that this variant promotes the pyrin inflammasome. Finally, I investigated somatic mosaicism which could explain around 15-20% of undiagnosed AID cases. I developed a cost effective ultra deep amplicon sequencing of the third exon of NLRP3, a part of the gene in which somatic mosaicism is particularly well described. These three projects intend to broaden our knowledge about the mechanism of autoinflammation.

Purpose NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis. Methods Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1 beta/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal. Results A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1 beta therapy partially controlled symptoms. While on treatment, serum IL-1 beta and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1 beta/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305. Conclusion NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.

SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Objectives: Fatigue is a significant issue in psoriatic arthritis. The objective was to assess the effect of biological disease modifying antirheumatic drugs and apremilast on fatigue in psoriatic arthritis randomised controlled trials and to compare this effect with the effect in the same trials, on pain, through a systematic literature review and meta-analysis. Methods: A systematic literature review was performed up to January 2017 in PubMed, Embase and Cochrane databases. All randomized controlled trials in psoriatic arthritis of biological disease modifying antirheumatic drugs or apremilast, assessing fatigue (whatever the score used), were included. Data were collected by 2 assessors regarding levels of fatigue and pain at baseline and at the time point closest to 24 weeks after the treatment introduction. Pooled standardized mean differences were calculated using RevMan. Results: After screening 295 publications, 7 randomised controlled trials were analysed: they pertained to adalimumab (n = 2), certolizumab pegol (n = 1), secukinumab (n = 2), ustekinumab (n = 1) and apremilast (n = 1), compared to placebo. The studies included 2341 patients: weighted mean ± standard deviation age: 48.6 ± 1.3 years, disease duration: 7.7 ± 1.6 years, 51.6% were females. Fatigue levels were high at baseline (Functional Assessment of Chronic Illness Therapy score: 28.7 ± 2.4). The pooled standardized mean difference was, for fatigue −0.44 (95% confidence interval: −0.54, −0.35) and for pain, −0.62 (−0.73, −0.52). Conclusions: Biological disease modifying antirheumatic drugs and apremilast had a small effect on fatigue at 24 weeks in psoriatic arthritis randomized controlled trials and a higher effect on pain. These results are important to take into account in shared decision-making., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: le.j, FLWIN, info:eu-repo/semantics/published

"Spondyloarthritis" consists of a group of several diseases sharing clinical, radiological and genetic similarities. Ankylosing spondylitis is the main representative of this group and is characterized by a predominant axial involvement. The presence of radiographic sacroiliitis is essential for the diagnosis of ankylosing spondylitis according to the modified New York criteria. Because the occurence of radiographic sacroiliitis takes 8 to 11 years, the diagnosis of spondyloarthritis is often delayed. Magnetic resonance imaging can depict sacroiliac joint inflammation before the appearance of radiographic damage thereby defining the concept of "non-radiographic axial spondylo-arthritis". This entity was defined by the axial spondyloarthritis classification criteria published by the Assessment of SpondyloArthritis international Society (ASAS). Some factors, such as elevated levels of C-reactive protein at baseline, have been identified as predictors of radiographic sacroiliitis progression, leading to a definite diagnosis of ankylosing spondylitis. These two entities show similar clinical expression (clinical features and activity levels), suggesting continuity between the two diseases. Non-radiographic forms most often affect women and patients with recent symptoms, and are therefore considered as a pre-radiographic status. If the use of magnetic resonance imaging is necessary for the identification of non-radiographic axial spondyloarthritis according to the ASAS criteria, the presumptive diagnosis is mainly based on complaints of inflammatory back pain. The presence of other typical clinical features, such as HLA B27 positivity and/or radiographic sacroiliitis increases the diagnostic probability and indicates the need for referral to a specialist., SCOPUS: ar.j, info:eu-repo/semantics/published