Current and New Candidate Genes in Childhood Recurrent Immune-Mediated Pericarditis

1. Current and New Candidate Genes in Childhood Recurrent Immune-Mediated Pericarditis Ruxanda Rusu, MSc Candidate, Dept. of Biochemistry, Western University Northern Health Research Conference, Thunder Bay, Oct. 14, 2017

2. Faculty/Presenter DisclosureSlide Ruxanda Rusu, MSc Candidate, Western University Relationships with commercial interests: NONE Potential for conflict(s) of interest: NONE

3. Outline • Characteristics of secondary and idiopathic chronic recurrent pericarditis in children • Two cases • Current genetic tests • New candidate genes • Treatment options

4. Pericarditis - Causes • Pericarditis: inflammation of the pericardium • Causes of pericarditis • Infections (viral, bacterial – TB etc) • Chronic inflammatory diseases - SLE, IBD, FMF, scleroderma etc • Metabolic diseases ( thyroid, uremia etc) • Cancer • Drugs/toxins • Radiation • Trauma • Idiopathicpericarditis is a diagnostic of exclusion http://www.mayoclinic.org/diseases-conditions/pericarditis/home/ovc-20324983

5. Pericarditis - Types • Recurrent pericarditis(RP): ≥ 2 episode per year of pericarditis ± other extra-cardiac features (pleuritis, abdominal pain, arthralgias or arthritis); diagnosis based on the following ≥ 2 of the 4 criteria: • Pericardial chest pain • Pericardial rubs • Pericardial effusion • ECG: widespread ST-elevation or PR depression • Diagnosis of pericarditis is supported by: • Laboratory features (elevation of inflammatory markers, etc.) • CXR, cardiac echography • Chronic pericarditis (pericarditis lasting ≥ 3 months)

6. Incidence of Pericarditis in Chronic Inflammatory Disease • SLE: ≤ 54% of SLE patients have pericardial abnormalities (Doria et al, 2005) • Familial Mediterranean Fever • Pericarditis is rare • Pleural attacks in 45% of patients (Shohat et al, 2011) • Systemic Sclerosis • 7-20% of patients have symptoms of pericarditis • Necropsy studies revealed pericardial involvement in 33-72% of patients (McWhorter et al, 1974) • Rheumatoid arthritis • 2-10% of patients have manifestations of pericarditis • Incidence based on autopsy: 30% (Kirk et al, 1969)

7. CASE 1 • 15-yo Caucasian boy presented with chest pain, SOB, fever, dry cough, vomiting at Thunder Bay Regional Health Sciences Centre • ESR & CRP: highly elevated • Infection work-up negative • CXR, Cardiac echography: severe pericarditis and pleuritis • Started on Prednisone 50 mg daily; pericarditis re-occured when prednisone was weaned to 30 mg daily • Referred to a pediatric rheumatologist in London (Dr. Ardelean) • Immune work-up negative • Molecular genetic testing for 17 auto-inflammatory genes: negative • Diagnosed with idiopathic recurrent pericarditis • Treatment • Prednisone weaned slowly over 10 months • No response to Colchicine 1.8 mg daily x 8 months • Excellent response to IL1 receptor antagonist Anakinra given at 100 mg sc daily • Follow-up: 22 months after onset he is symptom-free, on Anakinra every 2nd day

8. CASE 2 • 15-yo Arabic boy admitted in Windsor with high fever, chest pain, SOB, sore throat, mouth ulcers, arthralgias • ESR & CRP: highly elevated • Infection work-up negative • CXR, Cardiac echography: severe pericarditis and pleuritis • Treated with Advil until discharge (10 days after admission); discharged symptom-free • Three months later – 2nd similar episode • Referred by his pediatrician to pediatric rheumatologist (Dr. Ardelean) • Immune work-up negative • Genetic testing: MEFV c.2177T>C (p.Val726Ala) • Diagnosed with Familial Mediterranean Fever • Treatment: Colchicine 0.9 mg daily and Naproxen 375 mg 2x/day with Prevacid • Follow-up: 10 months after diagnosis, he is symptom-free, on Colchicine and Naproxen

9. Current Gene Panels for Autoinflammatory Diseases & Periodic Fever Syndromes

10. Mechanism of Action NLRP3 PYCARD NOD2 CASP4/5 CASP1 MEFV RIPK2 NLRP1 XIAP, BIRC2/3, LUBAC FADD Immune response Caspase-8 TNFRSF1A http://www.genecards.org

11. Potential New Candidate Genes for Pericarditis • Methods • Literature search for adult and pediatric pericarditis cases (1960-2017) • Exclusion: cancer, trauma, medication-induced pericarditis, metabolic cases • Potential candidate genes • Associated with SLE & pericarditis • LEP/LEPR (Li et al, 2017) • STAT4 (Ciccacciet al, 2014) • MIR1279 (Ciccacciet al, 2017) • Associated with CACP • PRG4 (Albuhairanet al, 2013), (CiulliniMannuritaet al, 2014), (Peters et al, 2016)

12. Conclusions • Chronic cases should be referred to pediatric rheumatologist • Management is multidisciplinary • Pediatrician, pediatric cardiologist and rheumatologist, allied health care professional • Colchicine—and often naproxen—is first line of treatment • Genetic testing available for several periodic fever and autoinflammatory diseases • New potential candidate genes may be considered

13. Acknowledgements Ranjit Baboolal, MD, MRCP, FRCPC Daniela Ardelean, MD, PhD, FRCPC Amjar Zaher, MD, FRCPC Robert Hegele, MD, FRCPC Natasha Lepore, MD Candidate 2018 University of Cork

14. Thank you