Abstract: The Interleukin-1 (IL-1) mediated systemic autoinflammatory diseases (SAIDs), including the cryopyrin-associated periodic syndromes (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA) belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, recently-approved treatments targeting the pro-inflammatory cytokine IL-1 have been life-changing and have significantly improved patient outcomes. Objectives We aimed to establish evidence-based recommendations on diagnosis, treatment, and monitoring to standardize the management of these patients. Methods A multinational, multidisciplinary task force consisting of physician experts including rheumatologists, patients or caregivers, and allied health care professionals was established. Evidence synthesis including systematic literature review and expert consensus (Delphi) via surveys were conducted. Consensus methodology was utilized to formulate and vote on statements to guide optimal patient care. Results The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and 9 focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported therapies of CAPS, TRAPS, MKD, and DIRA. Conclusion The 2021 EULAR/ACR points to consider provide state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment, and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and inform the various stakeholders about optimized patient care to improve disease outcomes. References [1]Masters SL, Simon A, Aksentijevich I, et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol 2009;27:621-68. Disclosure of Interests micol romano: None declared, Zehra Serap Arici: None declared, David Piskin: None declared, Sara Alehashemi: None declared, Daniel Aletaha Speakers bureau: Lilly, Merck, Pfizer, Roche, Sandoz, Consultant of: Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Grant/research support from: Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi, Karyl Barron: None declared, Susa Benseler: None declared, Roberta Berard Consultant of: Sandoz and Roche, Lori Broderick Grant/research support from: Novartis and Regeneron, Fatma Dedeoglu Consultant of: Novartis, Michelle Diebold: None declared, Karen Durrant: None declared, Polly Ferguson Consultant of: Novartis, Grant/research support from: NIH, CARRA, Inc, Dirk Foell Speakers bureau: Novartis, Peer Voice and SoBi, Consultant of: Boehringer Ingelheim, Chugai-Roche, Merck, Novartis, SoBi, Grant/research support from: Novartis and SoBi, Jonathan Hausmann Consultant of: Novartis, Biogen and Pfizer, Grant/research support from: CARRA, SoBi, Olcay Jones: None declared, Daniel Kastner: None declared, Helen J. Lachmann: None declared, Ronald Laxer Consultant of: SoBi, Novartis, Sanofi, Dorelia Rivera: None declared, Nicolino Ruperto Speakers bureau: Eli-Lilly, GSK, Pfizer SoBi and UCB, Consultant of: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squib, Cambridge Healthcare research, Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, GSK, Idorsia, Janssen, Novartis, SoBi, Pfizer and UCB, Anna Simon: None declared, Marinka Twilt: None declared, Joost Frenkel: None declared, Hal Hoffman Consultant of: Novartis, Regeneron, SoBi, Aclaris, Grant/research support from: Bristol-Meyer-Squib, Jecure, Takeda and Zomagen, Adriana de Jesus: None declared, Jasmin Kuemmerle-Deschner Speakers bureau: Novartis and SoBi, Consultant of: Novartis and SoBi, Grant/research support from: Novartis and SoBi, Seza Özen Speakers bureau: Novartis and SoBi, Marco Gattorno Speakers bureau: Novartis and SoBi, Grant/research support from: Novartis, Raphaela goldbach-mansky: None declared, Erkan Demirkaya Grant/research support from: Sobi

Abstract: Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is one of the best-known monogenic auto-inflammatory disorders resulting from an autosomal dominant variation in the TNF super family receptor 1A ( TNFRSF1A ) gene (1). Objectives: To define best treatment approach in patients with TRAPS and effect on long-term outcomes. Methods: We reviewed all data on patients with TRAPS enrolled in the Eurofever international registry according the INSAID gene variant classification and the new Eurofever/PRINTO classification criteria (EPCC). Results: Data on 226 patients were available. Patients not fulfilling the EPCC carrying likely benign/benign variants (21 patients, 9%) or VOUS/not classified variants (40 patients, 18%) displayed a milder disease than the patients fulfilling the EPCC with VOUS/not classified variants (38 patients, 17%) or pathogenic/likely pathogenic variants (127 patients, 56%). In particular, in patients not fulfilling the EPCC, less frequent abdominal pain and skin rashes, higher efficacy rate of colchicine and no development of AA amyloidosis have been reported. Almost 90% of patients fulfilling the EPCC required maintenance therapy and anti-interleukin (IL)-1 drugs were the most frequently used, with the highest efficacy rate ( 〉 85% complete response), while Etanercept was less effectively used and discontinued in 65% of patients. Conclusion: Anti-IL-1 drugs are the best maintenance treatment in TRAPS with potential to reverse the most serious disease complications of AA amyloidosis and infertility. The diagnosis of TRAPS should be considered very carefully in patients carrying VOUS/not classified variants not fulfilling the EPCC. References: [1]Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Annals of the rheumatic diseases 2014;73:2160-7. Acknowledgments: RP would like to thank the European Federation of Immunology (EFIS) for the short-term bursary and HL for her continuous support and guidance during the fellowship at the National Amyloidosis Centre in London. Disclosure of Interests: Riccardo Papa: None declared, Thirusha Lane: None declared, Francesca Bovis: None declared, Kirsten Minden Consultant of: GlaxoSmithKline, Sanofi, Speakers bureau: Roche, Isabelle Touitou: None declared, Luca Cantarini: None declared, Marco Cattalini: None declared, Laura Obici: None declared, Annette Jansson: None declared, Alexander Belot: None declared, Beata Woska-Kuśnierz: None declared, Rainer Berendes: None declared, Agustin Remesal: None declared, Marija Jelusic: None declared, Graciela Espada: None declared, Irina Nikishina: None declared, Esther Hoppenreijs: None declared, Maria Cristina Maggio: None declared, Taryn Youngstein: None declared, Tamer Rezk: None declared, Charalampia Papadopoulou: None declared, Paul Brogan Grant/research support from: Roche, Novartis, SOBI, Chemocentryx, Novimmune, Consultant of: Roche, SOBI, UCB, Novartis, Speakers bureau: Roche, SOBI, UCB, Novartis, Philip N Hawkins: None declared, Patricia Woo: None declared, Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis, Helen J. Lachmann: None declared

Abstract: Cryopyrin associated periodic syndromes (CAPS) are a group of ultra-rare autoinflammatory diseases caused by mutations in the NLRP3 gene, leading to overproduction of IL-1β. CAPS includes the following subdiagnoses: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous articular syndrome/neonatal-onset multisystem inflammatory disease (CINCA/NOMID), where FCAS is the mildest form of CAPS and CINCA/NOMID the most severe. A graduated pre-filled syringe of the IL-1 receptor antagonist anakinra was introduced to meet the need of smaller and varying doses when treating children with CAPS. Objectives: To evaluate the safety of anakinra in CAPS patients using the novel pre-filled syringe. Methods: Investigators managing patients with CAPS treated with anakinra were identified via the Eurofever registry. Follow-up data of at least 3 years for each patient were prospectively collected and analyzed (EUPAS6366). The primary study endpoints were the occurrence of adverse events (AEs) with focus on serious infections, malignancies, injection site reactions, allergic reactions and medication errors, including re-use of the syringe. Secondary endpoints included dose at specific time points, discontinuations, and switch to other IL-1 blocking treatment. Results: 12 patients with CAPS were included in the study, 8 with MWS, 2 with FCAS and 2 with CINCA/NOMID. The majority were male (75%) and white (83.3%). At baseline, all but one patient were already using the graduated prefilled syringe with anakinra. 5 patients required a median dose of 2 to 3 mg/kg/day and 6 patients below 2 mg/kg/day. During a total of 26.1 patient years of treatment, there were 7 AEs with rate of 26.8 (95% CI 4.2-169.6) per 100 patient years. All AEs were infections from 1 patient with CINCA/NOMID and were considered unrelated to anakinra by the investigator. Two of the AEs were considered serious as hospitalization was required (1 tonsillitis and 1 urinary tract infection). No AEs were severe, 6 of the AEs were of moderate severity and 1 was of mild severity. In total, 6 patients discontinued anakinra permanently, 2 during the first year of treatment, 3 during the second year and 1 after the third year of follow-up. The reasons for discontinuation included switch to canakinumab (4 patients), switch to canakinumab and inefficacy (1 patient) and non-compliance (1 patient). The remaining 5 patients continued anakira until the end of the study. 1 patient discontinued anakinra temporarily during the second year of treatment due to non-compliance. No deaths, malignancies, injection site reactions, allergic reactions or medication errors, including re-use of the pre-filled syringe, were observed. Table 1. Study results Patients 12 (100) Gender, M:F 9:3 (75:25) Ethnicity, white:black 10:2 (83.3:16.7) Age at baseline, median (range), years 25.3 (1.4-54.9) Age at disease onset, median (range), years 2.5 (0-29.5) Age at diagnosis, median (range), years 24.4 (0.6-54.6) Disease duration, median (range), years 15.5 (1.4-51.3) Patients already using anakinra at baseline 11 (91.7) Patients with history of other IL-1 blocking treatments at baseline 3 (25) Anakinra dose at baseline, median (range), mg/kg/day 1.7 (1.1-2.5) Anakinra dose during follow-up years 1:2:3: 〉 3, median (range), mg/kg/day 1.6:1.6:2.6:1.4 (1.1-3.9:1-4.4:1.7-3.7:1-3.2) Patients with AEs 1 (8.3) Patients with permanent discontinuation of anakinra 6 (50) Patients with continuation of anakinra until the end of the study 5 (41.7) Patients with temporary discontinuation of anakinra 1 (8.3) Total duration of anakinra exposure, median (range), years 1.3 (0.5-7) Any AE 7 (100) Urinary tract infection 1 (14.3) Upper respiratory tract infection 1 (14.3) Tonsillitis 5 (71.4) Results are shown as number (%) unless stated otherwise. Conclusion: The results of the present study confirm the safety profile of anakinra treatment in CAPS patients using the graduated pre-filled syringe. No new safety findings were identified. Disclosure of Interests: Riccardo Papa: None declared, Gabriella Giancane: None declared, Helen J. Lachmann: None declared, Paul Brogan: None declared, Elizabeth Legger: None declared, Daniel Lindqvist Shareholder of: Sobi employee and holder of Sobi shares, Speakers bureau: Sobi employee and holder of Sobi shares, Paid instructor for: Sobi employee and holder of Sobi shares, Consultant of: Sobi employee and holder of Sobi shares, Grant/research support from: Sobi employee and holder of Sobi shares, Employee of: Sobi employee and holder of Sobi shares, Susanna Cederholm Shareholder of: Sobi employee and holder of Sobi shares, Speakers bureau: Sobi employee and holder of Sobi shares, Paid instructor for: Sobi employee and holder of Sobi shares, Consultant of: Sobi employee and holder of Sobi shares, Grant/research support from: Sobi employee and holder of Sobi shares, Employee of: Sobi employee and holder of Sobi shares, Francesca Bagnasco: None declared, Nicolino Ruperto: None declared, Marco Gattorno: None declared