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Introduction: Colchicine is the standard treatment for Familiar Mediterranean Fever (FMF), however about 5% of patients (pts) experience colchicine resistance. There is no standard definition of colchicine resistance. Recently a panel of experts elaborated a new definition based on a Delphi consensus approach. Objectives: We aim to describe main features of the disease and clinical outcome of a cohort of FMF pts with particular interest on the colchicine resistance and tolerability according to the definitions proposed by the recent consensus.

Recurrent pericarditis (RP) is a rare cause of morbidity in children. Non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and colchicine are the standard of care in adults. Recently, anakinra has been proven to be effective in patients with steroid-dependence and colchicine resistance.

BackgroundThe 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.ObjectivesWe aimed to establish evidence-based recommendations on diagnosis, treatment, and monitoring to standardize the management of these patients.MethodsA 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.ResultsThe 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.ConclusionThe 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 Interestsmicol 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

BackgroundSAPHO is a heterogeneous autoinflammatory disease, characterized by bone and joint involvement and by a wide variety of dermatologic manifestations, including palmo-plantar pustulosis (PPP), acne, hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), psoriasis, Snedd-Wilkinson disease and Sweet syndrome. In children, the osteo-articular manifestations are characterized by chronic recurrent multifocal osteomyelitis (CRMO), involving the metaepiphysis of the long bones and the axial skeleton, as in the adult form. The SAPHO treatment still today is a challenge, and no therapeutic guidelines are available in children: NSAIDs are frequently used as first line treatment for CRMO lesions, followed by bisphosphonates, methotrexate and biologic therapies. In the literature there are many case reports but only a few case series1-3, of which this is the largest in Europe (29 cases reported in China4).Objectivesto report the clinical and radiological features and the response to therapy of SAPHO children.Methodsthe clinical data (serological, imaging and therapy) of 13 SAPHO patients, followed between 2001 and 2021 at the Unit for Autoinflammatory diseases at the Gaslini Hospital were reviewed.Results7/13 patients were male. At disease onset, acne-HS was present as the only manifestation in 8/13 patients while PPP was concomitant or subsequent to bone manifestations. The skin involvement was characterised by acne (comedonic in 3 cases, nodulo-cystic in 4 cases), PPP (5), HS (3), PG (1). Multifocal inflammatory bone lesions with axial or long bone involvement were both present in 92% of patients, whereas sternoclavicolar involvement was observed in 85% of patients.At disease onset all patients were treated with NSAIDS but only 4, with also PPP, achieved remission. In 7/13 patients, Methotrexate or salazopirin were used, and in 2/13 with severe painful bone lesions bisphosphonates were successfully employed. In the 5 PPP patients, the cutaneous involvement was mild and did not need treatment. In 9/13 patients, the skin manifestations required a therapeutic upgrade with biologics: Etanercept in 5 with partial result, Adalimumab in 6 had an optimal response, in 1 a partial response, even if requiring an increased dose (80 mg per week) and 1 was swapped to dapsone. Anakinra (3), ustekinumab and secukinumab (2) were not efficacious. It is to note that the 3 patients with comedonic acne were refractory to all treatments and needed multiple therapy cycling to achieve a partial remission only.ConclusionOur patients were characterised by well known SAPHO clinical manifestations. Despite the optimal therapeutic response of CRMO, comedonic acne was refractory to any treatment while PPP and nodulo-cystic acne achieved remission. This may suggest that the skin involvement in SAPHO may identify clinical phenotypes with a different response to treatments.References[1]Luzzati M, Ital J Pediatr. 2020;46(1):169.[2]Tlougan BE, Pediatr Dermatol. 2009;26(5):497[3]Beretta-Piccoli BC, Eur J Pediatr. 2000;159(8):594[4]Wu N, Clin Rheumatol. 2021;40(4):1487Disclosure of InterestsCaterina Matucci-Cerinic: None declared, Gianmaria Viglizzo: None declared, Roberta Caorsi Speakers bureau: Sobi, Consultant of: Novartis, Eli Lilly, Stefano Volpi: None declared, Clara Malattia: None declared, Marco Gattorno Speakers bureau: Novartis, SOBI

Background:Colchicine is the standard treatment for Familiar Mediterranean Fever (FMF), however about 5% of patients experience colchicine resistance. There is no standard definition of colchicine resistance. Recently a panel of experts elaborated a new definition based on a Delphi consensus approach.Objectives:We aim to describe main features of the disease and clinical outcome of a cohort of FMF patients with particular interest on the colchicine resistance and tolerability according to the definitions proposed by the recent consensus.Methods:Since November 2009, 425 Italian pediatric and adult FMF patients (pts) from 13 centers were enrolled in a national longitudinal cohort study, using the international EUROFEVER registry. Demographic, genetic and clinical data, including response to treatment, were analyzed. Supplementary information on health related quality of life and treatment adherence was also collected by a specific questionnaire.Results:Complete information were available in 341 pts (189 M and 152 F, 211 children and 120 adults). The median age at disease onset was 5.0 years (1 m-59 y); the mean diagnostic delay was 8.7 y (range 0-61 y). The median age at enrollment was 12.1 y (range 3 m - 82 y). The MEFV genotype was the following: 103 (30.2%) pts carried biallelic pathogenic variants; 59 (17.3%) one pathogenic variants and one VOUS /LB variant; 27 (7.9%) had biallelic VOUS/LB variants; 97 (28.45%) were heterozygous for pathogenic variants; 30 (8.8%) were heterozygous for VOUS/LB, 25 (7.33%) were genetically negative.Colchicine treatment was used in 280 pts; during treatment, biologic treatment (anti-IL1) in 22 pts. 61 pts received NSAID or steroid on demand.We analyzed the behavior of the pts treated with colchicine according to the statements on colchicine resistance/intolerance defined by Ozen et al (1) (Table 1).Table 1.Adherence62% displayed a total adherence (> 90% of prescription); 10.8% a good adherence (50-89% of prescriptions); 1.9% poor adherence (< 50% of prescriptions); 0.9% no adherenceDose adjustment criteria/ Recommended maximum colchicine doseMean colchicine dose:Pts 5-10 year: 0.77mg/die (std. dev. 0.23)10-18 years: 1.1mg/die (std. dev. 0.39)Adults: 1.16 mg/die (std. dev. 0.37)Pts with a dose inferior to the minimum recommended dose5-10 years: 2.5%10-18 years: 15%Adults: 4%Resistance to ColchicineResistance was be defined as persistence of fever attacks, despite optimal treatment. 41.6% pts had a complete disease control32.8% Pts had < 1 episode/month for 3 months25.5% had ≥1 episode/month for 3 monthsInclusion of secondary amyloidosis in the definition of colchicine resistance5 adult pts (1.5%) displayed amyloidosisColchicine intolerance11 pts (3.2%) withdraw colchicine because of drug intolerancePatient quality of life and patient-reported outcomes20.7% of pts experience fatigue or chronic pain, 16.9% limitations in daily activities, and 16.9% have lost school/work days.Conclusion:Almost 58% of FMF pts display disease activity despite colchicine treatment. The treatment is generally under-dosed, especially in children. The adherence and the compliance to the treatment is generally good.References:[1]Ozen S et all. Recommendation on colchicine dosing and definition of colchicine resistance/intolerance in the management of FMF. Pediatric Rheumatology, 2019.Acknowledgments:This research was financial supported by Novartis AGDisclosure of Interests:Romina Gallizzi: None declared, Marta Bustaffa: None declared, Francesca Mazza: None declared, Diana Sutera: None declared, Giovanna Fabio: None declared, Laura Obici: None declared, Maria Alessio: None declared, Donato Rigante: None declared, Luca Cantarini: None declared, Antonella Insalaco: None declared, Marco Cattalini: None declared, Maria Cristina Maggio: None declared, Gabriele Simonini: None declared, Alma Nunzia Olivieri: None declared, Serena Pastore: None declared, Maddalena Lancieri: 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

Background:ALPS is a rare disorder due to a defective apoptotic mechanism leading to abnormal lymphoproliferation and autoimmunity. The disease is difficult to identify in the early phase when it may be misdiagnosed. Elevated TCR alpha-beta CD4-CD8- lymphocytes (double negative T lymphocytes DNT) together with hyperIgG, high levels of IL10, Il18, vitamin B12 and soluble Fas ligand have been suggested as the main ALPS hallmarks (1). Therefore, a specific flow cytometry panel (DNT cells, ratio of CD25+CD3+ to HLA−DR+CD3+ cells, increased B220+ T-cells, and decreased CD27+ memory B cells) has been proposed to serve as a diagnostic screen for ALPS (2).Objectives:To evaluate the usefulness of a specific lymphocyte flow cytometry panel in the early identification of ALPS/ALPS-like disorders in a cohort of patients with undefined autoinflammatory or autoimmune disorders.Methods:The clinical data of patients referred to the pediatric Rheumatology Unit of the Istituto Giannina Gaslini Hospital for a suspicion of autoimmune or autoinflammatory condition from October 2015 to April 2018, were retrospectively analyzed. Data on clinical manifestations, laboratory workup, genetic analysis and treatment were collected. Flow cytometry was included among the screening panel: DNT, CD25+CD3+, HLA−DR+CD3+ cells, B220+ T-cells, and CD27+ memory B cells were included. A statistical analysis was performed: data were analyzed with an univariate logistic regression analysis, to identify the most significant variables associated with ALPS. These variables were then included in a multivariate analysis to select a set of clinical and laboratory parameters, each of them associated with a significant probability to be associated with ALPS independently from other variables.Results:475 patients were retrospectively analized. 211 patients not fulfilling the inclusion criteria were excluded. The patients were classified as follows: i) Autoimmune disease 26 pts (10 SLE; 3 MCTD; 6 jDM; 5 Behçet; 1 SjS; 1 Kawasaki) ii) Juvenile Idiopathic Arthritis 35 pts iii) Monogenic systemic autoinflammatory disease (MSAID) 27 pts (17 FMF; 3 MKD; 1 TRAPS; 4 DADA2; 2 SAVI) iv) PFAPA 100 pts v) Systemic Undefined Recurrent Fever 45 pts vi) Undetermined-SAID 15 pts vii) ALPS/ ALPS probable 16 pts. The flow cytometry panel showed, as expected, an elevation of DNT in all ALPS patients. Among the other parameters, CD3CD25+/CD3HLADR+, and B220+ T cells, were significatively altered in 75% of ALPS patients. Conversely, B CD27+ did not differentiate ALPS from the other subgroups. The multivariate analysis revealed 5 clinical/laboratory parameters that showed the higher independent association to ALPS in the cohort of patients. Splenomegaly, female gender, elevated DNT, arthralgia and elevated alfabeta+B220+ lymphocytes were positively and significantly associated to ALPS.Conclusion:The use of the specific flow cytometry panel, comprehensive of DNT, B220+, HLA-DR and CD25, in patients with undefined autoinflammatory or autoimmune disorders may identify a subgroup of patients with ALPS.References:[1]Joao B. Oliveira et al. Blood 2010; 116 (14): e35–e40.[2]Lenardo MJ et al.Immunity. 2010;32(3):291–295.Disclosure of Interests:Caterina Matucci Cerinic: None declared, Leonardo Oliveira Mendonca: None declared, maurizio miano: None declared, paola terrnaova: None declared, federica casabona: None declared, Marta Bustaffa: None declared, Francesca Bovis: None declared, Roberta Caorsi: None declared, Stefano Volpi: None declared, Angelo Ravelli: None declared, Carlo Dufour: None declared, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis

Background Canakinumab (CAN), a selective, human anti-interleukin (IL)−1β mAb, has demonstrated efficacy and safety in patients (pts) with colchicine-resistant familial Mediterranean fever (crFMF), TNF receptor-associated periodic syndrome (TRAPS), and hyper-IgD syndrome (HIDS)/mevalonate kinase deficiency (MKD) in the epoch 2 and 3 (E2 and E3) of the CLUSTER study (NCT02059291).1 2 Objectives To evaluate the long-term maintenance of optimal control of disease activity (median of no or 1 flare, and no uptitration) and safety on every 4 weeks (q4w) and every 8 weeks (q8w) dosing regimens of CAN in pts with crFMF, TRAPS or HIDS/MKD from the epoch 4 (E4; 112 weeks) of the CLUSTER study. Methods The study comprised 4 epochs (E1-E4). Study design for E2 and E3 have been reported earlier.1 After lead-in E1, in E2, a 16 wk randomised, double-blind, placebo (PBO)-controlled epoch, efficacy of CAN 150/300 mg q4w to induce complete response (absence of flares) was assessed. E3 (24 wks) evaluated whether responders to CAN 150/300 mg q4w in E2 could maintain clinical efficacy on 150/300 mg q8w or PBO. In E4, a 72 wk, open-label epoch, the long-term maintenance of efficacy and safety of CAN 150/300 mg q4w or q8w in pts with crFMF, TRAPS or HIDS/MKD was evaluated. Pts who did not maintain clinical response on q8w could be uptitrated to 150/300 mg q4w. Safety assessments included adverse events (AEs) and serious AEs. Results At the end of E4 (Wk 112), a substantial proportion of pts maintained optimal control of disease activity following treatment with 150/300 mg q4w or q8w in all 3 cohorts (figure 1). HIDS/MKD pts more often required uptitration to 300 mg q4w. Majority of pts in all 3 cohorts had 1 or no new flare (crFMF: 96.6%, TRAPS: 94.3%, HIDS/MKD: 83.3%) and physician global assessment Conclusions Epoch 4 of the CLUSTER study demonstrated that optimal control of disease activity in the crFMF, TRAPS and HIDS/MKD patients can be maintained following long-term treatment with canakinumab 150/300 mg q4w. For all 3 cohorts, patients requiring 150/300 mg q8w in epoch 3 to maintain disease control were less likely to control disease during epoch 4 and therefore a substantial number of these patients were uptitrated to q4w regimen by the end of epoch 4. No new or unexpected safety issues were reported over 112 weeks of canakinumab treatment. References [1] De Benedetti F, et al. Ann Rheum Dis2016;75:615–6. [2] De Benedetti F, et al. Arthritis Rheumatol2016;68(suppl 10). Disclosure of Interest F. De Benedetti Grant/research support from: Novartis, Roche, Pfizer, SOBI, AbbVie, Novimmune, BMS, Sanofi, J. Frenkel Grant/research support from: Novartis and SOBI, A. Simon Grant/research support from: Novartis, Xoma/Servier, CSL Behring, Consultant for: Novartis, Takeda, SOBI, Xoma, J. Anton Grant/research support from: Novartis, Consultant for: Novartis, H. Lachmann Consultant for: Novartis, SOBI, Takeda and GSK, Speakers bureau: Novartis and SOBI, M. Gattorno Grant/research support from: Novartis and SOBI, Consultant for: Novartis and SOBI, Speakers bureau: Novartis and SOBI, S. Ozen Speakers bureau: Novartis and SOBI, I. Kone-Paut Grant/research support from: Novartis, SOBI and Roche, Consultant for: Novartis, SOBI, Pfizer, AbbVie and Roche, E. Ben-Chetrit Consultant for: Novartis, M. Wozniak Employee of: Novartis, J. Wang Employee of: Novartis, E. Vritzali Employee of: Novartis

Background: Rituximab (RTX) in combination with methotrexate (MTX) has been licensed since 2006 for the management of severe active rheumatoid arthritis (RA) in patients who have failed at least one anti-tumour necrosis factor (anti-TNF) therapy. Published clinical trials have demonstrated the efficacy of RTX in improving both clinical symptoms and patients' physical function. This study aimed to assess the effectiveness of RTX in RA patients treated in routine clinical practice by examining clinical and patient reported outcomes six months after receiving a first course of RTX. Methods: The analysis involved 550 RA patients registered with the BSRBR, who were starting RTX and were followed up for at least 6 months. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical response while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients 6 months after starting RTX. The change in DAS28 and HAQ was compared between seronegative and seropositive patients and anti-TNF naïve patients versus anti-TNF failures. The response was also compared between patients receiving RTX in combination with MTX, other non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) or no nbDMARDs. Results: The mean (s.d.) age of the cohort was 59 (12) years and 78% of the patients were females. The patients had a mean (s.d.) of 15 (10) years of disease duration. 16% were biologic naïve while 84% were anti-TNF failures. 32% of the patients were seronegative and 68% were seropositive. The mean (95% CI) DAS28 at baseline was 6.2 (6.1, 6.3) which decreased to 4.8 (4.7, 4.9) at 6 months of follow up. 16% were EULAR good responders, 43% were moderate responders and 41% were non responders. The mean (95% CI) change in HAQ was −0.1 (−0.2, −0.1) (Table 1). The mean change in DAS28 was similar in seropositive and seronegative patients (p = 0.18) while the anti-TNF naïve patients showed a greater reduction in DAS28 scores than anti-TNF failures (p = 0.05). Patients receiving RTX in combination with MTX showed similar changes in DAS28 and HAQ compared to patients receiving RTX alone or with other nbDMARDs. Conclusions: RTX has proven to be effective in the routine clinical practice. Anti-TNF naïve patients seem to benefit more from RTX treatment than anti-TNF failures. Disclosure statement: The authors have declared no conflicts of interest

Background AIDAI is a novel validated tool for assessment of disease activity in autoinflammatory diseases. 1 CLUSTER study (NCT02059291) demonstrated that canakinumab (CAN; an anti- IL-1β antibody) is efficacious in resolving active flare and in preventing new flare in patients (pts) with colchicine resistant familial Mediterranean fever (crFMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic syndrome (TRAPS). 2 Objectives To assess AIDAI score and evaluate correlation between AIDAI and disease/response characteristics over 16 weeks (wks) of CAN treatment in CLUSTER. Methods CLUSTER study design and results have been presented. 2 AIDAI was calculated as the sum of 12 items 1 for 30 consecutive days. AIDAI score was calculated if the first score was recorded ≥29 days before baseline (BL). Missing items were imputed beyond last evaluable measurement by LOCF. Proportion of pts with inactive disease (ID; AIDAI score Results Median AIDAI scores decreased over time (Fig 1). Proportion of pts with ID at Wk 16 was 52% in crFMF, 40% in HIDS/MKD and 46% in TRAPS cohorts. AIDAI at Wk 16 correlated significantly with: SDS in all 3 cohorts; PGA in HIDS/MKD and TRAPS; SF12–MCS in crFMF and HIDS/MKD (Table 1). CRP and SAA did not correlate with AIDAI. Conclusions CAN demonstrated rapid and sustained disease control assessed with AIDAI over 16 wks. Approximately half of crFMF and TRAPS pts, and 40% of HIDS/MKD patients had inactive disease after 16 wks of treatment. AIDAI improvements at Wk 16 correlated with patient and physician driven evaluations (PGA, SF12–MCS and SDS). CRP and SAA are indicators of response to treatment, rather than a disease activity parameter. References Piram M, et al. Ann Rheum Dis. 2014;73: 2168–73. De Benedetti F, et al. Ann Rheum Dis. 2016;75:615–6. Disclosure of Interest I. Kone-Paut Grant/research support from: Novartis, SOBI and Roche, Consultant for: Novartis, SOBI, Pfizer, AbbVie and Roche, M. Piram Consultant for: Novartis, Pfizer, AbbVie, Speakers bureau: Novartis, S. Benseler Consultant for: Novartis, SOBI and AbbVie, M. Hofer Consultant for: Novartis and AbbVie, H. Lachmann Consultant for: Novartis, SOBI, Takeda and GSK, Speakers bureau: Novartis and SOBI, H. Hoffman Consultant for: Novartis, Speakers bureau: Novartis, M. Gattorno Grant/research support from: Novartis and SOBI, Consultant for: Novartis and SOBI, J. Frenkel Grant/research support from: Novartis and SOBI, J. Kuemmerle-Deschner Grant/research support from: Novartis, Consultant for: Novartis, SOBI and Baxalta, S. Ozen Speakers bureau: Novartis and SOBI, J. Levy Paid instructor for: Novartis, C. Karyekar Employee of: Novartis, F. De Benedetti Grant/research support from: Pfizer, AbbVie, Roche, Novartis, Novimmune and BMS

Background Canakinumab (CAN) is a fully human monoclonal antibody targeting IL-1β, a key cytokine in the pathogenesis of periodic fever syndromes (PFS) including familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic syndrome (TRAPS). Objectives The CLUSTER trial (NCT02059291) studied efficacy and safety of CAN in crFMF, HIDS/MKD and TRAPS. The primary objective was to demonstrate that CAN150 mg every 4 weeks (q4w) is superior to placebo (PBO) in resolving the flare by Day 15 with no new flares over 16 weeks (wks). Secondary objectives included the proportion of patients (pts) who maintained optimal control of disease activity (absence of new flares) between Wk 16 and Wk 40 after dose reduction. Methods The study comprised 4 epochs (E1-E4). 1 After lead-in E1, in E2 patients at time of an active fever flare were randomised to CAN 150mg q4w or PBO for 16 wks. Responders in E2 were re-randomised to PBO or 150 mg q8w for 24 wks. During E3, pts who escaped to open-label CAN in E2, were similarly down-titrated to open-label CAN q8w to gain additional information on the long-term maintenance dose. In pts with a flare, dose could be escalated up to 300 mg q4w. Safety assessments included adverse events (AEs) and serious AEs. Results The proportion of responders at Wk 16 was statistically higher with CAN vs PBO (Table). In E3, among the 41 re-randomised pts (PBO vs CAN 150 mg q8w) the proportion of pts who did not present new flares was numerically higher in the CAN vs PBO group (Table). Overall at Wk 40 (end of E3), including re-randomised pts and pts treated in open-label, 46% of the crFMF pts, 53% of the TRAPS pts and 23% of the HIDS/MKD pts maintained disease control with 150 mg q8w. Conversely, up-titration to 300 mg q4w was required in 28.8% of HIDS/MKD pts, and in 10.2% and 8.3% of pts with crFMF and TRAPS, respectively. In E3, the majority of pts who received CAN had PGA Conclusions Canakinumab (150 mg q4w) was efficacious in resolving flare at Day 15 and preventing new flares over 16 wks. In the longer term (40 wks), absence of flares was maintained in more than half patients at the extended dosing interval (150 mg q8w) in the crFMF and TRAPS cohorts. A higher dose was needed in HIDS/MKD patients. No unexpected safety issues were reported over 40 wks of canakinumab treatment. References De Benedetti F, et al. Ann Rheum Dis. 2016;75:615–6. Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, AbbVie, Roche, Novartis, Novimmune and BMS, M. Gattorno Grant/research support from: Novartis and SOBI, Consultant for: Novartis and SOBI, J. Frenkel Grant/research support from: Novartis and SOBI, I. Calvo Grant/research support from: Novartis, Pfizer, AbbVie and Roche, Speakers bureau: Novartis, AbbVie, Gebro and Roche, M. Moutschen: None declared, P. Quartier Grant/research support from: AbbVie, BMS, Chugai-Roche, Novartis and Pfizer, Consultant for: AbbVie, Novartis, Servier and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Medimmune, Novartis, Pfizer and SOBI, O. Kasapcopur Consultant for: Novartis, Speakers bureau: Novartis and Pfizer, S. Ozen Speakers bureau: Novartis and SOBI, A. Gul Grant/research support from: Novartis, J. Anton Grant/research support from: Novartis, Consultant for: Novartis, I. Kone-Paut Grant/research support from: Novartis, SOBI and Roche, Consultant for: Novartis, SOBI, Pfizer, AbbVie and Roche, H. Lachmann Consultant for: Novartis, SOBI, Takeda and GSK, Speakers bureau: Novartis and SOBI, H. Hoffman Consultant for: Novartis, Speakers bureau: Novartis, E. Ben-Chetrit Consultant for: Novartis, A. Zeft Shareholder of: Merck, Opko Health and Arno therapeutics, Consultant for: Novartis, Y. Gong Employee of: Novartis, E. Vritzali Employee of: Novartis, G. Junge Employee of: Novartis

**Background:** Cryopyrin-associated periodic syndromes (CAPS) is a group of rare autoinflammatory diseases. Little is known about the burden of disease, patients’ views on treatment, and adverse events (AEs) with current therapy. **Objectives:** The main study objective was to quantify the patients’ burden of disease in terms of flares and resource use and to characterize patient symptomatology and tolerability of treatment with anakinra. A secondary objective included comparing chart review and patient recall of symptoms and AEs. **Methods:** A retrospective medical chart review and concurrent online patient survey was conducted in four European countries. Data 12 months prior to initiation of/during anakinra treatment were entered into web-based case report forms by study groups. **Results:** Forty-two patients received/were receiving anakinra as primary treatment for at least 12 months. Patients experienced a 79.5% reduction in flares after commencing anakinra treatment. During the past 12 months on anakinra, four of five (80%) patients who recalled experiencing flares reported cancelling social activities and staying home as the most common courses of action. Most common AEs were injection site pain upon treatment initiation and weight gain. According to patient recall, 12 of 21 patients (57.1%) discontinued anakinra to enter another clinical trial; of the 12, eight (38%) specifically discontinued anakinra only for that reason, and four patients cited entering a clinical trial as one of many reasons for discontinuing anakinra. **Conclusions:** To our knowledge, this is the most comprehensive survey of patient experience with CAPS. Although improved, CAPS treatment remains suboptimal and a significant burden is placed upon patients, caregivers, and the healthcare system. With new agents available, it will be important to compare outcomes in patients using all therapeutic options.

We present the socio-economic consequences of the chronic infantile neurological cutaneous and articular syndrome (CINCA), one of the various forms of the cryopyrin-associated periodic syndrome (CAPS), through the analysis of the 18 years-long story of one patient. We interviewed the patient and his mother and collected clinical documentation to estimate his life-time costs from the perspectives of the healthcare system and society. Total societal and healthcare costs amount to €178,394 and €137,272, respectively. For about 12 years the patient was not correctly diagnosed; health care costs in this period amounted to €81,280, mainly due to hospital care. After the disease was diagnosed, the pattern of costs dramatically changed with a sharp reduction of hospital costs and an increase of costs for medical therapy. This socioeconomic case-study illustrates the categories of costs that may be associated to patients with rare diseases and suggests that prompter diagnosis and adequate therapies may be also beneficial from a socio-economic perspective.

BD is rarely encountered in children where the disease is very difficult to recognize. The outcome ofpatients with few symptoms is currently unknown

Osteolytic lesions are the hallmark of a number of inherited (DIRA and Majeed syndrome) and multifactorial (CRMO and SAPHO) autoinflammatory diseases.

The Q703K is a variant of NLRP3 gene has an unknown pathogenetic significance. It, has been considered to be a clinically unremarkable polymorphism, due to its presence in 12-20% of general population. However, a recent study has shown that carriers of the Q703K display an higher secretion of IL-1b, thus suggesting a possible pathogenic role of this variant.

One of the main features, in the follow-up of a patient with a chronic disorder is severity. Definition in severity is quite difficult since the disease manifests with various clinical and laboratory features. On the other hand, there have been many articles reported in literature about the lack of consistency between currently used severity scores such as Mor, Pras and Tel Hashomer criteria.

Recurrent pericarditis represents an important complication of acute pericarditis. Therapeutic approach during recurrences consists of NSAID (non-steroidal anti-inflammatory drugs) administration. However steroid is often necessary to control disease flares. IL-1 inhibitors efficacy has been anecdotally described as effective in the control of the disease in steroid-dependent and colchicine-resistant patients.

Results Monocytes isolated from PAPA patients tent to secrete higher levels of IL-1b but this was not consistent in all the patients (p = 0.144). Variability in IL-1b release occurred even in the presence of the same PSTPIP1 variant and it did not parallel disease activity when the whole cohort was taken in consideration. However, IL-1b levels varied according to the clinical picture (p = 0.0197), and it was significantly higher (P < 0.05) in patients displaying articular manifestations (N = 3) compared to those affected by cutaneous (N =6 ) or combined (N = 2) lesions. In the former, IL-1b secretion was increased in the presence of acute phase reactants elevation and active joint lesions, and treatment with Anakinra resulted in acute phase reactans normalization and symptom-free period. Silencing of of NLRP3 activity consistently inhibited LPS-induced IL-1b release in both PAPA and HD monocytes. Conclusion IL-1b secretion is higher in PAPA patients displaying prevalent articular manifestations. In these patients, IL-1b release correlates with disease activity and it is mediated by NLRP3.

Recurrent pericarditis represents an important complication of acute pericarditis. Therapeutic approach during recurrences consists of NSAID administration. However steroid is often necessary to control disease flares. IL-1 inhibitors efficacy has been anecdotally described as effective in the control of the disease in steroid-dependent and Colchicine-resistant patients.

The autoinflammatory diseases (AID) include monogenic and polygenic disorders characterized by primary dysfunction of the innate immune system.

In pediatric rheumatology, the lack of scales showing activities of illness in the patients groups, the absence of biomarkers for the severity of damage led the scientific world to develop a scale where the patient can make an self-assessment with quantitative results. So, a necessity has been occurred to develop a multidimensional scale which is understandable, applicable and comprehensive in the evaluation of children with auto-inflammatory diseases.

Background Periodic Fever Syndromes (PFS) are rare autoinflammatory conditions including Familial Mediterranean Fever (FMF), Hyper-IgD Syndrome/ Mevalonate Kinase Deficiency (HIDS/MKD), and TNF-Receptor Associated Periodic Syndrome (TRAPS). 1 It has been shown that colchicine-resistant FMF (crFMF), HIDS/MKD and TRAPS considerably impact physical and emotional aspects of patients9 lives. 2–4 Open label studies suggested that canakinumab (CAN), a fully human and highly specific anti-IL-1β monoclonal antibody, is efficacious in crFMF, HIDS/MKD and TRAPS. 5–7 To date, there is no data showing the effect of CAN on Health-Related Quality of Life (HRQoL) in PFS patients. Objectives To evaluate the effect of CAN on HRQoL using Child Health Questionnaire – Parent Form 50 (CHQ-PF50) and SF-12 Health Survey (SF-12) in PFS patients. Methods In a Phase 3 randomised placebo controlled study of CAN in PFS (NCT02059291), SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) were assessed in adults. For children (>5– Results 181 patients were randomised to CAN or placebo in 3 cohorts (63 crFMF, 72 MKD/HIDS, 46 TRAPS). 71 adults ≥18 years and 110 children (age range ≥2– Conclusions Canakinumab showed rapid improvement by Week 5 in patient reported outcomes in adults and children with PFS, which was sustained through Week 16. References Savic S. and Wood P. Clin. Med. 2011;11(4):396–401 Dandekar P, et al. Pediatr. Rheumatol. 13(S1):P22 Dandekar P, et al. Pediatr. Rheumatol. 13(S1):P23 Dandekar P, et al. Pediatr. Rheumatol. 13(S1):P24 Brik R, et al. Arthritis Rheumatol. 2014;66(11):3241–3 Arostegui, J.I, et al. Arthritis Rheumatol. 2015; 67 (S10) Gattorno M, et al. Arthritis Rheumatol. 2015; 67 (S10) User9s manual for the SF-12v2 Health Survey, 3rd ed. 2012 Cohen J, et. al. Statistical Power Analysis for the Behavioural Sciences,2nd ed. 1988 Disclosure of Interest H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: Bristol Myers Squibb, Consultant for: Novartis, Sob Biovitrum, Regeneron, Speakers bureau: Novartis, A. Zeft: None declared, Y. Joubert Employee of: Novartis, K. Lheritier Employee of: Novartis, A. Speziale: None declared, G. Junge Employee of: Novartis, J. Gregson Employee of: Novartis, F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS

Background Periodic fever syndromes are a group of rare autoinflammatory conditions that includes, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic syndrome (TRAPS). The pharmacokinetics (PK) of canakinumab (CAN) and total interleukin (IL)-1β kinetics have been well characterised in CAPS patients (pts). 1 Here we present the PK and pharmacodynamics (PD) of CAN in colchicine resistant/intolerant (crFMF), HIDS/MKD and TRAPS pts. Objectives To evaluate the PK and PD of CAN (solution for injection-liquid in vial [LIVI]) from the phase III study in crFMF, HIDS/MKD and TRAPS pts at Week 16. Methods The study (NCT02059291) comprised of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS). Each cohort followed the same study design across 4 epochs (screening epoch [up to 12 weeks], randomised treatment epoch [16 weeks], randomised withdrawal epoch [24 weeks] and open-label treatment epoch [72 weeks]). Pts (age, ≥2 years) with crFMF, HIDS/MKD or TRAPS who had a flare during Epoch 1 were randomised (1:1) in Epoch 2 to receive subcutaneous (sc) CAN 150 mg (or 2 mg/kg for pts weighing ≤40 kg) every 4 weeks (q4w) or placebo. Blinded uptitration (up to 300 mg) was allowed for pts not resolving the index flare by day15. Samples for CAN concentrations and total IL-1β were collected at baseline (Day 1), and trough samples at weeks 2, 4, 8, 12 and 16. Results In crFMF, HIDS/MKD and TRAPS pts, the serum clearance and steady-state volume of distribution of CAN varied according to body weight and were estimated to be 0.14±0.04 L/day and 4.96±1.35 L, respectively. The estimated half-life of CAN was 25.6±6.4 days. CAN minimal concentration at Week 16 following 150 mg sc q4w dosing was estimated to be 15.3±6.6 μg/mL. The estimated steady state area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUC tau ) was 648±202 μg.day/mL. Similar results were obtained in 3 diseases. CAN binding to circulating IL-1β was demonstrated by increase in total IL-1β following CAN dosing in all 3 diseases. In pts requiring up titration to 300 mg, levels of total IL-1β were higher suggesting higher production of IL-1β. Conclusions This was first study to evaluate the PK characteristics of canakinumab given in the LIVI form. The results observed in crFMF, HIDS/MKD and TRAPS patients were similar to those observed in other indications (CAPS and SJIA) using the lyophilisate form. These data suggested that new formulation did not affect PK/PD of the drug and similarly to CAPS, patients with higher levels of IL-1β may require canakinumab up-titration to have an optimal disease control. References Chakraborty A, et al. Clin Pharmacokinet. 2012;51:e1–18. Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, A. Zeft: None declared, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: BMS, Consultant for: Novartis, SOBI, Regeneron, Speakers bureau: Novartis, Y. Joubert Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Speziale Employee of: Novartis, G. Junge Employee of: Novartis, X. Xu Employee of: Novartis

Background Periodic fever syndromes (PFS) are a group of rare auto-inflammatory conditions, which includes, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF-receptor associated periodic syndrome (TRAPS). Canakinumab (CAN), a fully human, highly specific anti-IL-1β neutralising monoclonal antibody, is effective in CAPS.1 IL-1β has been shown to be involved in the pathogenesis of FMF, HIDS/MKD and TRAPS, for whom no approved treatment exists. A series of small open label studies suggested efficacy of CAN in colchicine resistant/intolerant FMF (crFMF), HIDS/MKD and TRAPS.2,3 We report the efficacy and safety of CAN from the randomised treatment epoch of a phase III trial in patients (pts) with crFMF, HIDS/MKD or TRAPS. Objectives Primary objective of this phase III pivotal trial was to demonstrate that CAN 150 mg (or 2 mg/kg for pts ≤40 kg) sc q4w is superior to placebo (PBO) in achieving a clinically meaningful response defined as resolution of the index flare at Day 15 and no new disease flares over 16 wks of treatment. Secondary objectives were: % pts who achieved a physician global assessment of disease activity (PGA) Methods The trial (NCT02059291) consists of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS) and 4 study epochs (E1–4): a screening epoch (E1) of up to 12 wks, a randomised treatment epoch (E2) of 16 wks, a randomised withdrawal epoch (E3) of 24 wks and an open-label treatment epoch (E4) of 72 wks. Pts (age ≥2 years) with crFMF, HIDS/MKD or TRAPS with a flare during E1 were randomised (1:1) in E2 to receive CAN or PBO. Safety assessments included adverse events (AEs). Results Of 181 pts (crFMF, n=63; HIDS/MKD, n=72; TRAPS, n=46) randomised in E2, 6 pts discontinued (5 PBO; 1 CAN). In all 3 disease cohorts, the proportion of pts who were responders for the primary outcome at Wk 16 was significantly higher with CAN vs PBO (Table). At Wk 16, a significantly higher proportion of pts achieved PGA score Conclusions These results demonstrated superior efficacy of canakinumab at dose level of 150 mg q4w after a 16 weeks treatment period compared to placebo. The overall safety profile was not distinct from previous controlled studies and expectations in an auto-inflammatory patient population. Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, A. Zeft: None declared, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: BMS, Consultant for: Novartis, SOBI, Regeneron, Speakers bureau: Novartis, Y. Joubert Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Speziale Employee of: Novartis, G. Junge Employee of: Novartis

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance., SCOPUS: re.j, info:eu-repo/semantics/published

Patients showed recurrent flares of pericarditis with malaise, precordial pain, tachyorthopnoea, sometimes fever. 2/3 developed a life-threatening cardiac tamponade needing pericardiotomy. None of them presented signs or symptoms consistent with a chronic rheumatic disease: antinuclear, anti-coxsackie and anti adenovirus antibodies were negative. Genetic analysis ruled out Familial Mediterranean Fever. Mean disease duration was 2 years and mean rate of recurrences was 4 yearly. Pericarditis seemed steroid dependent and poorly responsive to colchicine.

Mutations of CERC1 have been recently reported as causative of an inflammatory condition characterized by polyarteritis, cerebral stroke and immunodeficiency; the response to immunosuppressors and biological drugs is not univocal.

Methods We collected blood samples from a cohort of pediatric rheumatologic patients and scored them according to a qPCR based IFN gene signature assay. Expression of 6 type I IFN-related genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) was quantified by standard RTPCR techniques. An IFN score was calculated for each patient using the median fold change of gene expression related to a healthy control. Patients were selected based on the presence of the following features: i) atypical or incomplete SLE-like symptoms occurring in infancy or in preprepubertal age; ii) vasculopathy (skin ulcers, chilblains, strokes) iii) panniculitis with or without lypodystrophy iv) interstitial lung disease in the context of systemic inflammation.

Results The girl, first born from healthy, not relatives parents, at the age of 8 months started to present erythematosusinfiltrated skin lesions with pustular evolution and finally hesitating in scars in 15-20 days. From the age of three years chilblains and severe nail dystrophy appeared. A CT scan performed at the age of 8 years revealed the presence of diffuse interstitial thickening with ground-glass appearance. A restrictive framework was detected at spirometry (FVC 51%). The autoantibodies detection revealed positive ANA (1: 160), ANCA (1:80) and Coombs test. The skin biopsy revealed a predominantly granulomatous nodular dermatitis, with folliculitis and secondary fibrosis. The lung biopsy revealed focal hemorrhage, edema and predominantly lymphocytic inflammatory aggregates in the peribronchial interstitial areas with aspects of capillaritis and contiguous focal subatelettasia with alveolar cavity filled of macrophages. Steroidal treatment (prednisone 1 mg/kg/day) was started with improvement of clinical manifestation, anemia and normalization of inflammatory markers. However attempts to reduce such therapy were followed by an exacerbation of the clinical picture. Treatment with both immunosuppressive (azathioprine) and biologic (etanercept) drugs was tempted, without clear improvement. Unsatisfactory growth was also detected. In the following months the child started to present a mild renal involvement with microscopic hematuria and hypertension, requiring anti-hypertensive treatment. Given the evocative framework, interferon gene signature was performed, revealing a significant activation; the molecular analysis of TMEM173 gene showed the presence of the de novo Val155Met mutation, already described as causative of SAVI syndrome. The child continued to present persistent severe microcytic anemia, requiring erythrocytes’ transfusions, despite high levels of erythropoietin. Bone marrow aspiration revealed dysmaturative signs in the in erythroid progenitors. Treatment with jak1/2 inhibitor (Ruxolitinib, 5 mg day) was just started at the time of abstract presentation.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a more frequent cause of recurrent fever in children. The exact etiology of this pediatric disorder is still unknown. Palatine tonsils are sites where innate immunity leads to the onset of adaptive immunity, mediated by B and T lymphocytes.

Background ADA2 deficiency, a recently described disease, is characterized by systemic vasculopathy and episodes of strokes. The defect is due to a loss of function mutation of CECR1 gene, codifying for Adenosine Deaminase 2 protein. This protein regulates the catabolism of extracellular adenosine, which we have recently shown is an important regulator of Class Switch Recombination in B lymphocytes. Accordingly DADA2 patients can present hypogammaglobulinemia. Objectives The aim of the project is to characterize peripheral B-cell compartment of two patients to directly address if ADA2 mutation affects B-cell function. Methods Two brothers (15 and 7 years old) carrying mutations in CECR1 were followed up from the age of two. They showed similar clinical history with livedo reticularis, fever, vasculitis and neurological symptoms caused by haemorragic strokes. Both presented early hypogammaglobulinemia requiring intravenous immunoglobulin replacement therapy. Remarkably after etanercept treatment serum Igs slowly increased to a normal level. We analyzed peripheral B-cell phenotype by flow cytometry, in vitro B-cell proliferation and differentiation to plasmacells in response to CpG, BCR and T cell help. Results Flow cytometer analysis showed a significative reduction of total B cells compared with age matched controls. Intriguingly a defect in the memory B-cell compartment (CD19 + CD27 + ) was observed. We found that the rate of proliferation and differentiation to Igs secreting cells is lower as compared to normal controls and it is not supported by autologous T cells. Conclusions Our findings suggest that ADA2 defect could lead to a reduced formation of T cell dependent memory B cells. References Zhou Q. et al., N Engl J Med. 2014 Mar 6;370(10):911-20 Navon Elkan et al. P. N Engl J Med. 2014 Mar 6;370(10):921-31 Garg N. et al. Eur J Pediatr. 2014 Jun;173(6):827-30 Schena F. et al. Cell Rep. 2013 Jun 27;3(6):1824-31 Hasko G. et al. Trends Mol Med. 2013 Jun;19(6):355-67 Antonioli L. et al. Nat Rev Cancer. 2013 Dec;13(12):842-57 Eltzschig HK et al. N Engl J Med. 2012 Dec 13;367(24):2322-33. Disclosure of Interest None declared

Systemic AutoInflammatory Diseases (SAID) are a growing number of monogenic and multifactorial conditions secondary to deregulation of mechanisms controlling innate immune responses and are characterized by sterile inflammation. Originally these disorders were limited to a handful of rare monogenic diseases (recurrent fevers). Thanks to the great improvement in genetic diagnostic techniques, the number of known associated genes and associated autoinflammatory phenotypes has have dramatically expanded Depending on the pattern of inheritance, the identification of one or two mutations with a known pathogenic impact and high penetrance represents an essential final step for the diagnosis of SAID. However, in a considerable proportion of cases (70-80%) molecular analysis is unable to provide diagnostic confirmation (i.e. presence of a single mutation in autosomal recessive disorders, low-penetrance mutations, functional polymorphisms or novel variants of unknown functional impact). This is important because a delay in a proper diagnosis, further delay timely treatments leading to irreversible organ damage. The Next Generation Sequencing (NGS) approach has proven to be a successful strategy for inducing a marked acceleration in rare disease gene discovery, improving clinical diagnosis, providing insight into biological mechanisms, and increasing therapeutic opportunities. Indeed, NGS represents a potential revolutionary diagnostic tool for genetic conditions, allowing the simultaneous analysis of different genes associated to a given group of inherited disorders. Moreover, NGS allows the detection of somatic mosaicism, as demonstrated in patients presenting a typical clinical phenotype, but are negative for germ-line mutations. Such NGS could present an approach to enables a definitive diagnosis in some patients with monogenic SAID, but in other cases the results can be inconclusive or even misleading. Therefore, the definitive diagnosis and classification of inherited SAID should rely on the careful interpretation of results derived from several complementary molecular analyses, in the light of the clinical phenotype. So far, formal diagnostic criteria have been developed for a few SAID, but their accuracy has not been confirmed in different ages and populations. In spite of our increasing understanding of the molecular mechanisms of SAID, there is still a large number of individuals with a clinical diagnosis of SAID and but without mutations in known disease causing genes. In this lecture we will analyze the main technical issues associated to the possible application of NGS technique in daily practice and the possible difficulties in the interpretation of the results coming from the simultaneous analysis of different genes. Disclosure of Interest None declared

Background Mutations of CECR1 have been recently reported as causative of an inflammatory condition characterized by polyarteritis nodosa, cerebral stroke and immunodeficiency; the clinical manifestations of the disease are heterogeneous with a wide range of severity. Objectives To analyze the prevalence of CECR1 mutations in pediatric patients with polyarteritis nodosa, livedo reticularis and/or stroke. Methods Pediatric patients of Caucasian Italian origin with the following diseases/manifestations were included in the study: i) histologically confirmed polyartiritis nodosa (PAN) or cutaneous polyartiritis nodosa (cPAN), ii) persistent livedo reticularis with elevation of acute phase reactants, iii) ischemic or hemorrhagic strokes with systemic inflammation. Direct sequencing of CECR1 gene (exons 1-9) was performed with Sanger analysis. Results Up to January 2015, 27 patients from 25 families were included in the study. Homozygous or compound heterozygous CECR1 mutations with deleterious effects (G47R, G47A, P251L, R312X, E328D, T360A) were detected in 6 patients. A heterozygous causative mutation (G47V) was observed in 2 affected brothers, their father and the unaffected brother. So far a second mutation has not been detected; loss of heterozygosity could not be demonstrated and the mother is being investigated for a possible interstitial deletion. In the remaining patients common polymorphisms (L46L, N53N, H335R, Y453Y) were detected. The mean age of onset of the disease in genetically confirmed patients was 24 months (range 6 months – 5 years); all of them presented fever, elevation of acute phase reactants, livedo reticularis and a skin biopsy suggestive for vasculitis; two of them presented subcutaneous nodules while one of them presented ulcerations at extremities. Hypertension was detected in four patients, while one presented miocarditis. 3 patients presented one or more cerebral stroke during their disease course, while in 3 patients peripheral neuropathy was detected. 4 patients presented intestinal involvement (ranging from recurrent abdominal pain to intestinal perforation) and 2 patients presented growth delay, independent from steroidal treatment. Low immunoglobulin levels were detected in two patients. The clinical characteristics of the two heterozygous patients were similar: fever, livedo reticularis, increased acute phase reactants and hypogammaglobulinemia were detected in both; cerebral stroke occurred in one of them. Conclusions CECR1mutations are present in the Italian population and associated with severe cases of ADA2 deficiency. A clinical heterogeneity has been detected in genetically confirmed patients. In a few patients a typical phenotype was associated to incomplete or negative genotype, thus supporting the hypothesis of a genetic heterogeneity of this condition. Disclosure of Interest None declared

Background SAVI syndrome is a recently identified condition associated to mutations of TMEM173. Up to know only few cases of this disease have been described. Objectives To describe the clinical manifestation of an Italian patient affected by SAVI syndrome Results The girl, first born from healthy, not relatives parents, at the age of 8 months started to present erythematosus-infiltrated skin lesions with pustular evolution and finally hesitating in scars in 15-20 days. From the age of three years chilblains and severe nail dystrophy appeared. At the age of 8 years the girl presented a severe pneumonia, requiring prolonged antibiotic therapy. The chest CT performed showed, in addition to the lung infiltrate, the presence of diffuse interstitial thickening with ground-glass appearance. A restrictive framework was detected at spirometry (FVC 51%). The autoantibodies detection revealed positive ANA (1: 160), ANCA (1:80) and Coombs test; rheumatoid factor was slightly increased. Anti-DNA and ENA were negative. The skin biopsy revealed a predominantly granulomatous nodular dermatitis, with aspects of deep granulomatous folliculitis and secondary fibrosis. The lung biopsy revealed focal hemorrhage, edema and predominantly lymphocytic inflammatory aggregates in the peribronchial interstitial areas with aspects of capillaritis and contiguous focal subatelettasia with alveolar cavity filled of macrophages. In the following months, in light of the progression of the disease, steroidal treatment (prednisone 1 mg/kg/day) was started with improvement of clinical manifestation, anemia and normalization of inflammatory markers. However attempts to reduce such therapy were followed by an exacerbation of the clinical picture. In the attempt to reduce steroidal treatment, the child was treated wit both immunosuppressive (azathioprine) and biologic (etanercept) drugs, without clear improvement. Unsatisfactory growth was also detected. In the following months the child started to present a mild renal involvement with microscopic hematuria and hypertension, requiring anti-hypertensive treatment. Given the evocative framework, interferon gene signature was performed, revealing a significant activation; the molecular analysis of TMEM173 gene showed the presence of the de novo Val155Met mutation, already described as causative of SAVI syndrome. The child continued to present persistent severe microcytic anemia, requiring erythrocytes9 transfusions, despite high levels of erythropoietin. Bone marrow aspiration was therefore performed, that revealed dysmaturative signs in the in erythroid progenitors. Conclusions This report of the first Italian patient with SAVI syndrome confirms the presence of the previously described clinical manifestations. Persistent hematuria and hypertension are reasonably signs of an underlying renal involvement, not previously described in this condition. Thus a renal biopsy is needed for confirmation. The origin of severe anemia is still unclear. Thus a possible deregulatory effect of mutated STING protein on bone marrow progenitors has to be investigated and is actually under study in our patient. Disclosure of Interest None declared

Background Positional differences of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) mutations may trigger opposite clinical outcomes in Pyogenic sterile Arthritis Pyoderma gangrenosum and Acne (PAPA) syndorme. The typical triad may not be fully displayed, and clinical picture often vary along the disease history in the same individual. PSTPIP1-ASC-pyrin interaction may lead to caspase-1 dependent Interleukin (IL)1β secretion. However, the involvement of NLRP3 and IL1β signaling itself in PAPA were explored mostly in in vitro or in vivo systems. Furthermore, due to disease rarity, anti-IL1 effectiveness was unveiled or refuted based on brief clinical reports with significant variability in response to treatment. Differences in experimental conditions and assessments being performed in possibly differing stage of patients9 diseases activity may give reason of the discrepancies observed. Thus, to date univocal insights concerning the actual role of IL1β signaling, its extent and the underlying regulatory molecular mechanisms in PAPA remain undefined, thus challenging an evidence-based application of anti-IL1 regimen. Objectives To define whether IL1β secretion in PAPA syndrome (1) is enhanced, (2) requires NLRP3, and (3) correlates with different PSTPIP1 mutations, disease activity and/or clinical picture. Methods A clinically well characterized cohort including 13 genetically confirmed PAPA subjects (E250Q+ N =10, E250K+ N =1, E256G+ N =2) and 1 patient wild-type (WT) for the common PSTPIP1 mutations were evaluated and compared with 35 healthy donors (HD). Peripheral blood monocytes were purified and studied at baseline and following in vitro TLR4 activation. Secretion pattern of IL1β, IL1α, IL1Ra, IL6, IL18 and Tumor Necrosis Factor (TNF)α was assessed in supernatants by ELISA and correlated to genotype, disease activity, ongoing therapies and clinical picture. Requirement of NLRP3 for IL1β secretion was investigated by silencing NLRP3 in monocytes purified from patients and HD. Results Increased IL1β release was found in the overall PAPA cohort (P=0.254), and silencing of NLRP3 prevented it. Patients with active disease displayed higher IL1β oversecretion (P Conclusions Variable IL1 β secretion was obserbed in PAPA cohort according to disease activity and clinical phenotype. The availability of a relevant number of patients and the chance to clinically and experimentally evaluate them in different phases of their disease history, allowed us to better define the actual behavior of IL1β secretion in this condition. Even if other mechanisms related to the complex PSTPISP1 protein networking might play additional roles, these results are in agreement with preliminary anecdotal reports on anti-IL1 regimen in PAPA and support the use of IL1 blockade as a potential effective therapeutic strategy in the clinical management of this condition. Disclosure of Interest None declared

Background PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an ultra-rare autosomal dominant, auto-inflammatory disease associated to mutations in the PSTPIP1 / CD2BP1 gene. The therapeutic approach during recurrences consists of steroids, while no agreement exists on the chronic management. Evidences on the use of biologics are anecdotal and variable results have been reported. Objectives To evaluate the long-term response to treatment with IL1 antagonist in six patients affected by PAPA syndrome. Methods Six patients (M:F=3:3; 4 pediatric, 1 young adult and 1 adult, mean age 18 years, range 3-50) affected by PAPA syndrome were enrolled and treated with IL1 blockers (5 patients Anakinra, 1 patient Anakinra followed by Canakinumab). Three patients were already treated with anti-TNFα monoclonal antibodies without benefit. Data were collected retrospectively (mean follow-up 26 months, range 4-38). The frequency of articular and cutaneous flares in the 24 months before starting therapy where compared to those occurred during anti-IL1 regimen. Acute phase reactants (ESR, CRP, SAA) were assessed at the last visit before the study enrolment and at last follow-up. Results All the patients displayed a significant decrease in frequency of disease flares (Table) and normalization of acute phase reactants. Three patients were asymptomatic during whole follow-up. Patient#4, with a severe and persistent pyoderma gangrenosum, displayed a partial response to Anakinra partially due to a poor compliance to daily s.c. administration. The shift to Canakinumab lead to a fast and complete resolution of the skin manifestations. Conclusions The long-term use of IL1 blockers is associated to satisfactory and persistent control of clinical manifestations and laboratory findings in PAPA syndrome. Disclosure of Interest M. Finetti: None declared, R. Caorsi: None declared, D. Marotto: None declared, A. Buoncompagni: None declared, A. Omenetti: None declared, B. Lattanzi: None declared, F. Minoia: None declared, P. Picco: None declared, M. Jorini: None declared, A. Martini Grant/research support from: Unrestricted grants from SOBI and Novartis, Speakers bureau: Speaker9s fees, M. Gattorno Grant/research support from: Unrestricted grants from SOBI and Novartis, Speakers bureau: Speaker9s fees

Background CAPS are autoinflammatory diseases characterized by recurrent episodes of fever and systemic inflammation. Three nosological entities representing different phenotypes, from the milder to the most severe (FCAS, MWS, CINCA). Cryopyrin, renamed NLRP3, is part of the intracellular multiprotein complex inflammasome that mediates IL-1 processing and secretion through caspase-1 activation. NLRP3 mutations in CAPS are gain-of-function, as they enhance inflammasome activity. The result is hypersecretion of IL-1, responsible for the inflammatory clinical manifestations. Objectives –To increase the knowledge on the pathologic consequences of NLRP3 mutations in CAPS patients; –To understand the underlying molecular and regulatory mechanisms of CAPS disease; –To identify novel molecular targets for the treatment of cryopyrin/NLRP3 related disorders. Methods We have generated a KI mouse carrying the N475K mutation into the murine NLRP3 gene. This mutation corresponds to the N477K human mutation, associated to a severe CINCA phenotype with neurological complications; Phenotypical and immunological characterization of NLRP3 Knock In (KI) mice has been performed by flow cytometry; The IL1β secretion from bone marrow derived dendritic cells (BMDCs) and peritoneal macrophages (PMs) of NLRP3 Knock In Mice has been evaluated by ELISA. Results The NLRP3 KI mice that we have obtained show hair loss, presence of skin rash and reduced survival time when compared to wild type (WT). Autopsy of KI mice, prematurely dead, revealed splenomegaly and a relevant inflammatory status. We compared the IL-1 secretion of inflammatory cells from WT and KI mice. PMs and BMDCs from mutant mice did not secrete mature IL-1β spontaneously. When stimulated with 100 ng/ml of LPS KI cells secreted higher levels of IL-1b than WT cells. The kinetics of IL-1β secretion was much faster in KI cells, reaching the plateau at 3h from exposure to LPS, thus reproducing the results obtained from monocytes of CAPS patients. As in CAPS monocytes, brief exposure to ATP strongly induced the secretion of IL-1β by LPS-activated WT cells while failed to stimulate further IL-1β secretion by inflammatory cells of KI mice. Finally, PMs and BMDCs from KI are more responsive to agonists of TLRs when compared to WT cells: LPS at 0.01 ng/ml triggered high levels of IL-1β secretion (comparable to 100 ng/ml of LPS) in inflammatory cells from KI indicating that the presence of the mutation lowers the threshold of activation. The neurological studies by MRI are in progress Conclusions The NLRP3 KI mice recapitulates phenotype and functional characteristics of CAPS patients. Thus, this model will hopefully provide elucidations in the mechanisms underlying CAPS as well as other inflammasomepathies. References Brydges SD et al., Immunity. 2009. Meng et al., Immunity 2009. Gattorno M. et al., Arthritis Rheum. 2013. Disclosure of Interest None declared

Background Provisional evidence-based classification criteria for inherited periodic fever (TRAPS, FMF, MKD and CAPS) have been recently developed based on the Eurofever registry. However, no consensus on how to combine clinical criteria with results of molecular analysis has been reached so far. Moreover evidence-based classification criteria on PFAPA are still lacking. Objectives To understand how physicians involved in the clinical care of patients with Autoinflammatory diseases (AIDs) classify patients with inherited periodic fever and PFAPA in daily practice. Methods By using the Delphi and Nominal Group Technique, we started an initial phase of three following e-mail surveys. In the first survey, clinicians/biologists or other health professionals working in the field of autoinflammation were asked to identify the variables that they consider as important, in the current clinical practice, for the diagnosis of patients with inherited periodic fever and PFAPA. This survey was open to not influence the experts. Results We sent the first survey to 129 experts. The overall rate of response was 102 (79%): 96 experts responded to be interested in the survey and 72 completed and confirmed it; 6 experts responded not to be interested. Up to date, we have analysed 44 experts9 survey. Not all the participants completed the survey for each disease. The table shows the preliminary results of the analysis. There was any clinical variable chosen by all the participants for the five diseases. For a high rate of experts, a positive genetic test is a relevant element for the diagnosis of FMF, TRAPS and MKD. Conversely, for the PFAPA the exclusion of the inherited genetic periodic fever by genetic test is important for a little part of experts. The response to treatment was proposed as interesting variable for FMF, CAPS and PFAPA. Conclusions The preliminary results of the first Eurofever Delphi Survey show a high rate of response, underlying the interest of the scientific community in this topic. There is a wide heterogeneity in the experts9 response for each disease. At the end of the Delphi Survey rounds, we will obtain different set of clinical criteria and we will verify their performance in comparison to already existing criteria in a cohort of patients with inherited periodic fever and PFAPA enrolled in the Eurofever Registry. The final step will be a Consensus among experts (geneticists and clinicians) in order to define the best combination of clinical and genetic data for the definitive classification of patients with inherited periodic fevers and PFAPA. Disclosure of Interest None declared

Background Familial Mediterranean fever (FMF) and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome are inherited autoinflammatory diseases. FMF patients have mutations in pyrin, a protein that has been suggested to play a role in the regulation of the inflammasome, PAPA patients have mutations in PSTPIP1, which interacts with pyrin. In both diseases, extraordinarily elevated serum levels of MRP8/14 were detected. Recently, we have identified two novel autosomal dominant mutations in the PSTPIP1 gene, p.E250K or p.E257K substitution, as genetic cause for a novel, more severe autoinflammatory entity: PAMI syndrome (PSTPIP1-associated myeloid-related-proteinaemia inflammatory syndrome). PAMI patients present with even higher levels of MRP8/14. MRP8 and MRP14 belong to the family of proinflammatory Damage Associated Molecular Pattern (DAMP) proteins, are mostly expressed in phagocytes and activate innate immune cells via TLR4 (Fassl et al. J. Immunol. 2015) after released via a so-called alternative pathway. However, the mechanism of secretion of MRP8/14 is still unknown. Objectives We investigated if pyrin and PSTPIP1 play a role in the secretion of MRP8/14. Methods MRP8/14 serum concentrations of patients were determined by ELISA. PSTPIP1 gene sequencing was performed in 14 patients with PAMI syndrome. Monocytes from patients were isolated and MRP8/14 levels were measured in culture supernatants prior and after activation. PSTPIP1-Pyrin-MRP8/14 interactions were investigated by immunoprecipitations and structural analysis. Results Monocytes from patients with PSTPIP1 mutations release significantly higher amounts of MRP8/14 than control cells. Immunoprecipitation studies demonstrated that p.E250K-PSTPIP1 is hyperphsphorylated and binds stronger to pyrin compared to wildtype protein. Furthermore, we could prove a direct interaction of both PSTPIP1 and pyrin with MRP8/14. By using deletion constructs of PSTPIP1 we could demonstrate that the MRP8/14 binding motif is mutated in PAMI syndrome. Conclusions Phagocytes seem to be the responsible cell type for the high serum concentration of MRP8/14 in PAMI syndrome. The DAMP proteins MRP8 and MRP14 interact directly with PSTPIP1 and mutations found in all patients are apparently located inside the PSTPIP1-MRP8/14 binding region. Moreover, the PSTPIP1 mutations influence the interaction with pyrin. Overall, our data indicate that hypersecretion of MRP8/14 is a relevant pathomechanism in PSTPIP1- and pyrin-associated diseases. Disclosure of Interest None declared

Background Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) were found to cause plaque psoriasis in two families and severe generalized pustular psoriasis as a monogenic form of childhood (CARD14-mediated pustular psoriasis, CAMPS) [1]. CARD14 mutations have also been implicated in plaque-type psoriasis and pityriasis rubra pilaris [2]. Objectives Describing a family with an unusual clinical phenotype characterized by some members with childhood-onset erytrodermic psoriasis first localized and then diffuse over all the skin surface; in some family members is also reported psoriatic arthritis. Methods We assessed for the first time the family in december 2013, because of their skin lesions and family recurrence for erytrodermic psoriasis associated to arthritis in some cases. There are three pairs of twins, five of them presenting psoriasis and two of them presenting psoriatic arthritis. The children presented poor clinical response to topic and systemic therapy with antihistamine, steroid, retinoids, cyclosporine and etanercept. The whole pedigree is depicted in the figure with the grey symbols indicating the affected members and an asterisk pointing out members for whom we got a biological sample (Figure). After exclusion of the most common genes associated to autoinflammatory diseases (IL36RN, IL1RN, MVK, TNFRSF1A, NLRP3, NLRP12, MEFV, IL1RN, NOD2, PSMB8, PSTPIP1, LPIN2). Successively, we approached the new gene search by subjecting to Whole Exome Sequencing (WES) analysis five members of the family, namely those indicated by an arrow. Samples were processed in outsourcing and raw data were transferred to our lab for the bio-informatic analysis. Results Among variants shared by the four affected individuals and not present in the unaffected subject, a missense mutation of the CARD14 gene resulted worth of further investigation. In particular, it was the case of an exon4 heterozygous nucleotide change, c.446T>G, leading to the missense amino acid substitution p.L149R. The presence of this variant was validated by Sanger sequencing not only in the affected members undergone WES, but also assessed in all the rest of the available family members. This allowed us to confirm the expected segregation of the CARD14 mutation with the disease phenotype. Conclusions CARD14 gain of function mutations can give rise to unusual clinical phenotype like diffuse erytrodermic psoriasis and psoriatic arthritis. WES appears to be a powerful, suitable and proper approach to identify new SAID genes, thus also disclosing new molecular pathogenic mechanisms. References Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. PSORS2 is due to mutations in CARD14. American journal of human genetics. 2012; 90(5):784–95. Epub 2012/04/24. Fuchs-Telem D, Sarig O, van Steensel MA, Isakov O, Israeli S, Nousbeck J, et al. Familial pityriasis rubra pilaris is caused by mutations in CARD14. American journal of human genetics.n 2012; 91(1):163–70. Epub 2012/06/19. Disclosure of Interest None declared