Search

Background:Systemic juvenile idiopathic arthritis (SJIA) is characterized by extra-articular manifestations, as fever and rash, and rarely associated by a potentially lethal complication as macrophage activation syndrome (MAS). Anakinra is a recombinant human interleukin (IL)-1 receptor antagonist whose efficacy and safety profile has been studied for patients with SJIA.Objectives:To evaluate the long-term safety profile of anakinra in patients with SJIA.Methods:Data from patients with SJIA enrolled in the Pharmachild registry before 30 September 2018 and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (AEs) of at least moderate severity and serious AEs (SAEs), including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall, by 6 month-time windows and in different treatment sets represented by those patients continuously treated with anakinra for at least 12, 18 and 24 months (set-12, -18, -24, respectively).Results:306 patients were enrolled. 46%, 34% and 28% of them had been treated for at least 12, 18 and 24 months, respectively. 201 AEs, mostly represented by infections, were reported for 509.3 patient-years (py) with an overall incidence rate (IR) of 39.5/100 py. Among 56 SAEs (IR 11.0/100 py), (Table 1) 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra, followed by decreasing IR in the different long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most in the first 6 months, due to inefficacy (43%), remission (31%) or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment.Table 1.Number of SAEs and incidence rates (95% CI) by overall PT decreasing order and time window in the complete set (events with a frequency >1 by overall SOC and >1 by overall PT were reported) Only time windows Time window1-6 months7-12 monthsOverallN306194306Patient-time (years)117.380.2509.3SOCPTnRate (95% CI)nRate (95% CI)nRate(95% CI)AllAll3328.1 (19.1-41.5)45.0 (1.9-13.2)5611.0 (7.9-15.2)Infections and infestationsAll76.0 (2.9- 12.4)11.2 (0.2- 8.8)132.6 (1.4- 4.8)Pneumonia21.7 (0.4- 6.8)11.2 (0.2- 8.8)40.8 (0.3- 2.1)Immune system disordersAll76.0 (2.8- 12.5)11.2 (0.2- 8.8)112.2 (1.1- 4.1)Haemophagocytic lymphohistiocytosis76.0 (2.8- 12.5)11.2 (0.2- 8.8)112.2 (1.1- 4.1)Injury, poisoning and procedural complicationsAll54.3 (1.8- 10.2)--91.8 (0.9- 3.4)Infusion related reaction10.9 (0.1- 6.0)--20.4 (0.1- 1.6)Injection related reaction43.4 (1.3- 9.1)--61.2 (0.5- 2.6)Metabolism and nutrition disordersAll32.6 (0.8- 7.9)--40.8 (0.3- 2.1)Skin and subcutaneous tissue disordersAll32.6 (0.8- 7.9)11.2 (0.2- 8.8)40.8 (0.3- 2.1)Blood and lymphatic system disordersAll10.9 (0.1- 6.1)--20.4 (0.1- 1.6)General disorders and administration site conditionsAll10.9 (0.1- 6.1)11.2 (0.2- 8.8)20.4 (0.1- 1.6)InvestigationsAll21.7 (0.4- 6.8)--20.4 (0.1- 1.6)Nervous system disordersAll10.9 (0.1- 6.0)--20.4 (0.1- 1.6)Surgical and medical proceduresAll10.9 (0.1- 6.0)--20.4 (0.1- 1.5)Abbreviations: SAE, serious adverse event; SOC, system organ class; PT, preferred term, MedDRA version 21.1; N, number of patients ever treated with anakinra during the time window irrespectively of the length of any unexposed periods; 95% CI, 95% Confidence Interval.Conclusion:The results of the present study confirm the long-term safety profile of anakinra in SJIA patients and show a decreasing overall incidence rate of AEs over time.Disclosure of Interests:Gabriella Giancane Grant/research support from: The study was funded by SOBI Swedish, Riccardo Papa Grant/research support from: The study was funded by SOBI Swedish, Sebastian Vastert Grant/research support from: The study was funded by SOBI Swedish, Francesca Bagnasco Grant/research support from: The study was funded by SOBI Swedish, Joost F. Swart Grant/research support from: The study was funded by SOBI Swedish, Pierre Quartier Grant/research support from: The study was funded by SOBI Swedish, michael hofer Grant/research support from: The study was funded by SOBI Swedish, Jordi Anton Grant/research support from: The study was funded by SOBI Swedish, Sylvia Kamphuis Grant/research support from: The study was funded by SOBI Swedish, Helga Sanner Grant/research support from: The study was funded by SOBI Swedish, Mia Glerup Grant/research support from: The study was funded by SOBI Swedish, Fabrizio De Benedetti Grant/research support from: The study was funded by SOBI Swedish, Elena Tsitsami Grant/research support from: The study was funded by SOBI Swedish, Agustin Remesal Grant/research support from: The study was funded by SOBI Swedish, Estefania Moreno Ruzafa Grant/research support from: The study was funded by SOBI Swedish, Jaime de Inocencio Grant/research support from: The study was funded by SOBI Swedish, Charlotte Myrup Grant/research support from: The study was funded by SOBI Swedish, Chiara Pallotti Grant/research support from: The study was funded by SOBI Swedish, Isabelle Koné-Paut Grant/research support from: The study was funded by SOBI Swedish, Karin Franck-Larsson Employee of: I am employee of SOBI pharmaceutical company, Hakan Malmstrom Employee of: I am employee of SOBI pharmaceutical company, Susanna Cederholm Employee of: I am employee of SOBI pharmaceutical company, Angela Pistorio Grant/research support from: The study was funded by SOBI Swedish, Nico Wulffraat Grant/research support from: The study was funded by SOBI Swedish, Nicolino Ruperto Speakers bureau: NR has received honoraria for consultancies or speaker bureaus (< 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche,Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB., Consultant of: NR has received honoraria for consultancies or speaker bureaus (< 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche,Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB., Grant/research support from: The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties.

Background The Pharmachild study is aimed at observing children with JIA undergoing treatment primarily with biologics±methotrexate (MTX). It is conducted by the participating centres of over 60 countries belonging to PRINTO and PReS. Objectives Primary endpoint of the study is safety in JIA patients undergoing immunosuppressive therapy. A preliminary analysis of infections has been performed by an independent Safety Ajudication Committee of 6 experts (3 pediatric rheumatologists and 3 pediatric infectious disease specialists). Methods The centres were asked to report all infections encountered by the patients followed for JIA. Data were checked by PRINTO and the medical monitor based on MedDRA dictionary. Upon completion of these steps, all eligible cases for adjudication, represented by serious/severe/very severe infections, were submitted to the expert Committee. The experts were asked to answer 6 questions. The events with consensus of at least 4/6 experts on more than 3/6 questions were considered. An additional analysis was performed on opportunistic infections, with referral to the recommendations by Withrop et al.1, and on the correlation between infections and 3 treatment phases: MTX only, first biologic±MTX and at least 2 sequential biologics±MTX after failure of the first biologic. Results 7817 patients were enrolled in Pharmachild at the time of preliminary analysis, with 27% of total safety events reported as infections. 360 events were submitted to the Safety Adjudication Committee. 94 infections (26.1%) achieved maximum consensus among the experts (6/6 questions), 237 (65.8%) consensus on 4/6 or 5/6 questions, the remaining events were discarded. 330 infections were finally retained for the analysis, mostly represented by serious infections of moderate/severe intensity. With regard to the other questions, 74.2% infections were adjudicated as common, appropriately treated, with no clear correlation to the immunosuppressive therapy. The experts achieved consensus on 18 infections adjudicated as opportunistic. Referring to the list of opportunistic infections provided by Winthrop et al.1, we identified 89/330 (27%) opportunistic infections, mostly represented by EBV and herpes zoster infections. 98.8% of events were not recoded. A doubled risk of infections was found in the group of patients who were started on their first biologic±MTX or who had been treated with at least 2 sequential biologics±MTX (1.3 and 1.9 infectious events per 100 py, respectively), compared to the MTX only group (0.8 infectious events per 100 py). The same was found for serious and opportunistic infections. Conclusions Our preliminary analysis showed a significant number of infections in JIA patients on immunosuppressive therapy, with one third classified as opportunistic infection. The introduction of biologics in therapy increased the risk of opportunistic and serious infection. References Winthrop et al. Ann Rheum Dis. 2015;74:2107–16. Disclosure of Interest None declared

Background Juvenile systemic sclerosis (jSSc) is an orphan disease. We have currently new promising effective medication to treat systemic sclerosis, but no valid outcome measures to assess the activity of the disease. Objectives In the frame of the juvenile scleroderma working group of Paediatric Rheumatology European Society (PRES JSWG), we developed a provisional response index for jSSc. Methods The facilitating committee designed a 3-round Delphi-exercise to obtain a core set of disease activity measures in jSSc. In Round 1, they were asked to add unique items in 21 preleminary domains. Round 2 judged the items9 applicability and importance using a 1-10 scale. Previous respondents were asked to re-rate uncertain (score 4-7) items in Round 3. The aforementioned were followed by a face-to-face Nominal Group discussion to decide final items and domain structure. Results 52 participants of Round 1 suggested a total of 131 items for the 21 domains. In round 2, 56 responders rated the significance of the items. The Nominal Group accepted 11 main domains for further validation containing 41 items (see table 1). Conclusions We reached consensus and developed a Response Index, which should help to conduct clinical trials in jSSc. The validation of the JSSRI is planned in the frame of the Juvenile Scleroderma Inception Cohort. Disclosure of Interest None declared

Background Treatment of juvenile idiopathic arthritis (JIA) has greatly changed in the past 15 years thanks to the introduction of biologic agents but little is known on the long-term safety profiles. Objectives To evaluate the long-term safety profile of a large cohort of JIA patients treated with methotrexate (MTX) alone or in combination with one or more biologic agents in the Pharmachild registry. Methods Pharmachild is an ongoing, multicenter, non-interventional, retrospective/prospective observational registry of patients with JIA treated with either MTX alone or in combination with one or more biologic agents as part of their standard clinical care. 3 treatment groups of patients were considered: treated with MTX only, treated with MTX+1 biologic agent (MTX+1B) and treated with MTX+>1 subsequentially given biologic agent (MTX+>1B). Safety was re-coded by certified assessors according to the Medical Dictionary for Regulatory Activities (MedDRA). True incidence rate events9 100 patient-years (PY) for events at least moderate other adverse events (AE) including events of special interest (ESI) or were calculated for all MedDRA System Organ Class (SOC). Results Out of 5882 JIA patients: 1715 (29%, 3832 PY, median disease duration, DD, 2.9 years) treated primarily with MTX (no biologics), 3007 (51%, 7013 PY, DD 4.7 years) treated with MTX+1B (67% etanercept, 18% adalimumab, infliximab/tocilizumab 5% each) and 1117 (19%, 4892 PY, DD 7.1 years) treated with MTX+>1B (31% etanercept, 27% adalimumab, 15% infliximab, 9% tocilizumab). 2355 (40%) children were treated also with corticosteroids (82% in systemics) and 1176 (20%) with other DMARDS. There were 609 (10.4%) systemic, 1195 (20.3%) oligo persistent, 2914 (49.5%) extended/poly RF pos or neg and 1164 (19.8%) other JIA categories. The incidence rates (Table) of serious AE increases with the addition of ≥1 biologic agents (2.1, 3.2, 8.9). A similar trend was observed for infections (3.2, 3.3, 4.4); serious infections rates were 0.5, 1, 1.9 respectively. The incidence rates for varicella were 0.55, 0.34, 0.41 and for herpes zoster 0.08, 0.24, 0.51 in the 3 groups, respectively. Incidence rates for injury, poisoning and procedural complications, blood and lymphatic system, eye and other were higher in the group treated with more than 1 biologic agent. Incidence rates for gastrointestinal and hepatobiliary disorders were higher for the MTX only group when compared to the other 2. Patients who discontinued the MTX or biologics for AE or drug intolerance were 75 (4%), 483 (16%) and 210 (18%). There were a total of 4 malignancies (2 acute lymphocytic leukemia, 1 thyroid cancer, 1 fibroadenoma of breast). There were 12 deaths (1, 5 and 6 in each of the 3 groups). Conclusions The introduction of one or more sequential biologic agent increase the rate of serious adverse events, infection when compared to the treatment with MTX alone. Disclosure of Interest J. Swart: None declared, A. Pistorio: None declared, F. Bovis: None declared, E. Alekseeva Grant/research support from: Roche, Abbott, Pfizer, Bristol-Myers Squibb, Centocor, Novartis, Speakers bureau: Roche, Merck Sharp & Dohme, Abbott, Bristol Myers Squibb, Medac, Novartis, Pfizer, M. Hofer: None declared, S. Nielsen: None declared, J. Anton Grant/research support from: Pfizer, abbvie, Novartis, Roche and Sobi, Speakers bureau: Pfizer, abbvie, Novartis, Roche and Sobi, A. Consolaro: None declared, V. Panaviene: None declared, V. Stanevicha: None declared, M. Trachana Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Novartis, Pfizer, Roche, Speakers bureau: Novartis, Pfizer, Roche, C. Ailioaie: None declared, P. Quartier: None declared, F. De Benedetti: None declared, E. Tsitsami: None declared, B. Flato: None declared, P. Dolezalova Grant/research support from: Novartis, Speakers bureau: Novartis, Pfizer, Roche, Abbvie, T. Constantin Speakers bureau: Pfizer, Abbvie, Novartis, Roche, Bristol-Myers Squibb, T. Herlin: None declared, S. Kamphuis: None declared, S. Sawhney: None declared, D. Maritsi: None declared, V. Vargova: None declared, L. Villa: None declared, C. Pallotti: None declared, A. Ravelli Consultant for: Roche, Speakers bureau: Abbvie, Novartis, Pfizer, A. Martini Shareholder of: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the industries mentioned in this section. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Consultant for: Honoraria for consultancy: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Vertex., Speakers bureau: Honoraria for speaker9s bureau from: Abbvie, Medimmune, Novartis, Roche, Takeda, N. Wulffraat: None declared, N. Ruperto Shareholder of: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the industries mentioned in this section. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Consultant for: Honoraria for consultancy: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex., Speakers bureau: Honoraria for bureau speaker: Abbott, AbbVie, Amgen, Biogenidec, Astellas, BMS, CD-Pharma, Hoffman-La Roche, Pfizer