Search

Objective: Pregnancy may influence the course of inflammatory rheumatic diseases and, conversely, rheumatic and musculoskeletal diseases (RMDs) can affect the outcome of pregnancy. This study aimed...

Background There is no international consensus on an optimal ultrasound score for monitoring of rheumatoid arthritis (RA) on patient-level yet. Our aim was to reassess the US7 score for the identification of the most frequently pathologic and responsive joint/tendon regions, to optimize it and contribute to an international consensus. Furthermore, we aimed to evaluate the impact of disease duration on the performance of the score. Methods RA patients were assessed at baseline and after 3 and 6 months of starting/changing DMARD therapy by the US7 score in greyscale (GS) and power Doppler (PD). The frequency of pathologic joint/tendon regions and their responsiveness to therapy were analyzed by Friedman test and Cochrane-Q test respectively, including the comparison of palmar vs. dorsal regions (chi-square test). The responsiveness of different reduced scores and the amount of information retained from the original US7 score were assessed by standardized response means (SRM)/linear regression. Analyses were also performed separately for early and established RA. Results A total of 435 patients (N = 138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p ≤0.003 by GS/PD). The dorsal vs. palmar side of the wrist by GS/PD (p p No major differences between the groups of early and established RA could be detected. Conclusions The wrist, MCP2, EDC, and ECU tendons were most frequently pathologic and responsive to therapy in both early and established RA and should therefore be included in a comprehensive score for monitoring RA patients on patient-level.

BackgroundFilgotinib (FIL) is a Janus kinase 1 preferential inhibitor approved for the treatment of moderate to severe rheumatoid arthritis (RA) in patients (pts) with an inadequate response to disease-modifying antirheumatic drugs.1 In a pooled analysis of Phase 3 FINCH 1–3 studies of FIL in RA, median lymphocyte levels were relatively stable over 1 year with lymphocyte decreases observed in individual FIL-treated pts. Lymphocyte levels should be monitored.1ObjectivesTo assess the effect of FIL on lymphocyte levels and lymphopenia in the FINCH 4 long-term extension (LTE) study in RA.MethodsSafety data of FIL 100 mg (FIL100) and 200 mg (FIL200) from LTE baseline to data cut off (01 June 2020) are reported overall and by prior FIL exposure for pts who received ≥1 FIL dose in FINCH 4 (NCT03025308; adults with RA who had completed FINCH 1/2/3). Adverse events (AEs) of lymphopenia were graded based on clinical severity; laboratory abnormalities (decreased lymphocytes) were graded per Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Frequencies of both measures and exposure-adjusted incidence rates (EAIRs) of AEs are reported. Median lymphocyte levels are reported to LTE Week 48.ResultsThe safety analysis set included 2729 pts (FIL200: n=1530; FIL100: n=1199). Of these, 75.4% (n=2058) had prior FIL exposure in FINCH 1/2/3. Median FIL exposure to LTE Week 48 was 600 (FIL200: 696; FIL100: 533) days.In both treatment groups, median laboratory lymphocyte levels remained relatively stable to LTE Week 48 for pts with prior FIL exposure. Pts without prior exposure had numerically higher median lymphocyte levels at LTE baseline vs pts with prior exposure (Figure 1). These decreased over time, but medians remained within normal range. The frequency and EAIR of graded decreases in laboratory lymphocyte levels were higher with FIL200 vs FIL100 (Table 1); incidence was slightly higher in pts with vs without prior FIL exposure, with the difference most apparent for Grade 2 decreases.Table 1.Frequencies of treatment-emergent laboratory decreases in lymphocytesPrior FIL exposureNo prior FIL exposureOverallTotalFIL200FIL100FIL200FIL100FIL200FIL100(N=2729)(n=1195)(n=863)(n=335)(n=336)(n=1530)(n=1199)Decreased lymphocytes228 (19.1)125 (14.5)41 (12.3)40 (12.0)269 (17.6)165 (13.8)434 (16.0)(any grade), n (%)Grade 148 (4.0)35 (4.1)14 (4.2)7 (2.1)62 (4.1)42 (3.5)104 (3.8)Grade 2159 (13.3)82 (9.5)21 (6.3)26 (7.8)180 (11.8)108 (9.1)288 (10.6)Grade 321 (1.8)8 (0.9)6 (1.8)7 (2.1)27 (1.8)15 (1.3)42 (1.5)Grade 40000000A treatment-emergent laboratory decrease in lymphocytes was defined as an increase of ≥1 toxicity grade from baseline at any time post-baseline up to and including the date of last study drug dose + 30 days. Severity grades were defined per CTCAE (lower limit of normal: 9/L [Grade 1]; 9/L [2]; 9/L [3]; 9/L [4]).Figure 1.Of all pts receiving FIL, 43 (1.6%) reported a lymphopenia AE; frequencies and EAIRs of lymphopenia AEs were slightly higher with FIL200 (1.9%; EAIR [95% CI]: 1.2 [0.9–1.8]) vs FIL100 (1.2%; 0.8 [0.4–1.3]). Most were Grade 1 or 2 in severity. Grade 3 lymphopenia AEs occurred in 4 (0.3%) vs 1 (No serious AEs of lymphopenia or treatment discontinuations due to lymphopenia were reported. In total, 8 (0.3%) pts interrupted study treatment due to lymphopenia. Infection rates, but not serious infections, were slightly higher for pts with lymphopenia, however no relationship between lymphopenia severity and infection AE grade was seen.ConclusionIn FINCH 4, lymphopenia AEs were infrequent but numerically greater with FIL200 vs FIL100, suggesting a dose–response relationship. While exposure at either dose may be associated with decreased lymphocytes, median lymphocyte levels were comparable in both groups and all remained within normal range at LTE Week 48, similar to observations in FINCH 1–3.References[1]Filgotinib SmPC and Jyseleca EPAR, 2020. Available at: https://www.ema.europa.eu/enAcknowledgementsThe authors would like to acknowledge Nadia Verbruggen and Pieter-Jan Stiers for providing statistical analysis support. This study was co-funded by Galapagos NV (Mechelen, Belgium) and Gilead Sciences, Inc. (Foster City, CA, USA). Medical writing support was provided by Kristian Clausen, MPH, CMPP (Aspire Scientific Ltd, Bollington, UK), and funded by Galapagos NV.Disclosure of InterestsJacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Galapagos, Gilead, Lilly, and Pfizer, Grant/research support from: Bristol Myers Squibb, and Pfizer, Gerd Rüdiger Burmester Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Galapagos, Lilly, MSD, Pfizer, Roche, and Sanofi, Katrien Van Beneden Shareholder of: Galapagos NV, Employee of: Galapagos NV, Chris Watson Shareholder of: Galapagos Biotech Ltd, Employee of: Galapagos Biotech Ltd, Ineke Seghers Employee of: Galapagos NV, Vijay Rajendran Employee of: Galapagos NV, Lorenzo Dagna Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and Swedish Orphan Biovitrium (SOBI), Grant/research support from: Bristol Myers Squibb, Celltrion, Kiniksa Pharmaceuticals, Pfizer, and Swedish Orphan Biovitrium (SOBI), Maya H Buch Speakers bureau: Speaker fees paid to host institution by AbbVie, Consultant of: Consultant honoraria paid to host institution by AbbVie, Galapagos, Gilead, and Pfizer, Grant/research support from: Gilead and Pfizer.

BackgroundThe preferential Janus kinase-1 inhibitor FIL significantly improved signs and symptoms of RA in Phase 2 and 3 trials.1–5 FIL is approved for treatment of moderate to severe active RA in Europe and Japan. Integrated safety analysis of FIL with patient data through 2019 was presented at the 2020 ACR virtual meeting.6ObjectivesTo report updated, as-treated data from the FIL integrated safety analysis with increased study drug exposure.MethodsData were integrated from 2 Phase 2 (NCT01668641, NCT01894516), 3 Phase 3 (NCT02889796, NCT02873936, NCT02886728), and 2 long-term extension (LTE) (NCT02065700, NCT03025308) trials. Phase 2 and 3 LTE data were through Nov 2020 and Jan 2021, respectively. The as-treated analysis set included all available data for pts receiving ≥1 dose FIL 200 (FIL200) or 100 mg (FIL100), including those rerandomized to FIL for LTE. Exposure-adjusted incidence rates (EAIR)/100 patient-y exposure (PYE) of treatment-emergent adverse events (TEAEs; onset after first dose and no later than 30 days after last dose or new drug first dose date −1 day) and TEAEs of special interest (AESIs) are presented.Results3691 pts received FIL200 or FIL100 for 8085.1 PYE (median 2.2, maximum 6.8 y). In the as-treated set, 61% of FIL200 and 45% of FIL100 pts received FIL for ≥2 y, 19% and 5% for ≥3 y, and 11% and 0.5% for ≥4.5 y, respectively. EAIR for TEAEs was higher with FIL100 than FIL200; EAIRs for deaths were 0.5 and 0.3 for FIL200 and FIL100 (Figure 1). Incidences of infections and serious infections were numerically greater for FIL100 vs FIL200, while EAIRs for other AESIs were comparable between doses (Table 1). EAIRs for AESIs tended to decrease since the previous update, except for venous thromboembolism (total FIL 0.1 to 0.2) and malignancies excluding NMSC (total FIL 0.5 to 0.6).Table 1.TEAEs of special interest, as-treated setTEAE, n (%) and EAIR per 100 PYE (95% CI)FIL 200 mgn=2267PYE=5302.5FIL 100 mgn=1647PYE=2782.6Total FILN=3691PYE=8085.1Infectious AEs1206 (53.2)747 (45.4)1927 (52.2)EAIR21.1 (19.7, 22.5)30.2 (26.8, 34.0)21.0 (19.9, 22.3)Serious infectious AEs80 (3.5)57 (3.5)137 (3.7)EAIR1.5 (1.1, 1.9)2.7 (1.9, 3.9)1.6 (1.3, 2.0)Opportunistic infections5 (0.2)4 (0.2)9 (0.2)EAIR0.1 (0, 0.2)*0.1 (0.1, 0.4)*0.1 (0.1, 0.2)*Active tuberculosis03 (0.2)3 (EAIR00.1 (0, 0.3)*0 (0, 0.1)*Herpes zoster84 (3.7)30 (1.8)114 (3.1)EAIR1.6 (1.2, 2.0)1.1 (0.8, 1.5)*1.4 (1.1, 1.7)Major adverse cardiovascular eventsa19 (0.8)14 (0.9)33 (0.9)EAIR0.3 (0.2, 0.5)0.5 (0.3, 0.8)*0.4 (0.2, 0.6)Venous thromboembolismb11 (0.5)4 (0.2)15 (0.4)EAIR0.2 (0.1, 0.4)*0.1 (0.1, 0.4)*0.2 (0.1, 0.3)*Atrial systemic thrombotic eventsa1 (1 (2 (EAIR0 (0, 0.1)0 (0, 0.3)0 (0, 0.1)Malignancy excluding NMSC32 (1.4)17 (1.0)49 (1.3)EAIR0.6 (0.4, 0.9)0.6 (0.4, 1.0)*0.6 (0.4, 0.8)NMSC15 (0.7)5 (0.3)20 (0.5)EAIR0.3 (0.2, 0.5)*0.2 (0.1, 0.4)*0.2 (0.2, 0.4)*Gastrointestinal perforations3 (0.1)1 (4 (0.1)EAIR0.1 (0, 0.2)*0 (0, 0.3)*0 (0, 0.1)**Except when any study had 0 event within the treatment, the Poisson model was not adjusted by study. PYE was defined as (last dose date − first dose date + 1)/365.25.aPositively adjudicated.bAdjudicated as deep vein thrombosis or pulmonary embolism.NMSC, nonmelanoma skin cancerConclusionWith 1 additional year of exposure since the 2020 report, FIL continues to be well tolerated with no new safety concerns emerging. EAIRs of TEAEs, including deaths, and AESIs remained stable or decreased since the 2020 report, except for slight increases in rates of NMSC and malignancies excluding NMSC. In the context of demonstrated efficacy, both FIL doses had an acceptable risk/benefit profile.References[1]Westhovens R et al. Ann Rheum Dis 2017;76:998–1008.[2]Kavanaugh A et al. Ann Rheum Dis 2017;76:1009–19.[3]Combe B et al. Ann Rheum Dis 2021;80:848–58.[4]Genovese MC et al. JAMA 2019;322:315–25.[5]Westhovens R et al. Ann Rheum Dis 2021;80:727–38.[6]Winthrop K et al. Arthritis Rheumatol 2020;72(suppl 10); abstract 0229.AcknowledgementsFunding for DARWIN 1 and 2 was provided by Galapagos NV, and funding for DARWIN 3, FINCH 1, 2, 3, and 4 was provided by Gilead Sciences, Inc., Foster City, CA. Funding for this analysis was provided by Gilead Sciences, Inc. The sponsors participated in the planning, execution, and interpretation of the research. Medical writing support was provided by Gregory Bezkorovainy, MA, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA.Disclosure of InterestsKevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, Roche, Regeneron, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, and Pfizer, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol Myers Squibb, Eisai, Chugai, AbbVie, Astellas, Pfizer, Sanofi, Asahi-Kasei, GSK, Mitsubishi-Tanabe, Gilead Sciences, Inc., and Janssen, Consultant of: AbbVie, Ayumi, Daiichi-Sankyo, Eli Lilly, GSK, Taisho, and Sanofi, Grant/research support from: AbbVie, Asahi-Kasei, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, and Takeda, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Mitsubishi-Tanabe, Novartis, Pfizer Japan, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly Japan, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan, Alan Kivitz Shareholder of: Amgen, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, and Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead Sciences, Inc., Janssen, Novartis, Pfizer, Regeneron, Sanofi, and SUN Pharma Advanced Research, Mark C. Genovese Shareholder of: Gilead Sciences, Inc., Consultant of: AbbVie, Amgen, Beigene, Eli Lilly and Co., Genentech, Inc., Gilead Sciences, Inc., Sanofi Genzyme, RPharm, and SetPoint, Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Kun Chen Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos BV, Employee of: Galapagos BV, Sander Strengholt Shareholder of: Galapagos BV, Employee of: Galapagos BV, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer, Consultant of: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer, Jacques-Eric Gottenberg Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos BV, Gilead Sciences, Inc., Roche, Sanofi Genzyme, and UCB, Consultant of: Bristol Myers Squibb, Sanofi Genzyme, and UCB, Grant/research support from: Bristol Myers Squibb and Pfizer

BackgroundBaricitinib (BARI), an oral selective JAK 1/2 inhibitor, is approved for treating adults with moderate to severe active rheumatoid arthritis (RA). RA-BE-REAL is a 3-year, multinational, prospective, observational study of adult patients with RA evaluating time to discontinuation of initial RA treatment for all causes (excluding sustained clinical response) over 24 months (M).ObjectivesThis analysis reports time to discontinuation in the European (France, Germany, Italy, Spain, UK) subgroup, treated with either BARI, biologic (b) disease-modifying anti-rheumatic drugs (DMARDs) or any other targeted synthetic (ts)DMARDs, as well as, the effectiveness of RA treatment, at 12M.MethodsIn the two cohorts, patients were initiated with BARI 2-mg or 4-mg (cohort A), or any bDMARD or tsDMARD (b/tsDMARDs; cohort B). Treatment initiation and changes are at the discretion of the patient or physician. Response rates for remission, low disease activity (LDA), moderate disease activity (MDA) or high disease activity (HDA) were determined using the Clinical Disease Activity Index (CDAI) at 12M. Quality of life using the EQ-5D-5L and patient reported outcome (PRO) measures for pain (pain visual analogue scale; VAS) and physical functioning (Health Assessment Questionnaire Disability Index; HAQ-DI) were also assessed at 12M. This pre-specified interim analysis reports descriptive 12M data using summary statistics, without any inferential testing.ResultsThis analysis involved 1073 adult RA patients with a mean age (standard deviation; SD) of 59.1 (13.2) (cohort A) and 57.0 (13.9) yrs (cohort B), respectively, and a mean disease duration (SD) of 10.0 (9.1) (cohort A) and 8.9 (9.6) yrs (cohort B), respectively. At baseline, 50.9% of patients in cohort A and 31.2% in cohort B initiated treatment as a monotherapy. At 12M, 26.7% of patients in cohort A and 44.1% of patients in cohort B had discontinued treatment. The most common reason for discontinuation in both cohorts was primary non-response. At 12M, 24.1% of patients in cohort A and 16.6% in cohort B achieved CDAI remission (Figure 1). The mean CDAI reduction was -14.5 and -12.0, respectively in cohorts A and B. Mean reductions from baseline in physician global assessment (PhGA) and in patient global assessment (PGA) were -3.4 and -2.5, respectively in cohort A and -3.0 and -2.1, respectively in cohort B. Improvements from baseline in EQ-5D-5L, HAQ-DI, and pain (VAS) were reported in both cohorts at 12M. The mean pain (VAS) reduction from baseline was -24.6 and -19.3 in cohort A and cohort B, respectively.Figure 1.Percentage of pts in cohorts A and B achieving remission and LDA at 12MConclusionThe majority of BARI-treated patients were in remission or had low disease activity and continued treatment at 12M.Table 1.Disease activity and patient reported outcomes at baseline and 12MCohort A BaricitinibCohort B b/tsDMARDsBaseline12MCFBBaseline12MCFBCDAI24.0 (11.7)9.1 (8.2)-14.5 (12.4)23.8 (12.4)10.7 (9.8)-12.0 (12.6)SJC5.2 (4.8)1.3 (2.4)-3.9 (4.8)4.7 (4.9)1.3 (2.8)-3.0 (4.6)TJC7.3 (6.1)2.2 (3.6)-4.7 (6.0)7.8 (6.5)3.0 (4.8)-4.0 (6.1)PhGA5.6 (2.0)2.3 (2.1)-3.4 (2.5)5.5 (2.1)2.5 (2.1)-3.0 (2.6)PGA5.9 (2.3)3.4 (2.5)-2.5 (2.9)5.8 (2.4)3.8 (2.6)-2.1 (3.0)HAQ-DI1.4 (0.7)1.0 (0.8)-0.4 (0.6)1.3 (0.7)1.0 (0.8)-0.3 (0.6)Pain (VAS)59 (23.1)33.2 (26.2)-24.6 (28.7)56.5 (24.3)36.6 (26.5)-19.3 (30.4)EQ-5D-5L0.5 (0.3)0.7 (0.2)0.1 (0.3)0.5 (0.3)0.7 (0.2)0.1 (0.3)Values represent observed mean (SD)b/tsDMARDs; biologic/targeted synthetic disease-modifying anti-rheumatic drugs, CFB; change from baseline, CDAI; clinical disease activity index, SJC; swollen joint count, TJC; tender joint count, P(h)GA; patient (physician) global assessment of disease activity, HAQ-DI; health assessment questionnaire disability index, VAS; visual analogue scale (mm), EQ-5D-5L; European quality of life 5 dimensions 5 levelsDisclosure of InterestsRieke Alten Speakers bureau: Eli Lilly and Company, Pfizer, Galapagos, Consultant of: Eli Lilly and Company, Pfizer, Galapagos, Grant/research support from: Eli Lilly and Company, Pfizer, Galapagos, Gerd Rüdiger Burmester Speakers bureau: Amgen, AbbVie, BMS, Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche, Sanofi, Consultant of: Amgen, AbbVie, BMS, Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche, Sanofi, Marco Matucci Cerinic Speakers bureau: Biogen, Eli Lilly and Company, Grant/research support from: Actelion, Biogen, Novartis, MSD, Andrew Ostor Consultant of: AbbVie, BMS, Roche, Janssen, Eli Lilly and Company, Novartis, Pfizer, UCB, Gilead, Paradigm, Liliana Zaremba-Pechmann: None declared, Marta Herrera Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kathy Gibson Speakers bureau: UCB, Consultant of: Janssen, Novartis, Grant/research support from: Novartis, Employee of: Eli Lilly and Company, Tamas Treuer Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jens Gerwien Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Bruno Fautrel Consultant of: AbbVie, Biogen, BMS, Celgene, Janssen, Eli Lilly and Company, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, SOBI, UCB, Grant/research support from: AbbVie, MSD, Pfizer, Eli Lilly and Company

BackgroundThe preferential Janus kinase-1 inhibitor FIL is approved for treatment of moderate to severe active RA in Europe and Japan.ObjectivesIn this post hoc, exploratory analysis, efficacy and safety of long-term treatment with FIL (± MTX) were assessed in MTX-naïve pts treated with FIL or MTX in the Phase 3 PS (NCT02886728).1MethodsPts received FIL 200 mg (FIL200)+MTX, FIL 100 mg (FIL100)+MTX, FIL200 alone, or MTX alone up to 52 W in PS.1 Those completing PS on study drug could enter LTE (NCT03025308; data cutoff: June 1, 2020). MTX completers were rerandomized, blinded, to FIL200 or FIL100; pts on FIL in PS remained on the same dose in LTE. MTX was washed out for 4 W at LTE baseline (BL); pts could (re)start MTX and/or other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) ≥4 W after LTE first dosing.1 Efficacy data to LTE W48 and safety data are reported.ResultsAs of June 1, 2020, 439/492 (89%) and 144/169 (85%) pts who entered LTE from PS FIL200 and PS FIL100 groups, respectively, remained on LTE study treatment; of those rerandomized from MTX, 131/148 (89%) FIL200 and 133/151 (88%) FIL100 pts remained on study treatment. LTE BL characteristics were similar between FIL200 and FIL100 groups. After MTX washout, 17% of FIL200 and 23% of FIL100 pts (re)started MTX (at clinical judgment). ACR20/50/70 response rates among pts from PS FIL arms decreased modestly from LTE BL to W12 then stabilized. Among pts who switched from PS MTX to LTE FIL, response rates remained stable or improved to approach those of PS FIL pts by W48 (Figure 1). Similar trends were seen in DAS28(CRP) and CDAI. Treatment-emergent adverse events (TEAEs), Grade ≥3 AEs, serious AEs, and infections were largely comparable across groups and did not increase after MTX to FIL switch. There were 6 deaths, all among PS FIL200 pts (Table 1).Table 1.EAIRs of TEAEs through June 2020EAIR (95% CI)FIL200+MTX →FIL200 →FIL100+MTX →MTX →MTX →FIL200 LTEFIL200 LTEFIL100 LTEFIL200 LTEFIL100 LTEn=325n=167n=169n=148n=151PYE=474.4PYE=232.5PYE=236.4PYE=213.4PYE=215.4TEAE49.7 (43.8, 56.5)46.9 (38.9, 56.6)49.9 (41.7, 59.8)50.6 (41.9, 61.1)46.4 (38.2, 56.5)TEAE Grade ≥37.2 (5.1, 10.0)6.5 (3.9, 10.7)10.2 (6.8, 15.1)7.0 (4.2, 11.7)7.0 (4.2, 11.6)TE serious AE5.9 (4.1, 8.5)6.0 (3.6, 10.2)8.9 (5.8, 13.6)6.6 (3.9, 11.1)6.5 (3.9, 11.0)Death1.1 (0.3, 2.5)0.4 (0.1, 3.1)0 (0, 1.6)0 (0, 1.7)0 (0, 1.7)Infections28.5 (24.0, 33.7)29.7 (23.4, 37.6)27.5 (21.6, 35.1)28.6 (22.2, 36.7)27.4 (21.2, 35.4)Serious infections1.1 (0.4, 2.5)3.0 (1.4, 6.3)2.5 (1.1, 5.7)1.9 (0.7, 5.0)1.9 (0.7, 4.9)Opportunistic infections0.2 (0, 1.5)0 (0, 1.6)0.8 (0.2, 3.4)0 (0, 1.7)0 (0, 1.7)Herpes zoster0.8 (0.3, 2.2)1.7 (0.6, 4.6)0.8 (0.2, 3.4)1.9 (0.7, 5.0)0.9 (0.2, 3.7)MACE (adjudicated)0.6 (0.1, 1.8)0.9 (0.2, 3.4)0 (0, 1.6)0 (0, 1.7)0 (0, 1.7)VTE (adjudicated for DVT/PE)0.2 (0, 1.2)0.4 (0.1, 3.1)0 (0, 1.6)0 (0, 1.7)0 (0, 1.7)Malignancies (excluding NMSC)0.6 (0.2, 2.0)0 (0, 1.6)1.7 (0.6, 4.5)0.5 (0, 2.6)0 (0, 1.7)NMSC0.6 (0.2, 2.0)0.4 (0.1, 3.1)0.8 (0.2, 3.4)0.5 (0, 2.6)0 (0, 1.7)DVT, deep vein thrombosis; EAIRs, exposure-adjusted incidence rates (per 100 patient-years of exposure); MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; PE, pulmonary embolism; VTE, venous thromboembolismFigure 1.ConclusionOverall, response rates improved from LTE BL to W48 for pts switched from PS MTX to FIL and decreased modestly for PS FIL pts. Rates of AEs of special interest were generally low and tended to be higher in pts maintained on FIL from PS. Safety findings in this subpopulation were comparable with the PS through W521 and with a 7-trial integrated safety analysis.2 Limitations: the LTE was not formally randomized at BL, the groups were of unequal size, and the switch from MTX to FIL for LTE was by design rather than based on disease activity.References[1]Westhovens R et al. Ann Rheum Dis 2021;80:727–38.[2]Winthrop K et al. Arthritis Rheumatol 2020;72(suppl 10): abstract 0229.AcknowledgementsFunding for the trials was provided by Galapagos NV and Gilead Sciences, Inc. The sponsors participated in the planning, execution, and interpretation of the research. This study was funded by Gilead Sciences, Inc., Foster City, CA. Medical writing support was provided by Gregory Bezkorovainy, MA, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA. Funding for this analysis was provided by Gilead Sciences, Inc.Disclosure of InterestsDaniel Aletaha Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme, and UCB, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, and Sanofi/Genzyme, Grant/research support from: AbbVie, Merck Sharp & Dohme, Novartis, and Roche, Rene Westhovens Consultant of: Celltrion, Galapagos, and Gilead Sciences, Inc., Grant/research support from: Celltrion, Galapagos, and Gilead Sciences, Inc., Tatsuya Atsumi Speakers bureau: AbbVie Inc., Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eisai Co. Ltd, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Ltd, Pfizer Inc., Takeda Pharmaceutical Co., Ltd, UCB Japan Co. Ltd, Consultant of: AbbVie Inc., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K., Gilead Sciences, Inc., Pfizer Inc., UCB Japan Co. Ltd, Grant/research support from: AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., Pfizer Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Vijay Rajendran Shareholder of: Galapagos NV, Employee of: Galapagos NV, Sander Strengholt Shareholder of: Galapagos BV, Employee of: Galapagos BV, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead Sciences, Inc. and Pfizer, Consultant of: AbbVie, Eli Lilly, Gilead Sciences, Inc. and Pfizer

Die Prognose der rheumatoiden Arthritis (RA) hat sich in den letzten Jahrzehnten deutlich verbessert. Dazu haben im Wesentlichen eine fruhere Erkennung, bessere Diagnostik und neue Therapieoptionen wie optimierter Einsatz von klassischen DMARDs („disease modifying antirheumatic drugs“) und Biologika beigetragen. Weitere Faktoren waren auch eine fruhere Intervention, eine verbesserte Verfugbarkeit von Informationen und Analysen und sicher auch die Standardisierung der Versorgung (z. B. Leitlinien). Ein zusatzlicher wichtiger Baustein ist eine engmaschige Kontrolle der Krankheitsaktivitat, um die Therapie rechtzeitig anpassen zu konnen und somit Schaden zu verhindern. Die Forderung nach dieser Kontrolle, im englischen „tight control“, ist Gegenstand dieses Beitrags.

Objective Systemic sclerosis (SSc) can lead to ischemic complications such as digital ulcers (DUs). The aim of the study was to find predictors of DUs by clinical and new imaging methods. Patients and methods All 79 SSc patients included in the study received a clinical, colour Doppler ultrasound (CDUS), fluorescence optical imaging (FOI) and capillaroscopy examination at baseline, and their capacity to predict new DU development was analysed in 76 patients at 12 months follow-up. Results Twenty-two of 76 patients (28.9%) developed new ulcers during follow-up (diffuse SSc 48.1%; limited SSc 18.4%). Receiver operating characteristic (ROC) curve analysis revealed an area under the curve of 0.7576 for DU development, with a specificity of 87% and a sensitivity of 54.6% (p = 0.0003, OR = 8.1 [95%CI 2.5–25.6]) at a cut-off of ≥ 21 points (ACR/EULAR classification criteria for SSc). Capillaroscopy and CDUS had high sensitivity (100% and 95.5%) but low specificity (28.9% and 22.2%) for ulcer occurrence when used alone, but better specificity (46.3%) when combined (OR = 18.1 [95%CI 2.3–144.4]; p = 0.0004). Using FOI, fingers with pathologic staining had a higher risk for new ulcer development in the same finger (p = 0.0153). General future DU (i.e. DU also in other fingers) was associated with a missing FOI signal in the right digit III at baseline (p = 0.048). Conclusion New imaging modalities can predict digital ulcer development in SSc patients with high sensitivity for capillaroscopy and CDUS and enhanced specificity when combined. A missing signal of FOI in the right digit III at baseline was associated with general future DU.

Background:Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for rheumatoid arthritis (RA). The safety and efficacy of UPA has been evaluated across a spectrum of patients (pts) with RA in the phase 3 SELECT clinical program.1,2Objectives:To describe long-term laboratory profiles (cutoff date: June 30, 2020) associated with exposure to UPA, adalimumab (ADA), and methotrexate (MTX) in pts with RA treated in the SELECT trials.Methods:Data were analyzed from 6 randomized controlled UPA RA trials.1,2 The proportions of pts experiencing potentially clinically significant laboratory changes at a single time point were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15; 6 trials), pooled UPA 30 mg QD (UPA30; 4 trials), ADA 40 mg every other week (EOW; 1 trial), and MTX monotherapy (1 trial). Pts received UPA with/without background conventional synthetic disease-modifying antirheumatic drugs. Treatment-emergent adverse events are reported as exposure-adjusted event rates (events/100 pt-years [E/100 PY]). Toxicity was graded per OMERACT criteria, or NCI CTCAE for creatine phosphokinase (CPK) and creatinine.Results:4413 pts received ≥1 dose of UPA (UPA15, n=3209; UPA30, n=1204). Exposures were comparable between treatment groups (Table). Proportions of pts with Grade (Gr) 3 and 4 decreases in hemoglobin were highest with UPA30 and MTX (Table). Rates of anemia, as reported by the investigator, were comparable between UPA15, ADA, and MTX groups (Figure); the frequency of UPA-treated pts who discontinued due to anemia was low in all arms. Gr 3 and 4 decreases in neutrophils and lymphocytes with UPA were dose-dependent and higher vs ADA or MTX. Discontinuations due to neutropenia and lymphopenia were rare (Table 1.Pts with potentially clinically significant laboratory changesVariable, n (%)MTX monotherapy (n=314; 637.4 PY)ADA 40 mg EOW (n=579; 1051.8 PY)UPA 15 mg QD (n=3209; 7023.8 PY)UPA 30 mg QD (n=1204; 3091.6 PY)Mean (SD) exposure, weeks106 (67)95 (70)114 (64)134 (66)Median (range) exposure, weeks144 (1, 221)118 (2, 231)136 (0, 232)160 (0, 231)Hemoglobin, g/LGr 3 (70–28a (9.0)24b (4.2)254d (7.9)169f (14.2)Gr 4 (16a (5.1)16b (2.8)101d (3.2)78f (6.5)Neutrophils, 109/LGr 3 (0.5–3a (1.0)3b (0.5)40d (1.2)37g (3.1)Gr 4 (1a (0.3)1b (0.2)10d (0.3)5g (0.4)Lymphocytes, 109/LGr 3 (0.5–74a (23.7)53b (9.2)802d (25.1)423g (35.5)Gr 4 (5a (1.6)3b (0.5)75d (2.3)47g (3.9)ALT, U/LGr 3 (3.0–8.0 × ULN)26a (8.3)13c (2.3)152e (4.8)71h (5.9)Gr 4 (>8.0 × ULN)5a (1.6)4c (0.7)26e (0.8)10h (0.8)AST, U/LGr 3 (3.0–8.0 × ULN)15a (4.8)9c (1.6)101e (3.2)36h (3.0)Gr 4 (>8.0 × ULN)1a (0.3)5c (0.9)18e (0.6)8h (0.7)CPK, U/LGr 3 (>5.0–10.0 × ULN)2a (0.6)3c (0.5)65e (2.0)36i (3.0)Gr 4 (>10.0 × ULN)0a (0)3c (0.5)27e (0.8)15i (1.3)Creatinine, μmol/LGr 3 (>3.0–6.0 × ULN)0a (0)1c (0.2)3e (2j (0.2)Gr 4 (>6.0 × ULN)0a (0)4c (0.7)8e (0.3)1j (an=312. bn=576. cn=577. dn=3201. en=3199. fn=1193. gn=1192. hn=1195. in=1196. jn=1197ULN, upper limit of normalConclusion:This long-term analysis of UPA-treated pts with RA showed dose-dependent relationships for several laboratory abnormalities. Incidences of these with UPA15 were typically higher than with ADA but similar to MTX, except for increased CPK elevations. Treatment discontinuations due to laboratory abnormalities were infrequent and similar across all treatment groups.References:[1]Tanaka Y. Mod Rheumatol 2020;30:779–87; 2. Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Sanofi/Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, and UCB, Grant/research support from: Pfizer, Nancy Lane Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm, and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi, and UCB, Daniel Furst Speakers bureau: AbbVie, Continuing Medical Education, and Novartis, Consultant of: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, Novartis, and Pfizer, Grant/research support from: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and Sanofi, Jiří Vencovský Speakers bureau: AbbVie, Biogen, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, and Octapharma, Anthony G Wilson: None declared, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Tim Shaw Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jillian Yee Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer, Roche, and UCB

Introduction Filgotinib (FIL), inhibiteur preferentiel de JAK1 per os, a ameliore les signes et les symptomes de la polyarthrite rhumatoide (PR) dans 3 essais de phase 3. [1] , [2] , [3] . Les patients (pts) PR ont une augmentation du risque de reactivation du zona vs la population generale. L’inhibition de JAK est associee a une incidence accrue des infections, y compris de zona [4] . Objectifs Evaluer la tolerance a long terme pour le zona dans l’ensemble du programme clinique du FIL. Patients et methodes Les pts dans l’analyse poolee des etudes DARWIN1–2, FINCH1–3 et des extensions DARWIN3 et FINCH4 ont ete inclus. L’ensemble des donnees controlees vs PBO incluait les pts recevant FIL100, FIL200 ou PBO jusqu’a S12 et l’ensemble controle par traitement actif comprenait les pts recevant FIL100, FIL200, adalimumab (ADA) ou methotrexate (MTX) jusqu’a S52. L’ensemble des donnees a long terme incluait les patients recevant FIL100 ou FIL200, ADA, MTX ou PBO dans les 7 etudes ; les donnees apres re-randomisation ont ete incluses et ont contribuees au traitement recu. Les taux d’incidence ajustes en fonction de l’exposition (TIAE) pour 100 patients-annees, jusqu’au dernier jour de suivi, et les IC95 % ont ete calcules a l’aide de la regression de Poisson. Un modele de regression logistique a ete utilise pour l’analyse des facteurs de risque de zona apparu sous traitement, et les risques relatifs (RR) (IC95 %) et les p valeurs ont ete fournis. Resultats Le Tableau 1 montre les TIAE de zona apparus sous traitement dans l’analyse poolee. Les taux de zona etaient inferieurs pour FIL200 vs PBO dans l’analyse controlee vs PBO de 12S. A S52, les taux de zona etaient plus eleves pour FIL200/100 vs controle par traitement actif. Les taux de zona a long terme sont plus eleves pour FIL200 vs FIL100. La Fig. 1 montre les facteurs de risque de zona apparu sous traitement selon un modele de regression logistique multivariee. Dans l’analyse a long terme, sur 104 pts avec un zona apparu sous traitement, 5 recevant FIL200 avaient des ATCD de zona ; le TIAE (IC95 %) etait de 8,7 (3,6–21,0). En Asie, dans l’analyse a long terme, les TIAE (IC95 %) de zona sous traitement etaient : 3,7 (1,7–8,1) pour FIL200, n = 197 ; 2,8 (1,3–6,3) pour FIL100, n = 158 ; 0 pour ADA, n = 40 ; 2,8 (0,4–19,6) pour MTX, n = 43 ; et 3,4 (0,5–23,8) pour PBO, n = 77. Dans l’analyse a long terme du reste du monde, les TIAE (IC95 %) etaient : 1,6 (1,2–2,1) pour FIL200, n = 2070 ; 0,9 (0,6–1,5) pour FIL100, n = 1489 ; 0,8 (0,2–3,1) pour ADA, n = 285 ; 0,9 (0,3–2,9) pour MTX, n = 373 ; et 0,7 (0,2–2,9) pour PBO, n = 704. La plupart des zona apparus sous traitement etait d’intensite legere a moderee et sans gravite ; 6 etaient graves ; 2 etaient des recidives. Aucun zona visceral n’est survenu au cours du programme ; il y a eu 1 zona genital, 1 zona dissemine et 1 zona ophtalmique. Le zona dissemine est survenu chez un pt avec un ATCD de zona. La lymphopenie n’etait pas associee au zona dans l’analyse controlee vs PBO de 12S. Conclusion Le zona etait plus frequent dans les 2 groupes FIL vs ADA ou MTX jusqu’a 52S mais comparable au PBO dans l’analyse controlee par PBO de 12S. Dans les analyses multivariees, les ATCD de zona, la region asiatique et l’âge ≥ 50 ans etaient associes a un risque accru de zona.

Introduction Les formes sévères de COVID-19 comportent à une hyperinflammation systémique intense ; ce qui a justifié des essais thérapeutiques avec des immunomodulateurs régulièrement utilisés chez les patients atteints de maladies systémiques auto-immunes ou inflammatoires Depuis février 2021 où les premières recommandations EULAR sur l’utilisation de thérapeutiques immunomodulatrices dans le COVID-19 ont été publiées [1], de nouveaux essais thérapeutiques ont été réalisés ce qui rend nécessaire une mise à jour ces recommandations. Matériels et méthodes Selon les procédures standardisées de l’EULAR [2], les résultats d’une revue de la littérature systémique réalisée jusqu’au 15 décembre 2020 puis mise à jour jusqu’au 14 juillet 2021 incluant tous types d’études ont été présentés à un groupe de travail multidisciplinaire composé d’experts internationaux comprenant des rhumatologues, des immunologistes translationnels, des hématologues, des pédiatres, des patients et des professionnels de la santé. La mise à jour des recommandations a été discutée et votée par l’ensemble du panel d’experts sur la base des résultats présentés, principalement des essais randomisés contrôlés (ECT) sur différents traitements immunomodulateurs. Résultats La mise à jour comprend deux principes généraux et dix recommandations. Les recommandations concernent uniquement la prise en charge des patients présentant des formes de COVID-19 modérées à sévères ou critiques, faute de preuves suffisantes avec très peu d’ECT concernant les patients asymptomatiques et ceux avec des formes légères de la maladie. Les molécules suivantes ont montré une efficacité dans le traitement de formes modérées à sévères ou critiques du COVID-19. L’association de glucocorticoïdes et de tocilizumab est bénéfique dans les cas de COVID-19 nécessitant une oxygénothérapie et dans les cas critiques de COVID-19. L’utilisation d’inhibiteurs de Janus kinase (baricitinib et tofacitinib) et peut-être d’Ac anti-GM-CSF est prometteuse dans les mêmes populations. Les anticorps monoclonaux anti-SARS-CoV-2 et l’utilisation de plasma convalescent pourraient trouver une application dans les phases précoces de la maladie et dans certains sous-groupes de patients immunodéprimés. D’autres immunomodulateurs comme l’hydroxychloroquine, la colchicine ou l’anakinra n’ont pas démontré leur efficacité sur la mortalité et ou sur l’aggravation clinique (évolution vers une détresse respiratoire), quel que soit le stade de la maladie. Conclusion Un nombre grandissant d’ECT soutiennent l’efficacité de l’association de glucocorticoïdes et d’autres agents immunomodulateurs tels que le tocilizumab dans le traitement de formes modérée à sévère et critique du COVID-19. De plus, certaines études en cours pourraient confirmer l’efficacité potentielle d’autres approches thérapeutiques comme les inhibiteurs de JAK ou les Ac anti-GM-CSF. L’implication des rhumatologues, en tant qu’experts des maladies inflammatoires et auto-immunes systémiques et des traitements immunomodulateurs est nécessaire dans le design des nouveaux essais cliniques et dans l’élaboration de nouvelles recommandations pour la prise en charge du COVID-19.

Introduction Les patients atteints de maladies musculosquelettiques inflammatoires/auto-immunes (I-RMD) n’ont pas ete inclus dans les etudes de tolerance des vaccins contre le SARS-CoV-2 et sont souvent inquiets quant a la tolerance de la vaccination. Notre objectif est d’etudier la tolerance des vaccins contre le SARS-CoV-2 chez les patients atteints de maladies musculosquelettiques inflammatoires/auto-immunes (I-RMD). Patients et methodes Pour cela, nous avons cree avec l’EULAR un registre international de cas rapportes par les medecins rhumatologues et internistes de patients atteints d’I-RMD et de RMD non inflammatoire (NI-RMD) vaccines contre le SARS-CoV-2. Du 5 fevrier 2021 au 27 juillet 2021, nous avons recueilli des donnees sur la demographie, la vaccination, le diagnostic de RMD, l’activite de la maladie, les traitements immunomodulateurs/immunosuppresseurs, les poussees, les evenements indesirables (EI) et les infections COVID-19 chez les patients vaccines. Les donnees ont ete analysees de maniere descriptive. Resultats L’etude a inclus 5121 participants de 30 pays, la majorite de France (40 %), Italie (16 %) et Portugal (14 %), 90 % avec des I-RMD (n = 4604, 68 % de femmes, âge moyen 60,5 ans) et 10 % avec des NI-RMD (n = 517), 77 % de femmes, âge moyen 71,4 ans. La polyarthrite rhumatoide (33 %), les connectivites (18 %), les spondyloarthrites (11 %), le rhumatisme psoriaqique (10 %) et les vascularites (12 %) etaient les diagnostics les plus frequents ; 54 % des patients ont recu des traitements de fond synthetiques conventionnels (csDMARD), 42 % des DMARD biologiques ou cibles et 35 % des immunosuppresseurs. La plupart des patients ont recu le vaccin Pfizer/BioNTech (70 %), 17 % AstraZeneca/Oxford et 8 % Moderna. Une infection COVID post-vaccination a ete signalee dans 0,7 a 1,1 % des cas, selon le statut vaccinal (entierement/partiellement vaccine) et le groupe RMD. Des poussees d’I-RMD ont ete signalees dans 4,4 % des cas (0,6 % de poussees severes), dont 1,5 % ont entraine des changements de medicaments. Des EI ont ete signales dans 37 % des cas (37 % I-RMD, 40 % NI-RMD), des EI severes dans 0,4 % des cas, tres divers et avec une frequence comparable et meme inferieure a celle observee chez les patients atteints de NI-RMD (1,1 %). Discussion La tolerance au vaccin n’etait pas differente entre les groupes I-RMD et NI-RMD. Dans les essais cliniques de vaccins a ARN contre le SRAS-CoV-2 dans la population generale, les taux d’EI graves etaient tres semblables a ceux de notre etude, allant de 0,4 % a 0,6 % dans le groupe vaccine et de 0,5 % a 0,6 % dans le groupe temoin, ce qui suggere que ces EI graves ne sont pas necessairement lies au vaccin. Conclusion Il s’agit de la plus grande etude de la tolerance des vaccins anti-SRAS-CoV-2 chez pres de 5000 patients atteints de maladies inflammatoires/auto-immunes rhumatologiques. Le profil de securite des vaccins contre le SRAS-CoV-2 chez les patients atteints d’I-RMD etait rassurant, et comparable a celui des patients atteints de NI-RMD. La majorite des patients ont bien tolere leur vaccination, avec de rares poussee d’I-RMD et de tres rares EI severes probablement non lies a la vaccination. Ces resultats devraient rassurer les rhumatologues et les personnes vaccinees, et favoriser la confiance dans la securite du vaccin COVID-19 chez les patients atteints de I-RMD.

BackgroundSince the COVID-19 vaccination campaign was launched all over Europe, there has been general agreement on how benefits of SARS-CoV2 vaccines outweigh the risks in patients with rare connective tissue diseases (rCTDs). Yet, there is still limited evidence regarding safety and efficacy of such vaccines in these patients, especially in the long-term. For this reason, in the framework of ERN-ReCONNET, an observational long-term study (VACCINATE) was designed in order to explore the long-term outcome of COVID-19 vaccination in rCTDs patients. The consent form was developed thanks to the involvement of the ERN ReCONNET ePAG Advocates (European Patients Advocacy Group).ObjectivesTo evaluate the safety profile of COVID-19 vaccination in rCTDs patients and the potential impact on disease activity. Primary endpoints were the prevalence of adverse events (AEs) and of disease exacerbations post-vaccination. Secondary endpoints were the proportion of serious adverse events (SAEs) and adverse events of special interest for COVID-19 (adapted from https://brightoncollaboration.us/wp-content/uploads/2021/01/SO2_D2.1.2_V1.2_COVID-19_AESI-update-23Dec2020-review_final.pdf)MethodsThe first ad-interim analysis of the VACCINATE study involved 9 ERN-ReCONNET Network centres. Patients over 18 years of age with a known rCTD and who received vaccine against COVID-19 were eligible for recruitment. Demographic data and diagnoses were collected at the time of enrolment, while the appearance of AEs and potential disease exacerbations were monitored after one week from each vaccination dose, and then after 4, 12 and 24 weeks from the second dose. A disease exacerbation was defined as at least one of the following: new manifestations attributable to disease activity, hospitalization, increase in PGA from previous evaluation, addition of corticosteroids or immunosuppressants.ResultsA cohort of 300 patients (261 females, mean age 52, range 18-85) was recruited. Systemic lupus erythematosus (44%) and systemic sclerosis (16%) were the most frequent diagnoses, followed by Sjogren’s syndrome (SS,12%), idiopathic inflammatory myositis (IMM,10%), undifferentiated connective tissue disease (UCTD,8%), mixed connective tissue disease (MCTD,4%), Ehlers-Danlos’s syndrome (EDS,4%), antiphospholipid syndrome (APS,2%). AEs appearing 7 days after the first and second doses were reported in 93 (31%) and 96 (32%) patients respectively, mainly represented by fatigue, injection site reaction, headache, fever and myalgia. Otitis, urticaria, Herpes Simplex-related rash, stomatitis, migraine with aura, vertigo, tinnitus and sleepiness were reported with very low frequency. Less than 2% of patients experienced AEs within 24 weeks from the second dose. No SAEs or AEs of special interest were observed in the study period. There were 25 disease exacerbations (8%), 7 of which severe. The highest number of exacerbations was observed after 4 weeks from the second dose (12 within week 4, 6 within week 12 and 7 within week 24). Disease exacerbation was most frequent in patients with EDS (33%) and MCTD (25%).ConclusionThis preliminary analysis shows that COVID-19 vaccination is safe in rCTDs patients. AEs appear most often early after vaccination and are usually mild. Disease exacerbations are not frequent, but can be potentially severe and tend to occur most frequently within the first month after vaccination. Exacerbations can also occur 3-6 months after vaccination, although a causal relationship with the vaccination remains to be established. Our present data underline the importance of long-term observational studies.Table 1.AEs and disease exacerbations per diseaseDiagnosisPatients enrolled (%) (n=300)EAs after 1st and 2nd dose (%)Exacerbations (%)APS25714EDS45033IIM10527MCTD44225SS12598SLE44698SSC16492UCTD850-AcknowledgementsVACCINATE is a study promoted by the European Reference Network on rare and complex connective tissue diseases, ERN ReCONNET. This publication was funded by the European Union’s Health Programme (2014-2020)Disclosure of InterestsNone declared

BackgroundThe development of RA is described by a preclinical phase of autoimmunity, that precedes clinical disease. This autoimmune phase is characterized by the presence of anti-modified protein antibodies that recognize citrullinated proteins (ACPA). A subset of individuals with ACPA develops RA, i.e. those with imaging signs of subclinical inflammation in the joints. As T cell mediated B cell activation is a key step in developing autoimmunity and RA, interventions that target this process may be useful for preventing the onset of RA. In this context, abatacept seems being an attractive therapeutic tool as it interrupts the activation of T cells and has a favourable safety profile in the treatment of RA.ObjectivesTo test whether treatment of abatacept, as compared to placebo, delays the onset of RA in ACPA positive individuals with a high risk to develop RA.MethodsARIAA is an international, randomized double-blinded placebo-controlled multi-center study in RA-at risk individuals, being ACPA positive and showing MRI signs of inflammation. The study was composed of a 6 months treatment phase with either abatacept s.c. 125 mg weekly or placebo and a 12 months observation phase with no treatment. Primary endpoint was the improvement of MRI inflammation after 6 months, secondary endpoints were the progression to RA after 6 and 18 months. The primary analysis was done on the ITT population and missing values were classified as treatment failures.ResultsBetween November 2014 and December 2019 139 RA-at risk individuals were included into ARIAA by 14 study sites (11 in Germany, 1 in the Czech Republic and 2 in Spain). Of them, 100 patients were randomized to receive either abatacept or placebo. Two patients were excluded and 98 patients could be evaluated for efficacy and safety. The primary endpoint was met: 61% of abatacept and 31% of placebo treated individuals (p=0.0043) improved in MRI inflammation. Furthermore, only 4 patients (8.2%) in the abatacept group but 17 patients in the placebo group (34.7%) progressed to RA after 6 months (p= 0.0025). Even 1 year after cessation of treatment (18 months after inclusion) the number of patients progressing to RA was lower in the abatacept group (35%) than in the placebo group (57%; p=0.0421). With respect to safety, 12 serious adverse events (each one gastritis, cellulitis, pneumonia, tendinitis calcificans, rotator cuff syndrome, cholelithiasis, peripheral artery disease, idiopathic pain syndrome, prostate cancer, penile neoplasm; trabeculectomy, cataract surgery) were reported, with only one (pneumonia) being considered to be related to treatment.ConclusionAbatacept significantly reduces subclinical joint inflammation and delays the development of RA in at-risk individuals.Table 1.ABAPBOAllN494998Females, N (%)31 (63.3)39 (79.6)70 (71.4)Age (ys); mean (±SD)51.3 (±10.8)48.5 (±12.6)49.9 (±11.7)SJC (N); mean (±SD)000TJC (N); mean (±SD)3.06 (± 3.75)3.51 (± 4.42)3.29 (±4.08)VAS Pain (mm) mean (±SD)42.2 (± 27.1)42.8 (± 33.2)42.5 (± 30.2)VAS PG (mm) mean (±SD42.2 (±28.7)43.0 (± 33.8)42.6 (± 31.2)MRI improvement, N (%)30 (61.2)15 (30.6)45 (45.9)RA at 6 months, N (%)4 (8.2)17 (34.7)21 (21.4)RA at 18 months, N (%)17 (34.7)28 (57.1)45 (45.9)AcknowledgementsThe study was supported by BMS according to the items outlined in the IIS contract and the IMI funded project RTCure.Disclosure of InterestsJürgen Rech Consultant of: Abbvie, Biogen, BMS, Chugai, GSK, Lilly, MSD; Novartis, Roche, Sanofi, Sobi, UCB, Consultancy: Biogen, BMS, Chugai, GSK, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, UCB, Grant/research support from: Sobi, Novartis, Arnd Kleyer Consultant of: BMS, Pfizer, Sanofi, Abbvie, Janssen, Medac, Novartis, Lilly Deutschland GmbH, Gilead, Amgen, Grant/research support from: Novartis, Lilly Deutschland GmbH, Mikkel Østergaard: None declared, Melanie Hagen: None declared, Larissa Valor: None declared, Koray Tascilar: None declared, Gerhard Krönke: None declared, Verena Schönau: None declared, Stefan Kleinert: None declared, Xenofon Baraliakos: None declared, Juergen Braun: None declared, Martin Fleck: None declared, Andrea Rubbert-Roth: None declared, Frank Behrens: None declared, Martin Feuchtenberger: None declared, Michael Zaenker: None declared, David M Kofler: None declared, Reinhard Voll: None declared, Cornelia Glaser: None declared, Axel Hueber: None declared, Eugen Feist: None declared, Gerd Rüdiger Burmester: None declared, Kirsten Karberg: None declared, Johannes Strunk: None declared, Juan de Dios Cañete: None declared, Ladislav Šenolt: None declared, Esperanza Naredo: None declared, Georg Schett: None declared.

BackgroundPatients (pts) with rheumatoid arthritis (RA) are often administered glucocorticoids (GCs) as bridging therapy when initiating or adjusting disease-modifying antirheumatic drugs (DMARDs). Due to their systemic effects, short-term use of GCs at the lowest possible dose is recommended with rapid tapering.1ObjectivesWe describe GC discontinuation patterns and the associated clinical outcomes in pts with RA receiving upadacitinib (UPA) or adalimumab (ADA).MethodsSELECT-COMPARE is a randomized phase 3 trial of UPA vs placebo and ADA with a 48-week (wk) double-blind treatment period and a 10-year long-term extension in pts with RA receiving concomitant methotrexate (MTX) who had an inadequate response to MTX.2 Background GCs (≤10 mg/day prednisone or equivalent) were permitted and could be tapered or discontinued starting at wk 26 per physician discretion. This post hoc analysis included pts who received ≥1 dose of UPA 15 mg once daily or ADA 40 mg every other wk while on concomitant GCs at baseline. The proportion of pts with disease worsening (Clinical Disease Activity Index [CDAI] >2 and Disease Activity Score 28-joint count C-reactive protein [DAS28-CRP] >0.6) following GC discontinuation through follow-up is described. Maintenance of clinical response, including remission and low disease activity based on CDAI ≤2.8 and ≤10, respectively, as well as DAS28-CRP ResultsOf 1,629 pts randomized, 978 (60%) used GCs at baseline; 128 (13%) discontinued use at/after wk 26 (UPA, n=97; ADA, n=31). Baseline demographics and clinical characteristics were broadly similar between pts who continued or discontinued GCs. Median follow-up time after GC discontinuation was 60 wks for UPA and 84 wks for ADA. At the time of GC discontinuation, a numerically higher proportion of pts treated with UPA vs ADA were in disease control (CDAI ≤2.8: 55% vs 32%; CDAI ≤10: 85% vs 68%; DAS28-CRP 2; 7% DAS28-CRP increase >0.6) and none on ADA (Table 1). At 6 months follow-up after GC discontinuation, most pts treated with UPA and ADA maintained CDAI ≤2.8 (74% vs 88%) and ≤10 (92% vs 95%) and DAS28-CRP Table 1.Clinical outcomes of pts who discontinued GCs at/after wk 26n/N (%)Pts who discontinued GCs N=128UPAn=97ADAn=31CDAI≤10 at discontinuation79/93 (85%)21/31 (68%) Maintained at 6 months post discontinuationa61/66 (92%)18/19 (95%)≤2.8 at withdrawal51/93 (55%)10/31 (32%) Maintained at 6 months post discontinuationa32/43 (74%)7/8 (88%)Increase >2 any visit after withdrawal1/93 (1%)0DAS28-CRP≤3.2 at withdrawal78/90 (87%)18/29 (62%) Maintained at 6 months post discontinuationa58/64 (91%)15/16 (94%)64/90 (71%)14/29 (48%) Maintained at 6 months post discontinuationa47/53 (89%)11/13 (85%)Increase >0.6 any visit after withdrawal6/92 (7%)0aAs a proportion of pts achieving outcome at GC discontinuation and with observed data 6 months post GC discontinuation.ConclusionIn pts who achieved disease control and discontinued GCs, disease control was maintained in almost all without worsening disease activity over time following GC discontinuation.ConclusionIn pts who achieved disease control and discontinued GCs, disease control was maintained in almost all without worsening disease activity over time following GC discontinuation.References[1]Smolen JS, et al. Ann Rheum Dis. 2020;79:685–99.[2]Fleischmann R, et al. Ann Rheum Dis. 2019;78:1454–62.AcknowledgementsAbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing assistance was provided by Julia Zolotarjova, MSc, MWC of AbbVie Inc.Disclosure of InterestsRoy M. Fleischmann Consultant of: AbbVie, Amgen, BMS, Galvani, Gilead, GSK, Janssen, Eli Lilly, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Astra-Zeneca, BMS, Flexion, Galvani, Gilead, GSK, Janssen, Eli Lilly, Novartis, Noven, Pfizer, Samumed, Selecta, Teva, UCB, Viela, and Vorso., Bernard Combe Speakers bureau: AbbVie, BMS, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche-Chugai, Consultant of: AbbVie, BMS, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche-Chugai, Grant/research support from: Pfizer and Roche-Chugai, Andrew Ostor Consultant of: AbbVie, BMS, Eli Lilly, Gilead, Janssen, Novartis, Paradigm, Pfizer, Roche, and UCB., Cesar Francisco Pacheco Tena Consultant of: AbbVie, Astra-Zeneca, Eli Lilly, Gilead, Janssen, Pfizer, Roche, R-Pharm, Sanofi Regeneron, and UCB., Grant/research support from: AbbVie, Astra-Zeneca, Eli Lilly, Gilead, Janssen, Pfizer, Roche, R-Pharm, Sanofi Regeneron, and UCB., Nasser Khan Shareholder of: May own AbbVie stock or stock options, Employee of: AbbVie, Jessica Suboticki Shareholder of: May own AbbVie stock or stock options, Employee of: AbbVie, Anna Shmagel Shareholder of: May own AbbVie stock or stock options, Employee of: AbbVie, Yanna Song Shareholder of: May own AbbVie stock or stock options, Employee of: AbbVie, Ivan Lagunes-Galindo Shareholder of: May own AbbVie stock or stock options, Employee of: AbbVie, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Pfizer, Roche, Sanofi, and UCB., Consultant of: AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Pfizer, Roche, Sanofi, and UCB.

BackgroundIn patients with arthritis, psychological co-morbidities are very common. Previous studies have found a relatively high prevalence of depression, anxiety, and post-traumatic stress disorder (PTSD), especially in long-term disease. Recent research has begun to study psychiatric co-morbidities not just as an outcome, but also as a probable risk factor, evaluating patients in the early disease stages. [1] Furthermore, some sources suggest that childhood adversities could impact the autoimmune process in adulthood. [2]ObjectivesTo compare the prevalence of depression, anxiety, PTSD, and childhood trauma in a prospective early arthritis cohort to a healthy age- and gender-matched control group. Moreover, to explore whether these factors may contribute to the early arthritis development.MethodsThis selective data analysis of prospective single-centre, observational study included 60 patients with an early arthritis and 60 healthy controls. The control group was defined as no inflammatory joint pain and further subdivided into 2 subgroups, differentiating 24 patients with arthralgia and 36 with no arthralgia and not from the outpatient consultation. Early arthritis was defined as the presence of at least one inflammatory joint from 4 weeks to 12 months, independent of rheumatic diagnosis. For the assessment of current and prior psychological co-morbidities, included patients underwent semi-structured interview and received the standardized questionnaires for depression/anxiety (Hospital Anxiety and Depression Scale (HADS)), childhood trauma (Childhood Trauma Questionnaire (CTQ)) and PTSD (Posttraumatic Diagnostic Scale (PDS)) respectively. Differences among the groups were analyzed with Chi Square and Mann-Whitney U tests. A backwards binominal logistic regression model in reference to the healthy patients was performed to identify the significant factors for the early arthritis group.ResultsThe mean age of the total group was 47.4 ± 16.0 (♀ 58.3%, mean symptom duration 4.5±3.3 months). Depression rate of 41.7% according to interview was significantly higher in early arthritis group compared to 16.7% in healthy patients (p=0.03). Regarding arthralgia subgroup, depression was also high with 34%. HADS-D score was also significantly higher in early arthritis (5.4±4.8) to healthy cohort (3.6±3.3) (p=0.047). Compared to 3.3% in healthy patients, PTSD rate of 13.3% was also significantly higher in the arthritis group (p=0.048). We could not detect a significant difference between these two groups using the U test while evaluating CTQ dimensions. We performed a subsequent subgroup analysis and found that childhood trauma dimensions were relevant in arthralgia group, as 25% presented with high emotional abuse score. The logistic regression model showed that emotional neglect, sexual abuses in childhood as well as HADS-D were significant covariates for early arthritis. (p=0,048 OR=1.2; p=0.040 OR=1.4, p=0.025 OR=1.2 respectively).ConclusionAs the rates of depression and PTSD, as well as HADS-D score were significantly higher in the early arthritis cohort compared to healthy individuals, our findings suggest a potential link between psychiatric outcomes and inflammation. According to our regression model certain childhood adversities and depression are significant factors for an early arthritis group. Arthralgia group had similar aberrant scores regarding childhood trauma, implying that early-life stress might be an important factor in understanding this condition.References[1]Vallerand IA et al. Depression as a risk factor for the development of rheumatoid arthritis: a population-based cohort study. RMD Open.2018; 4(2)[2]Dube SR et al. Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med. 2009; 71(2):p.243-50.Disclosure of InterestsNone declared

BackgroundGetting access to specialists for autoinflammatory diseases (AIDs) is challenging. Therefore, an increasing number of patients and healthcare professionals are seeking information on this topic via the internet, e.g., on the video platform YouTube, which has attracted a huge audience in recent years (1). However, not much is known about the quality of videos pertaining on AIDs.ObjectivesTo assess videos about AIDs uploaded on YouTube and to evaluate the quality and usefulness of available information from both the patient’s and professional healthcarer´s perspective.MethodsA YouTube.com search was conducted in January 2022: Selected keywords were “autoinflammatory diseases” (AID), “periodic fever syndrome” (PFS), “familial mediterranean fever” (FMF), “cryopyrin associated periodic syndrome” (CAPS), “tumor necrosis factor associated periodic syndrome” (TRAPS), “adult onset of still´s disease” (AOSD) and “systemic juvenile idiopathic arthritis”(sJIA). For every keyword, the top 20 videos in their order of relevance were included. Video duration, number of views, likes, dislikes, comments and uploading source were extracted. The quality of a video´s information was evaluated independently by two physicians based on the modified global quality scale (GQS) (2). Subgroup analyses were performed classifying healthcare professionals and patients as target group.ResultsIn total 140 videos were screened. We excluded 5 videos due to language other than English, 7 duplicates and 23 not suitable ones. 105 videos met the inclusion criteria for further analysis. Video characteristics are presented in Table 1. Based on the GQS, overall quality of videos for patients was found to be low in 64,8%, intermediate in 27,6%, and high in 7,6% of videos. The quality of videos for professionals was similar: 54,3% were judged to be of low, 23,8% of intermediate, and 21,9% of high quality (Figure 1). Subgroup analyses focusing on videos for professionals found sJIA videos to achieve the highest scores (31,6% with high quality) whereas videos regarding CAPS were rated the least useful ones (15,4% with high quality). In videos for patients, sJIA videos also ranked highest (42,1% with high quality) whereas no high quality videos could be identified for TRAPS. Videos are more often aimed at specialists such as doctors or medical students (65.7%) and less often at affected patients or relatives (34.3%). Video duration was significantly longer in videos targeting a professional audience (p < 0.001). In videos for professionals, length was significantly correlated with higher quality (p < 0.001).Table 1.Video CharacteristicsFigure 1.Quality ScaleConclusionYouTube as a source of information could have great potential for rare diseases. However, this study demonstrates that the majority of videos regarding AIDs is of limited quality and available videos more often adress users with a professional medical background. Only a small proportion of existing videos provide understandable and useful information for AID patients.References[1]Madathil KC, Rivera-Rodriguez AJ, Greenstein JS, Gramo- padhye AK (2015) Healthcare information on YouTube: a sys- tematic review. Health Inform J 21(3):173–194. https://doi. org/10.1177/1460458213512220[2]Bernard A, Langille M, Hughes S, Rose C, Leddin D,Veldhuyzen Van Zanten S (2007). A systematic review of patient inflammatory bowel disease information resourceson the World Wide Web.Am J Gastroenterol102: 2070–2077Disclosure of InterestsNone declared

BackgroundAn unmet need remains in patients with failure and/or inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARD-IR) and/or Janus kinase inhibitors (JAKi-IR). The CD40/CD40L (CD154) costimulatory pathway is linked to inflammation and joint destruction in RA via production of autoantibodies and inflammatory mediators. KPL-404 is a humanized IgG4 antibody engineered to bind CD40 without triggering Fc effector functions (Muralidharan, 2019), which are known to have been associated with thromboembolic events seen in the first generation of CD40L-targeting therapies.In a first-in-human Phase 1 single ascending dose study, 52 healthy volunteers received single doses of KPL-404 administered either subcutaneously (SC) or intravenously (IV) with no dose-limiting safety findings, infectious episodes, or toxicities (Samant, 2021). The study demonstrated that with 10 mg/kg IV, full receptor occupancy (RO) was observed through day 71, and there was complete suppression of T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin challenge on day 1 and re-challenge on day 29 through day 57. With 5 mg/kg SC, full RO was observed through day 43, and there was complete suppression of TDAR through at least day 29. Complete suppression of ADA to KPL-404, an independent indicator of target engagement, was also observed while KPL-404 serum concentrations were above approximately 0.1 to 0.2 µg/mL and continued for at least 50 days and 57 days after 5 mg/kg SC and 10 mg/kg IV administration, respectively.ObjectivesUsing Phase 1 and nonclinical data, identify chronic dosing regimens anticipated to yield PK in the sub-therapeutic, therapeutic, and supra-therapeutic ranges to be utilized in a Multiple Ascending Dose Phase 2 Study.MethodsA PK model was used to simulate multiple dosing scenarios, including: 2.5, 5, and 10 mg/kg SC qwk, q2wk, and q4wk, as well as 10 mg/kg IV q4wk. The model was used to identify optimal Phase 2 dosing schedules by generating 1000 virtual subjects using the typical parameter estimates with between-subject variability included.ResultsFollowing SC administration, all subjects were predicted to achieve complete ADA suppression for the full dosing interval at/above 2.5 mg/kg SC q2wk. At 2 mg/kg SC q2wk (starting dose level), simulated steady-state 8-week data predicted PK in a sub-therapeutic range for most subjects and an approximately 31- and 18-fold safety margin relative to preclinical NOAEL dose. At 5 mg/kg SC q2wk, 100% of patients were predicted to be in a therapeutic range, indicating a potential practical efficacious dose level. At 10 mg/kg SC q2wk, 100% of patients were predicted to be in the supratherapeutic range.These results support a Multiple Ascending Dose (MAD) Phase 2 study design, with PK lead-in comprised of 3 Cohorts at 2, 5, or 10 mg/kg SC q2wk (each randomized 6:2) and Proof-of-Concept phase (Cohort 4) comprised of 48-60 subjects randomized 1:1:1 to 10 mg/kg, 5 mg/kg, and placebo SC q2wk. The ongoing study will evaluate efficacy (Disease Activity of 28 joints using C-reactive protein [DAS28-CRP]), safety, PK, and pharmacodynamics (PD) of escalating doses levels of KPL-404 compared with placebo in patients with moderate to severe RA (bDMARD-IR or JAKi-IR). The study also allows the flexibility of optional cohorts including additional dosing regimens and/or subpopulations identified based on clinical response and biomarkers.ConclusionInhibition of the CD40-CD154 co-stimulatory interaction holds promise for the management of a spectrum of autoimmune diseases. KPL-404 demonstrated prolonged absorption/excretion capable of suppressing TDAR for extended periods allowing for use of extended dosing intervals irrespective of IV or SC dosing. These analyses supported the design of the ongoing Phase 2 study assessing the efficacy and safety KPL-404 in RA.References[1]Muralidharan S et al. 2019. Poster at Keystone Symposia[2]Samant M et al. Arthritis Rheumatol. 2021; 73(suppl 10)Disclosure of InterestsAnastassia Papandrikopoulou Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Gerd Rüdiger Burmester Speakers bureau: Abbvie, Amgen, BMS, Lilly, MSD, Pfizer, Roche, Sanofi, Consultant of: Abbvie, Amgen, BMS, Kiniksa, Lilly, MSD, Pfizer, Roche, Sanofi, Fang Fang Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Alan Kivitz Shareholder of: Amgen, Gilead Sciences, Inc., GlaxoSmithKline, Novartis, Pfizer, Sanofi,, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Sanofi, UCB, Horizon, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Gilead Sciences, Inc., Janssen, Pfizer, Sanofi, SUN Pharma Advanced Research, Moses Njenga Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Arian Pano Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Costantino Pitzalis Speakers bureau: Abbott/AbbVie, Astra-Zeneca/MedImmune, BMS, Janssen/J&J, MSD, Pfizer, Roche/Genentech/Chugai, UCB.,, Consultant of: Abbott/AbbVie, Astellas, Astra-Zeneca/MedImmune, BMS, CelGene, Grunenthal, GSK,Janssen/J&J, Kiniksa, MSD, Pfizer, Sanofi, Roche / Genentech / Chugai, UCB., Grant/research support from: Abbott/AbbVie, Astellas, Astra-Zeneca/MedImmune, BMS, Janssen/J&J, MSD, Pfizer, Roche/Genentech/Chugai, UCB., Manoj Samant Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Steve Schmitz Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Madeline Spiers Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., Eben Tessari Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp., John Ziemniak Consultant of: Kiniksa Pharmaceuticals, Ltd., John F. Paolini Shareholder of: Kiniksa Pharmaceuticals Corp., Employee of: Kiniksa Pharmaceuticals Corp.

BackgroundThe use of bDMARDs treatments in patients with psoriatic arthritis (PsA) usually requires treatment failure or intolerance of csDMARD/MTX before initiation. The value of MTX in combination with bDMARDs is still unclear. We designed an investigator-initiated, randomized, placebo-controlled trial (IIT) in active PsA to examine if outcomes of treatment with ustekinumab (UST) in combination with MTX (either newly initiated or ongoing) were different from UST only (+Placebo; PBO). With known efficacy of MTX on skin psoriasis outcomes may differ in patients with or without significant skin involvement of their psoriatic disease.ObjectivesTo compare efficacy outcomes in UST+PBO vs UST+MTX in dependency of skin involvement (Body Surface Area [BSA]) at baseline.MethodsA total of 186 patients with active PsA (defined as TJC≥4, SJC≥4 [68/66 joint count] and DAS28≥3.2) were screened for eligibility. 173 patients were randomized to UST+MTX (new or ongoing) or UST+PBO.With this post hoc subgroup analysis outcome parameters were compared between patients with or without skin psoriasis > 3 % BSA. Demographic data and disease activity status of arthritis (joint count [TJC/SJC], DAPSA, DAS28), skin (PASI, BSA), HR-QoL (EQ5D, DLQI) and physical function (HAQ) were compared between groups.ResultsBL data were well-balanced between main treatment groups (UST+MTX, n=86; UST+PBO, n=74) including gender (42.5% vs 40.5% female) and mean values for age (49.2 vs 47.2 years), BMI (29.4 vs 28.9 kg/m2), SJC (8 vs 8), TJC (12 vs 12), DAS28-CRP (4.6 vs 4.4), DAPSA (36.7 vs 34.9) and PASI (2.8 vs 2.4. Disease activity remained well-balanced even after dividing groups according to skin involvement ((a) BSA ≤3% and (b) BSA >3%) with a trend of more severe joint involvement (SJC, TJC) in BSA >3% for UST+MTX compared to UST+PBO. At week 24, relative changes in TJC (-62% vs -62%), change in DAS28 and DAPSA were equal in all treatment groups independent from skin involvement (Table 1). Differences between the groups according to skin involvement were seen for relative changes in SJC (BSA >3%: -74.8% UST+MTX vs -84.3% UST+PBO), subject global assessment (SGA), physician global assessment (PGA), DLQI and EQ5D. Highest levels for changes were detected in the UST+PBO group with high skin involvement (BSA >3%).Table 1.Outcomes at Week 24 (LOCF)UST+MTXUST+PBOBSA ≤3%BSA >3%BSA ≤3%BSA >3%n=46n=40n=51n=23TJC68 change from BL-7.83 (SD 10.3)-9.5 (SD 10.3)-8.9 (SD 9.5)-7.3 (SD 7.4)SJC66 change from BL-6.0 (SD 5.4)-7.1 (SD 3.5)-6.5 (SD 6.2)-6.4 (SD 3.8)PASI change from BL+-1.3 (SD 1.9)-8.5 (SD 9.6)-1.5 (SD 2.4)-9.0 (SD 10.7)DAS-28 ESR [mm/hr] change from BL-1.6 (SD 1.1)-1.8 (SD 1.2)-1.7 (SD 1.4)-1.8 (SD 1.1)DAS-28 CRP [mg/l] change to BL-1.5 (SD 1.2)-1.5 (SD 1.3)-1.6 (SD 1.2)- 1.7 (SD 1.1)DAPSA change from BL-17.4 (SD 16.8)-20.8 (SD 13.2)-20.5 (SD 16.6)-20.4 (SD 15.3)HAQ change from BL-0.1 (SD 0.4)-0.2 (SD 0.5)-0.3 (SD 0.3)-0.3 (SD 0.5)DLQI change from BL-3.1 (SD 5.5)-5.5 (SD 8.2)-2.3 (SD 3.3)-6.4 (SD 7.9)EQ5D VAS Health State change from BL6.7 (SD 24.7)11.7 (SD 23.6)8.0 (SD 24.2)21.3 (SD 25.3)ConclusionIL12/23 inhibition with UST is an effective treatment for active PsA independent of MTX use. Data from this IIT indicate that additional MTX has no positive impact on UST efficacy for arthritis, skin, HR-QoL and physical function. This independency of UST effect from MTX can also be demonstrated in patients with active skin involvement despite known efficacy of MTX for skin psoriasis.AcknowledgementsWe thank Janssen for support of the study with a research grant.Disclosure of InterestsMichaela Köhm Speakers bureau: Janssen, Consultant of: Janssen, Grant/research support from: Janssen, Tanja Rossmanith Grant/research support from: Janssen, Ann Christina Foldenauer Grant/research support from: Janssen, Herbert Kellner Speakers bureau: Janssen, Consultant of: Janssen, Uta Kiltz Speakers bureau: Abbvie, Fresenius, Hexal, Janssen, MSD, Novartis, Pfizer, Roche, UCB, Consultant of: AbbVie, Amgen, Biocad, Biogen, Chugai, Eli Lilly, Hexal, Grünenthal, Janssen, MSD, Novartis, Pfizer, Roche, UCB, Grant/research support from: AbbVie, Amgen, Biogen, Fresenius, GSK, Hexal, Novartis, Pfizer, Jürgen Rech Speakers bureau: Abbvie, Biogen, BMS, Chugai, GSK, Lilly, MSD; Novartis, Roche, Sanofi, Sobi, UCB, Consultant of: Biogen, BMS, Chugai, GSK, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, UCB, Grant/research support from: Novartis, Sobi, Gerd Rüdiger Burmester Speakers bureau: Janssen, Consultant of: Janssen, Grant/research support from: Janssen, David M Kofler Speakers bureau: Janssen, Consultant of: Janssen, Grant/research support from: Janssen, Jan Brandt-Juergens Speakers bureau: Janssen, Consultant of: Janssen, Grant/research support from: Janssen, Christin Jonetzko Grant/research support from: Janssen, Harald Burkhardt Speakers bureau: Janssen, Consultant of: Janssen, Grant/research support from: Janssen, Frank Behrens Speakers bureau: Janssen, Consultant of: Janssen, Grant/research support from: Janssen

BackgroundAs outlined in previous studies, different rheumatic joint diseases present specific characteristic patterns and features in fluorescence optical imaging (FOI) (1-4).ObjectivesWe tested different features in FOI for their ability to differentiate various rheumatic joint diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and psoriatic arthritis (PsA) with the aim to identify clear FOI criteria for the diseases.MethodsFOI images from patients with RA, OA, PsA and healthy volunteers were evaluated by two readers blinded for diagnosis and calibrated against each other, using the prima vista mode (PVM) and the 5-phase model. For the latter, the overall time course of FOI in each hand was divided into 5 phases with a computational algorithm. Phases 1 and 2 describe the inflow (start to 15% and 15%-90% on rising edge), phase 3 is the peak phase and phases 4 and 5 comprise the outflow (90%-36.8% and 36.8% to end on falling edge). Twenty-six different features were defined by an atlas, for example the streaky pattern feature (T) as a signal enhancement around the PIP area that appears streaky, whereby the stripes are orthogonal to the finger axis (Figure 1a). The cloudy pattern (W) is visible during the inflow on the back of the hand (Figure 1b). The enthesis feature (E) depicts a V shaped and filled pattern between nail and DIP (Figure 1c). The feature frequency in each patient and phase (PVM, 5-phase) was counted and statistically analysed.Figure 1.Examples for FOI patterns and features: a) (T) Streaky pattern in PVM image (OA); b) (W) Cloudy pattern on the back of the hand in phase 1 (PsA); c) (E) Enthesis pattern in phase 3.ResultsIn total, 128 patients (RA (age mean 54.2; SD 10.6; median 52.4), OA (58.0; 14.3; 60.1), and PsA (47.9; 12.7; 46.8)) and healthy volunteers (32 in each group) were included in the feature reading. In our analysis, OA can be differentiated from RA on the basis of the feature T. Feature T is found in phase 3 (χ2: 4.61; diagnostic odds ratio (DOR): 7.49; sensitivity (TPR) 0.11; specificity (TNR): 0.98; positive predictive value (PPV): 0.87; negative predictive value (NPV): 0.52), phase 5 (χ2: 18.5; DOR: 5.60; TPR 0.55; TNR: 0.82; PPV: 0.76; NPV: 0.64 and PVM (28.3; 12.1; 52%; 92% 87%; 65%). By means of the feature E, a distinction between RA and PsA is only limited possible (χ2: 9.58; DOR: 3.65; TPR 0.40; TNR: 0.84; PPV: 0.71; NPV: 0.59). But PsA can well be distinguished from RA by the appearance of pattern W in phase 1 (χ2: 7.68; DOR: 6.92; TPR 0.19; TNR: 0.97; PPV: 0.86; NPV: 0.54).Other significant features yield high specificity (70%-98%) while having low sensitivity (12%-52%).ConclusionThis work demonstrates that FOI feature analysis has the potential for differential diagnosis with FOI, which could optimize the (early) diagnostic process of rheumatic joint diseases. A majority of features yield high specificity, but only low sensitivity. The combination of different features using artificial intelligence might lead to improved diagnostic accuracy.References[1]Werner SG, et al. Inflammation assessment in patients with arthritis using a novel in vivo fluorescence optical imaging technology. Ann Rheum Dis. 2012; 71(4):504-510.[2]Glimm AM, et al. Analysis of distribution and severity of inflammation in patients with osteoarthitis compared to rheumatoid arthritis by ICG-enhanced fluorescence optical imaging and musculoskeletal ultrasound: a pilot study. Ann Rheum Dis. 2016; 75(3):566-570.[3]Wiemann O, et al. The “green nail” phenomenon in ICG-enhanced fluorescence optical imaging - a potential tool for the differential diagnosis of psoriatic arthritis. J Dtsch Dermatol Ges. 2019;17(2):138-147.[4]Schmidt A, et al. Detection of subclinical skin manifestation in patients with psoriasis and psoriatic arthritis by fluorescence optical imaging. Arthritis Res Ther. 2020; 22(1):192.Disclosure of InterestsNone declared

BackgroundBy definition, rare diseases occur in fewer than 5 in 10,000 people. However, in Germany alone, there are approximately 4 million people affected (1). Due to their rarity, rare diseases are often overlooked by general practitioners with limited knowledge about them. There are often only a handful of specialized experts for each condition. Yet, those experts are frequently not evenly distributed across the healthcare system, and often, patients lack access. Therefore, the time to diagnosis is often long and poses many challenges. Artificial intelligence (AI) approaches, such as those used in symptom assessment apps can potentially help to detect disease and thus, shorten the time to diagnosis (2).The general approach underlying the AI of symptom assessment apps is to gather medical knowledge from data (e.g. electronic health record or literature searches). However, for rare diseases, there is only limited research available. In this study we used a new approach: to abstract medical expert knowledge by conducting guided interviews and transforming them into clinical vignettes.ObjectivesThere are two objectives. First, we aimed to integrate expert knowledge on the lysosomal storage diseases (LSDs) Fabry, Gaucher and Pompe into the Ada symptom assessment application and use this expert knowledge to optimize Ada’s LSD condition models. LSDs are of particular importance as they represent import differential diagnoses to rheumatic diseases.Second, we will conduct questionnaires with patients and LSD experts, comparing the optimized to the previous condition models’ performance. We will investigate whether the novel approach of guided interviews, in combination with literature research, results in a better performance than literature research alone.MethodsOur novel approach is to curate expert medical knowledge from guided interviews with medical experts. The interviews aim to gather knowledge on the symptom constellations with which patients typically present to their physicians. This knowledge is subsequently used to create prototype clinical cases and transform them into structured case vignettes. The rare disease structured case vignettes can be readily transcribed into Ada’s knowledge base.ResultsWe conducted guided interviews with clinical experts from the Medizinische Hochschule Hannover (MHH) to create clinical vignettes for the LSDs Fabry, Gaucher and Pompe disease. We conducted interviews with four medical experts and created a total of 11 clinical vignettes: five vignettes for Fabry disease, four for Gaucher disease and two for Pompe disease. Figure 1 demonstrates the vignette creation process. Then, in combination with systematic literature searches, the vignettes were used to update Ada’s existing condition models for Fabry and Gaucher disease and to add Pompe disease.Figure 1.The novel medical model creation approach uses guided expert interviews to create prototypic clinical vignettes, which can be readily transcribed in a medical modeling language to create individual disease modelsConclusionParticipants will complete two assessments: an Ada version with the old knowledge base and an Ada version with the updated models. The study plans to enroll 15 LSD patients - five per condition - and nine LSD experts. For the conditions Fabry and Gaucher disease, we will ask the participants to rate both Ada versions. For Pompe disease, we will ask participants to rate the latest Ada version with the updated knowledge base. This novel approach has various clinical implications, including potentially shortening the ‘time to diagnosis’ for rare diseases, thus giving patients faster access to the treatments they need.References[1]National Organization for Rare Diseases, Globel genes Project[2]Ronicke, S., Hirsch, M. C., Türk, E., Larionov, K., Tientcheu, D., & Wagner, A. D. (2019). Can a decision support system accelerate rare disease diagnosis? Evaluating the potential impact of Ada DX in a retrospective study. Orphanet journal of rare diseases, 14(1), 1-12.Disclosure of InterestsAnne Pankow Grant/research support from: The study originates from a collaboration project between Ada Health, Charité and Sanofi. However Sanofi was neither directly nor indirectly involved in the concept, conduction or interpretation of the study (results)., Nico Meißner Grant/research support from: The study originates from a collaboration project between Ada Health, Charité and Sanofi. However Sanofi was neither directly nor indirectly involved in the concept, conduction or interpretation of the study (results)., Laura Fouquette: None declared, Ewelina Türk: None declared, Stephen Gilbert: None declared, Thilo Tübler: None declared, Anhib Das: None declared, Christoph Terkamp: None declared, Jessica Kaufeld: None declared, Gerd Rüdiger Burmester: None declared, Annette D. Wagner: None declared

BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by genetic predisposition and associated immunological features including the production of autoantibodies against various epitopes. Several pathways have been implicated in the induction of autoantibodies against novel epitopes through post-translational modifications such as citrullination, carbamylation and acetylation (1). However, the contributions of these anti-modified protein antibodies (AMPAs) in the pathogenesis and formation of immune complexes (IC) in the synovial fluid has not been fully uncovered.ObjectivesTo analyze reactivity of monomeric and IC antibodies of RA patients to citrullinated, carbamylated and acetylated modified antigens in comparison to disease control group and healthy donors.MethodsSynovial fluid (SF) was collected from 17 RA patients and 40 individuals from a disease control group (CG) including reactive arthritis and psoriasis arthritis. Paired serum and SF samples were used from 16 RA and 19 CG compared to serum from 70 healthy donors (HD). Immune complexes (IC) were purified from sera and SF by applying a technique using purified human C1q, which was immobilised on magnetic tosylactivated microparticles (Dynabeads M-280) according to the manufacturer’s recommendations for activation of amine groups. Additionally, sucrose gradient centrifugation was used to fractionate SF and sera into 21 fractions and according to protein markers, protein G was used to isolate monomeric IgG from fractions 3-9 and IC IgG from fractions 11-22. ELISA kits for anti CCP-IgG, anti-mutated citrullinated vimentin (MCV)-IgG, anti-acetylated Lysine Antibody (anti-HC55)-IgG and anti-carbamylated vimentin (carbVim)-IgG were used to test reactivity against modified proteins. Extracted antigens from the IC were investigated with Western blot for specific modifications or individual antigens with the corresponding antibodies. Citrullinated and acetylated vimentin was identified as part of IC via mass spectroscopy. Purified AMPAs from serum or SF (isolated from IC or as soluble antibodies) were investigated on a custom-made LineBlot array containing 24 different antigens either citrullinated, carbamylated, acetylated or unmodified/native counterparts.ResultsTiters of anti-CCP, anti-MCV and anti-acetylated (anti-HC55) reactivity were higher in SF of RA patients compared to CG. AMPAs were detected in SF in IC as well as free antibodies. Some isolated IgG (monomeric and IC) showed reactivities against citrullinated and acetylated peptides that could not be detected in native samples. Surprisingly, in addition to citrullinated vimentin, the acetelylated form was also detected in the IC eluted fractions. Haptoglobin and fibrinogen fragments were identified as carbamylated modified proteins in small concentrations. The spectrum of identified acetylated proteins included human proteins such as histones as well as fragments of bacterial filament proteins. SF of RA patients showed reactivity against MCV and citrullinated desmin in LineBlot array.ConclusionAMPAs recognize different modified antigens and form immune complexes in the SF of RA patients. The elevated titer of anti-acetylated protein antibodies and the inclusion of its epitope in immune complexes in the synovium points to its contribution in the pathogenesis of RA.Figure 1.The identification of acetylated antigens in the synovium of RA patients is especially intriguing, as infections (bacteria) are known to not only acetylate their own proteins, but also modify host proteins.References[1]Grönwall C, Liljefors L, Bang H, et al. A Comprehensive Evaluation of the Relationship Between Different IgG and IgA Anti-Modified Protein Autoantibodies in Rheumatoid Arthritis. Front Immunol. 2021;12:627986-.AcknowledgementsThis work was supported by a grant from DFG.Disclosure of InterestsKhetam Ghannam: None declared, Holger Bang Employee of: Employee of ORGENTEC Diagnostika GmbH, Thomas Häupl: None declared, Sarah Ohrndorf: None declared, Jan Zernicke: None declared, Ulrike Kuckelkorn: None declared, Eugen Feist: None declared, Gerd Rüdiger Burmester: None declared

BackgroundThere is no international consensus on an optimal ultrasound scoring system in patients with rheumatoid arthritis (RA) yet.ObjectivesTo assess the musculoskeletal ultrasound score on seven joints (‘US7 score’) (1) for the identification of the most frequently pathologic and responsive joint regions during 3 and 6 months of therapy in order to optimize the score. Furthermore, to evaluate the impact of disease duration on the performance of the score.MethodsRA patients were recruited from 54 German rheumatology centers when starting or changing DMARD therapy. Patients were assessed by the US7 score in greyscale (GS) and power Doppler (PD) at baseline, after 3 and 6 months. The frequency of pathologic joint/tendon regions and their responsiveness to therapy were assessed including the comparison of palmar vs. dorsal regions.Differences between the palmar and the dorsal sides were analyzed using Chi-square test, the gradings of the US-joint inflammation were compared between baseline, 3 months, and 6 months by Friedman test with Dunn test as post-hoc test.We used standard response mean to determine the responsiveness of possible reduced scores and linear regression to assess the amount of information retained from the original score. Analyses were also performed separately for early and established RA.ResultsA total of 435 patients (n=138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons out of 7 joints were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p≤0.003 in GS/PD).The dorsal vs. palmar side of the wrist by GS/PD (pConclusionThe wrist, MCP2, EDC and ECU tendons were most frequently pathologic and responsive to therapy, representing an optimized score for monitoring of RA patients for both early and established RA and should therefore be included in comprehensive scores for monitoring RA patients.References[1]Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W, et al. Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project. Arthritis Rheum. 2009;61(9):1194-201.AcknowledgementsWe thank Gabriela Schmittat for logistical support in the study.Disclosure of InterestsAnnika Franziska Podewski: None declared, Anne-Marie Glimm: None declared, Imma Fischer: None declared, George Bruyn: None declared, Petra Hanova: None declared, Hilde Berner Hammer Speakers bureau: Paid speaker for Lilly, Novartis and AbbVie, Employee of: Advisory board for AbbVie, Anna-Birgitte Aga Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer and UCB, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer and UCB, Espen A Haavardsholm: None declared, Sofia Ramiro Speakers bureau: Eli Lilly, MSD, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, Pfizer, UCB, Sanofi, Grant/research support from: AbbVie, Galapagos, Novartis, Pfizer, UCB, Gerd Rüdiger Burmester: None declared, Marina Backhaus Speakers bureau: Speaker fee from AbbVie, BMS, Galapagos, UCB, Novartis, Sarah Ohrndorf: None declared

BackgroundFilgotinib (FIL) is a Janus kinase 1 preferential inhibitor for the treatment of moderate to severe rheumatoid arthritis (RA)1. The recommended dose for adults with RA is 200 mg (FIL200); however, a starting dose of 100 mg (FIL100) is recommended for those aged ≥75 years (y) in view of limited clinical experience1. An important consideration is the generally higher incidence of adverse events (AEs) in the elderly due to comorbidities.ObjectivesTo evaluate the efficacy and safety of FIL100 and FIL200 in patients with RA aged ≥75 y.MethodsFINCH 4 (NCT03025308) is an ongoing phase 3 open-label LTE study of FIL100 and FIL200 for RA. Eligible patients completed a prior phase 3 randomized double-blind study of FIL lasting 52 weeks (FINCH 1 or 3) or 24 weeks (FINCH 2). In this post hoc analysis, safety and efficacy were assessed in patients aged ResultsAt LTE Week 48, 52% and 44% of patients aged Figure 1.The exposure-adjusted incidence rate (EAIR) of serious AEs and AEs of special interest (AESI) was generally higher in patients aged ≥75 y than Table 1.Exposure-adjusted incidence rate (95% CI) of AEs at Week 48 as events per 100 years of exposureFIL200FIL100Age, years≥75≥75n=1469n=61n=1136n=63(PYE 2253.9)(PYE 92.2)(PYE 1753.7)(PYE 98.4)With prior FIL exposure, n (%)1142 (77.7)53 (86.9)830 (73.1)33 (52.4)TEAE48.3 (45.5, 51.3)55.3 (42.1, 72.8)48.7 (45.5, 52.1)42.7 (31.6, 57.8)Serious TEAE6.8 (5.8, 8.0)17.4 (10.6, 28.3)7.4 (6.2, 8.7)14.2 (8.4, 24.0)AE leading to premature study discontinuation2.9 (2.3, 3.7)9.8 (5.1, 18.8)3.9 (3.1, 5.0)4.1 (1.5, 10.8)AE leading to death0.5 (0.3, 0.9)3.3 (0.7, 9.5)*0.3 (0.2, 0.8)0.0 (0.0, 3.8)Infections28.8 (26.6, 31.1)29.3 (20.1, 42.7)27.4 (25.0, 29.9)26.4 (18.0, 38.8)Serious infections1.6 (1.2, 2.2)2.2 (0.5, 8.7)1.7 (1.1, 2.4)3.1 (1.0, 9.5)Herpes zoster1.6 (1.2, 2.3)2.2 (0.5, 8.7)1.0 (0.6, 1.6)3.1 (1.0, 9.5)Adjudicated major adverse cardiovascular event0.4 (0.2, 0.7)2.2 (0.5, 8.7)0.5 (0.2, 0.9)1.0 (0.1, 7.2)Venous thrombotic and embolic events0.3 (0.1, 0.6)2.2 (0.5, 8.7)0.2 (0.1, 0.5)1.0 (0.1, 7.2)Malignancy excluding NMSC0.7 (0.4, 1.2)4.3 (1.6, 11.6)0.7 (0.4, 1.2)3.1 (1.0, 9.5)NMSC0.4 (0.2, 0.8)1.1 (0.0, 6.0)0.2 (0.1, 0.6)0.0 (0.0, 3.8)*Cause of death: esophageal carcinoma; cardiovascular; unknown. FIL(100/200), filgotinib (100/200 mg); NMSC, nonmelanoma skin cancer; PYE, patient years of exposure; (TE)AE, (treatment-emergent) adverse eventConclusionIn the ≥75 y group, response rates for key efficacy measures remained stable to Week 48 and were generally higher with FIL200 vs FIL100. The incidence of serious AEs and AESI was higher in those aged ≥75 than References[1]Filgotinib SmPCAcknowledgementsThe FINCH studies were funded by Gilead Sciences (Foster City, CA, United States). We thank the physicians and patients who participated in the studies. Medical writing support was provided by Debbie Sherwood, BSc (Aspire Scientific Ltd, Bollington, UK) and funded by Galapagos NV (Mechelen, Belgium).Disclosure of InterestsDaniel Aletaha Speakers bureau: AbbVie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, and Sandoz, Consultant of: AbbVie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, and Sandoz, Grant/research support from: AbbVie, Amgen, Lilly, Novartis, Roche, SoBi, and Sanofi, Rene Westhovens Speakers bureau: Celltrion, Galapagos, and Gilead, Consultant of: Celltrion, Galapagos, and Gilead, Bernard Combe Speakers bureau: AbbVie, BMS, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, MSD, Novartis, Pfizer, and Roche-Chugai, Consultant of: AbbVie, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, and Roche-Chugai, Jacques-Eric Gottenberg Consultant of: AbbVie, BMS, Galapagos, Gilead, Lilly, and Pfizer, Grant/research support from: BMS and Pfizer, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Galapagos, Gilead, and Pfizer, Grant/research support from: Gilead and Pfizer, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Amgen, BMS, Celltrion, Fresenius-Kabi, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB, José A Gómez-Puerta Speakers bureau: AbbVie, BMS, Galapagos, GSK, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi, Consultant of: GSK, Roche, and Sanofi, Paul Van Hoek Employee of: Galapagos, Vijay Rajendran Employee of: Galapagos, Pieter-Jan Stiers Shareholder of: Galapagos, Employee of: Galapagos, Thijs Hendrikx Employee of: Galapagos, Gerd Rüdiger Burmester Consultant of: AbbVie, Amgen, BMS, Galapagos, Lilly, MSD, Pfizer, Roche, and Sanofi, Yoshiya Tanaka Speakers bureau: AbbVie, Amgen, Astellas, Astra-Zeneca, Boehringer-Ingelheim, BMS, Chugai, Eisai, Eli Lilly, Gilead, Mitsubishi-Tanabe, and YL Biologics, Consultant of: AbbVie, Ayumi, Daiichi-Sankyo, Eli Lilly, GSK, Sanofi, and Taisho, Grant/research support from: AbbVie, Asahi-Kasei, Boehringer-Ingelheim, Chugai, Corrona, Daiichi-Sankyo, Eisai, Kowa, Mitsubishi-Tanabe, and Takeda

BackgroundPatients (pts) with rheumatoid arthritis (RA) and poor prognostic factors1 (PPF) are at risk for progression without adequate treatment. Filgotinib (FIL) is a once daily Janus kinase 1 preferential inhibitor. In FINCH 1 (NCT02889796), FIL 200 mg (FIL200) was effective vs placebo (PBO) and noninferior to adalimumab (ADA) in pts with RA and inadequate response to methotrexate (MTX-IR); FIL200 and FIL 100 mg (FIL100) were well tolerated.2ObjectivesThis post hoc, exploratory analysis examined efficacy and safety of FIL in MTX-IR pts with 4 or MethodsThe FINCH 1 52-week (W), double-blind trial randomised MTX-IR pts with moderate–severe RA to FIL200 or FIL100, ADA, or PBO; all received background MTX. PBO pts were rerandomised, blinded, at W24 to FIL200 or FIL100. We examined pts with 4 PPF at baseline (BL): erosions on X-ray, seropositivity for rheumatoid factor or anticyclic citrullinated peptide, high-sensitivity C-reactive protein (hsCRP) ≥6 mg/L, and disease activity score in 28 joints with CRP (DAS28[CRP]) >5.1, along with those with P values were nominal, not adjusted for multiplicity.ResultsAt BL, of 1755 randomized, treated pts, 687 had 4 PPF, and 1068 had 5.1). Pts with 4 vs P P P >.05). At W52, mTSS CFB in 4 PPF pts was 0.29, 0.84, and 0.80 for FIL200, FIL100, and ADA, respectively, and 0.14, 0.25, and 0.53 in Table 1.AEs and AEs of interest in BL 4 PPF and 4 PPFFIL200FIL100ADAPBO beforeFIL200FIL100ADAPBO(n = 191)(n = 189)(n = 126)W24 switch (n = 181)(n = 284)(n = 291)(n = 199)before W24 switch (n = 294)All AEs146 (76.4)136 (72.0)85 (67.5)90 (49.7)206 (72.5)214 (73.5)154 (77.4)164 (55.8)AEs of interestSerious infectious AE5 (2.6)4 (2.1)6 (4.8)2 (1.1)8 (2.8)9 (3.1)4 (2.0)2 (0.7)Opportunistic infections001 (0.8)0001 (0.5)0Active tuberculosis0000001 (0.5)0Herpes zoster1 (0.5)1 (0.5)1 (0.8)05 (1.8)3 (1.0)1 (0.5)2 (0.7)Hepatitis B or C01 (0.5)001 (0.5)01 (0.5)0MACE01 (0.5)01 (0.6)01 (0.3)1 (0.5)1 (0.3)VTE001 (0.8)1 (0.6)1 (0.4)001 (0.3)DVT001 (0.8)1 (0.6)0001 (0.3)PE00001 (0.4)000Malignancy0003 (1.7)2 (0.7)2 (0.7)2 (1.0)0(non-NMSC)GI perforation00001 (0.4)000Values are n (%). ADA, adalimumab; AE, adverse event; BL, baseline; DVT, deep vein thrombosis; FIL100, filgotinib 100 mg; FIL200; filgotinib 200 mg; GI, gastrointestinal; MACE, major adverse cardiac event; NMSC, nonmelanoma skin cancer; PBO, placebo; PE, pulmonary embolism; PPF, poor prognostic factor; VTE, venous thromboembolism; W, week.ConclusionIn high-risk (4 PPF) pts with MTX-IR RA, FIL200 and FIL100 showed similar reductions in disease activity vs PBO at W12 as in pts with References[1]Smolen JS et al. Ann Rheum Dis. 2020;79:685–99.[2]Combe B et al. Ann Rheum Dis. 2021;80:848–58.AcknowledgementsThis study was funded by Gilead Sciences, Inc., Foster City, CA. Medical writing support was provided by Rob Coover, MPH, of AlphaScientia, LLC, San Francisco, CA, and was funded by Gilead Sciences, Inc., Foster City, CA. Funding for this analysis was provided by Gilead Sciences, Inc. The sponsors participated in the planning, execution, and interpretation of the research.Disclosure of InterestsBernard Combe Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche-Chugai, Consultant of: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche-Chugai, Grant/research support from: Pfizer and Roche-Chugai, Yoshiya Tanaka Speakers bureau: AbbVie, Amgen, Astellas, AstraZeneca, Behringer-Ingelheim, Bristol-Myers, Chugai, Eisai, Eli Lilly, Gilead Sciences, Inc., Mitsubishi-Tanabe, and YL Biologics, Paid instructor for: AbbVie, Amgen, Astellas, AstraZeneca, Behringer-Ingelheim, Bristol-Myers, Chugai, Eisai, Eli Lilly, Gilead Sciences, Inc., Mitsubishi-Tanabe, and YL Biologics, Grant/research support from: AbbVie, Asahi-Kasei, Boehringer-Ingelheim, Chugai, Corrona, Daiichi-Sankyo, Eisai, Kowa, Mitsubishi-Tanabe, and Takeda, Maya H Buch Speakers bureau: AbbVie, Eli Lilly, Gilead Sciences, Inc., Merck-Serono, Pfizer, Roche, Sanofi, and UCB, Paid instructor for: AbbVie, Eli Lilly, Gilead Sciences, Inc., Merck-Serono, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead Sciences, Inc., Merck-Serono, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Eli Lilly, Gilead Sciences, Inc., Merck-Serono, Pfizer, Roche, Sanofi, and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Pfizer, and Gilead Sciences, Inc., Consultant of: AbbVie, Eli Lilly, Pfizer, and Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ling Han Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Kahaku Emoto Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences K.K., Shungo Kano Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences K.K., Thijs Hendrikx Employee of: Galapagos BV, Daniel Aletaha Speakers bureau: Bristol-Myers Squibb, Merck Sharp & Dohme, and UCB; AbbVie, Amgen, Celgene, Eli Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, and Sanofi/Genzyme., Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, and Sanofi/Genzyme; Janssen, Grant/research support from: from AbbVie, Merck Sharp & Dohme, Novartis, and Roche

BackgroundWork participation among people with rheumatic and musculoskeletal diseases (RMDs) remains reduced when compared to the general population. A EULAR taskforce was established to agree on Points to Consider (PtC) to support people with RMD in healthy and sustainable work participation. Non-pharmacological interventions (NPI) could have an important role in improving work participation in RMDs. However, a comprehensive evidence synthesis of the effectiveness of NPIs in people with RMDs is lacking.ObjectivesTo summarise the literature on effectiveness of NPIs on work participation in people with RMDs.MethodsA search in four databases (MEDLINE, EMBASE, CENTRAL and CINAHL) was performed. Randomised Controlled Trials (RCTs) and Longitudinal Observational Studies (LOS) assessing non-pharmacological/non-surgical interventions until August 2020 were screened. Studies including people with any RMD (except low back pain or work-related RMDs) and assessing a work participation outcome domain (sick leave, work status, presenteeism) were considered eligible. For qualitative evidence synthesis, RCTs and LOS were considered. For quantitative evidence synthesis, only RCTs were considered. For each randomized comparison, standardised mean differences (SMDs) were calculated for the three outcome domains and used as effect size in the meta-analyses; i.e. a negative SMD favouring the NPI over control. Next, Mixed Effects Meta-Regression Analyses were performed, with random effects for randomised comparisons, and a fixed effect factor for the stratified subgroups of clinical interest. Subgroups within diseases (musculoskeletal pain disorders vs. other types of RMDs), risk status for sick leave at baseline (on sick leave or at risk for sick leave; not at risk for sick leave; a combination; or not specified) and single vs. multiple component NPIs were pre-defined. Risk of Bias (RoB) of RCTs was assessed using the Cochrain tool.ResultsOut of 8,864 records, 64 studies (71 treatment comparisons) were included. Studies usually included a mixed population of several RMDs (42%). Most NPIs were conducted in a clinical setting (n=44, 62%) and NPIs usually had multiple components (n=57, 80%), such as vocational support combined with physical training (n=18, 25%). Sick leave was the most frequently reported outcome domain (n=56, 88%). In the qualitative syntheses, 30%/50%/29% of interventions were considered plausible in improving sick leave, work status and presenteeism, respectively.In the quantitative synthesis, NPIs (37 RCTs, 42 comparisons with mostly moderate to high RoB) showed small to moderate effect sizes, favouring NPIs over comparators for sick leave (SMD=-0.23, 95%CI -0.33 to -0.13), work status (SMD=-0.38, 95%CI -0.63 to -0.12) and presenteeism (SMD=-0.25, 95%CI -0.39 to -0.12). The forest plot for sick leave is shown (Figure 1).Subgroup analyses for sick leave revealed that, compared to control, NPIs were not effective in musculoskeletal pain disorders, in contrast to the other types of RMDs. For both other subgroup analyses (baseline risk for sick leave; single vs. multicomponent NPI), NPIs improved sick leave similarly in subgroups compared to the control. Subgroup analyses for work status and presenteeism had generally similar effects in subgroups, but the interpretation requires caution in view of the small number of comparisons. Of note, clinical and methodological heterogeneity between studies was substantial, with some concerns about methodological quality related blinding and completeness of follow up.ConclusionOverall, NPIs seem to have significant, but on the average population level only small to moderate effects on sick leave, work status and presenteeism in RMDs. However, effects on sick leave varied substantially between subgroups. This synthesis suggests that tailoring NPIs to individuals’ needs and context could be clinically valuable.Disclosure of InterestsNone declared.

BackgroundMany people with rheumatic and musculoskeletal diseases (RMDs) experience problems at work and some may even have to stop working due to ill health. In most countries, RMDs are a major cause of worker productivity loss. The peak age of onset of many adult onset RMDs is between ~30-50 years, meaning that the majority of patients are still in employment when diagnosed with their chronic disease. Uncertainty about employment prospects and job attainment is also a major concern for young adults with juvenile idiopathic arthritis (JIA) for whom their first job may influence their future employment prospects. From both a societal and patient perspective it is important to gain an understanding about the impact of juvenile and adult onset RMDs on work outcomes. Data comparing productivity loss with the general population are more relevant for care and healthcare planning. However, these data are more scarce and have not been summarized recently across RMDs.ObjectivesTo systematically summarize the literature on work outcomes in people with RMDs compared with the general population.MethodsA systematic literature review (SLR) was conducted to compare work outcomes in people with various RMDs (i.e. JIA, RA, PsA, AxSpA, SSc, SLE, gout, FM, and OA) with the general population or healthy controls as part of the EULAR Task Force on work. A search for eligible observational studies was performed in Medline, Embase and PsycInfo between 2000 and May 2021. Work outcomes were categorizedaccortding to employment status, work disability/stopped working due to ill health, absenteeism, presenteeism and other.Results541 abstracts were extracted and screened for eligibility. Results of 65 studies fulfilling the inclusion criteria were evaluated for this study, including 28 prospective/retrospective longitudinal cohort studies, 34 cross-sectional studies and 3 (nested) case-control studies. The majority of the studies were conducted in Europe (63.1%). The most common RMD evaluated was RA (26.2%) followed by OA (15.4%), SLE (15.4%), AxSpA (12.3%), FM (9.2%), mixed population (7.7%), JIA (7.7%), PsA (3.1%), SSc (1.5%), and gout (1.5%). In papers reporting disease duration (n=38), the majority of the study population had established disease (76.3%). Several work outcomes were evaluated with some papers reporting more than one work outcome: employment/work status (41.5%), unemployment (9.2%), work disability/pension or stopping work due to ill health (38.5%), absenteeism (52.3%), presenteeism (10.8%), and other (e.g. reduced working hours) (29.2%). Fifty-two papers applied statistical tests (e.g. indirect standardisation, logistic regression analysis, Cox regression analysis) to compare work outcomes in people with RMDs with a control/general population. The percentage of papers reporting the work outcomes to be worse, not significantly different or better in the RMD population compared to the control population (n papers included per work outcome; %) was, respectively: employment/work status (n=26; 73.1%, 23.0%, 3.8%), unemployment (n=6; 66.7%, 33.3%, 0%), work disability/stopping work (n=22; 90.9%, 9.4%, 0%), absenteeism (n=26; 92.3%, 7.7%, 0%), presenteeism (n=8; 87.5%, 12.2%, 0%), other (n=19; 84.2%, 15.8%, 0%).ConclusionDespite better disease management during the last two decades there is still a significant employment gap between people with RMDs and the general population. It is therefore essential that health professional organisations, policy makers, patient organisations and employers should collaborate to minimize the employment gap and optimize employment opportunities among people with juvenile and adult onset RMDs.Disclosure of InterestsSuzanne Verstappen Consultant of: EUOSHA, Grant/research support from: BMS, AbbVie, Pfizer, EULAR, Annelies Boonen Speakers bureau: Abbvie / Galapagos, Consultant of: Galapagos, Nicola Goodson Consultant of: UCB, Lilly, Abbvie, Novartis and Janssen, Grant/research support from: Novartis, Casper Webers: None declared, Maarten Butink: None declared, Neil Betteridge Consultant of: Amgen, Eli Lilly, EULAR, GAfPA, Grunenthal, Heart Valve Voice and Sanofi, Tanja Stamm Consultant of: AbbVie and Sanofi Genzyme, Grant/research support from: AbbVie and Roche, Dieter Wiek: None declared, Anthony Woolf: None declared, Hans Bijlsma: None declared, Gerd Rüdiger Burmester: None declared

BackgroundSeveral research groups have recently described a reduced vaccination response to COVID-19 vaccination under methotrexate (MTX) (1,2). The increase in humoral immune response when pausing MTX two weeks after vaccination has already been described for influenza vaccination (3). However, data regarding MTX-hold during COVID-19 vaccination are still lacking.ObjectivesTo study the effect of MTX and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).MethodsIn this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.ResultsMTX patients showed a significantly lower mean antibody response compared to AIRD patients without immunosuppressive therapy (71.8 % vs 92.4 %, pConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.References[1]Haberman RH, Herati R, Simon D, et al. Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease. Annals of the Rheumatic Diseases 2021[2]Mahil SK, Bechman K, Raharja A, et al. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study. The Lancet Rheumatology 2021;3(9):e627-e37.[3]Park JK, Choi Y, Winthrop KL, et al. Optimal time between the last methotrexate administration and seasonal influenza vaccination in rheumatoid arthritis: post hoc analysis of a randomised clinical trial. Annals of the rheumatic diseases 2019;78(9):1283-84.AcknowledgementsWe would like to thank Tanja Braun and Vera Höhne-Zimmer for theirsupport in obtaining the ethics vote and for their organisational support.Disclosure of InterestsNone declared

Additional file 1:. Supplement Table. Baseline patient characteristics, including diagnosis, sex, age (±SD), Raynaud’s phenomenon, digital ulcers and nailfold capillaroscopy patterns as described by Cutolo et al. (table cited from [8]).

Additional file 1: Figure S1. Flow-Chart: Patient recruitment. Figure S2. Subdermal skin enhancement read in “Temperature mode”. Table S1. Current medication. Table S2. Cardiovascular risk factors.

Additional file 2: FOI Atlas_subclinical skin enhancement.

Zahlreiche Studien und Registerdaten belegen, dass die Depression, haufig verbunden mit Angststorungen, bei Patienten mit einer rheumatoiden Arthritis (RA) sehr haufig zu finden ist. Inwiefern diese psychiatrischen Erkrankungen in einem sehr fruhen Erkrankungsstadium bereits relevant sind, ist aktuell noch unzureichend untersucht. 176 Patienten mit fruhen Gelenkssymptomen (

Sollte es dazu kommen, werden die Arzte meist als Sachverstandige, als Zeugen und gelegentlich als Beklagte in Zivilrechtsverfahren z. B. bei Regressforderungen vor Gericht erscheinen – nur selten als Angeklagte in einem Strafrechtsverfahren. Dies ist mit Ausnahme von Stellungnahmen als Gutachter bei routinierten Kollegen und Kolleginnen in der Regel keine einfache Situation. Der vorliegende Beitrag soll auf wichtige praktische Aspekte bei der Vorbereitung auf die Verhandlung und das Verhandlungsgeschehen selbst eingehen. Bei Beherzigung einer sorgfaltigen Vorbereitung und – falls erforderlich – mit einer guten anwaltlichen Vertretung sind jedoch auch die z. T. schwierigen emotionalen Situationen in der Regel gut zu meistern.

Rheumatische Erkrankungen gehören zu den häufigsten chronisch entzündlichen Krankheiten. Neben ausgeprägter Schmerzhaftigkeit und progredienter Gelenkzerstörung reduzieren die rheumatoide Arthritis (RA), die Spondyloarthritiden (SpA) und die Psoriasisarthritis (PsA) die Arbeitsfähigkeit, die Lebensqualität und bei unzureichender Behandlung auch die Lebenserwartung. Seit der Einführung der Biologika zur Therapie dieser Erkrankungen hat die Suche nach geeigneten Biomarkern zur Frühdiagnostik und Vorhersage des Therapieerfolgs zunehmend an Bedeutung gewonnen. Das Hauptziel des Verbundes ArthroMark ist, neue Biomarker zu identifizieren und moderne Bildgebungsverfahren einzusetzen mit dem Ziel, die Diagnose, die Verlaufskontrolle und die Stratifizierung von Patienten mit RA, SpA und PsA zu verbessern. Mit der Entwicklung geeigneter Biomarker für diese Erkrankungen trägt dieses Vorhaben zur Gesundheitsforschung im Bereich chronischer Erkrankungen des Bewegungsapparates bei. Durch die Zusammenarbeit verschiedener nationaler Zentren sollen standortspezifische Ressourcen wie Probenbanken und klinische Studien gemeinsam nutzbar gemacht werden und individuelle Schwerpunkte in der Biomarkeranalyse mit einem entsprechenden Mehrwert vernetzt werden. Gemeinsames Datenmanagement und Vereinheitlichung der Datenerhebung sowie bestmögliche Charakterisierung der Patienten durch neue Bildgebungsmethoden sollen die Qualität der Markerprüfung optimieren.

Background:The Janus kinase-1 preferential inhibitor filgotinib (FIL) improved rheumatoid arthritis (RA) signs and symptoms in phase (P)3 trials.1–3 RA elevates cardiovascular disease risk; statins are used to reduce risk.Objectives:To assess safety of statin and filgotinib coadministration across the clinical program.Methods:Patients (pts) meeting 2010 ACR/EULAR RA criteria in P2 DARWIN 1–2 (D1–2; NCT01888874, NCT01894516), P3 FINCH 1–3 (F1–3; NCT02889796, NCT02873936, NCT02886728), and long-term extensions DARWIN 3 and FINCH 4 (D3, F4; NCT02065700, NCT03025308) receiving FIL 100 mg (FIL100) QD, FIL 200 mg QD (FIL200), adalimumab (ADA), methotrexate (MTX), or placebo (PBO) were included. Events related to statin use were analysed as exposed by treatment received. N and % were provided.Week (W)12 PBO-controlled safety analysis included pts receiving FIL100, FIL200, or PBO for ≤12W (D1–2, F1–2); as-treated safety analysis included pts receiving long-term FIL100 QD (n=1647), FIL200 QD (n=2267), ADA (n=325), MTX (n=416), or PBO (n=781) (D1–3, F1–4); P3 as-randomised analysis included data up to W52 (F1–3) per assigned treatment.Results:In each arm, similar proportions of pts took statins at baseline (9.4%–11.9%); initiation during study was low (1.2%–6.8%). Through W12 in PBO-controlled analysis, mean creatine phosphokinase (CPK; Figure 1), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were similar regardless of statin use and remained within normal levels across all arms.Mean baseline ALT and AST levels were 20–23 and 20–22 U/L, respectively; at W12, ALT and AST ranged from 22–24 and 20–25 U/L, respectively. Graded CPK, ALT, and AST elevations are in Table 1.Table 1.Graded laboratory abnormalities at week 12 by baseline statin use in PBO-controlled analysisConcomitantNoneFIL200(n=68)FIL100(n=95)PBO(n=93)FIL200 (n=709)FIL100(n=693)PBO(n=688)CPK increased*598281562549537G1 (≤2.5×ULN)10 (16.9)13 (15.9)6 (7.4)71 (12.6)47 (8.6)18 (3.4)G2 (>2.5 to 5×ULN)3 (5.1)006 (1.1)2 (0.4)3 (0.6)G3 (>5 to 10×ULN)0001 (0.2)03 (0.6)G4 (>10×ULN)0001 (0.2)2 (0.4)0AST increased**689492708692684G1 (≤3.0×ULN)9 (13.2)11 (11.7)7 (7.6)97 (13.7)79 (11.4)60 (8.8)G2 (>3.0 to 5.0×ULN)0003 (0.4)2 (0.3)3 (0.4)G3 (>5.0 to 20.0×ULN)01 (1.1)02 (0.3)00G4 (>20.0×ULN)000000ALT increased**689492708692684G1 (≤3.0×ULN)13 (19.1)14 (14.9)13 (14.1)98 (13.8)92 (13.3)72 (10.5)G2 (>3.0 to 5.0×ULN)02 (2.1)010 (1.4)5 (0.7)6 (0.9)G3 (>5.0 to 20.0×ULN)0001 (0.1)01 (0.1)G4 (>20.0×ULN)000000Data are n (%). Grading per Common Terminology Criteria for Adverse Events v4.03*FINCH 1–2**DARWIN 1–2, FINCH 1–2ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; csDMARD, conventional synthetic disease-modifying antirheumatic drug; FIL200/100, filgotinib 200/100 mg + csDMARDs; Grade, G; PBO, placebo; ULN, upper limit of normal.In the long-term as-treated analysis, 1 (0.5%)/6 (3.2%)/0/0/0 treatment-emergent adverse events (AE) of myalgia occurred in pts on statins at baseline receiving FIL200/FIL100/ADA/MTX/PBO and in 12 (0.6%)/8 (0.5%)/3 (1.0%)/2 (0.5%)/1 (0.1%) pts not on statins. Muscle spasms occurred in 2 (0.9%)/3 (1.6%)/1 (3.2%)/0/1 (1.1%) pts on statins at baseline receiving FIL200/FIL100/ADA/MTX/PBO and 21 (1.0%)/8 (0.5%)/0/3 (0.8%)/1 (0.1%) pts not on statins at baseline. One patient not on statins receiving FIL200 reported rhabdomyolysis. For all treatment arms in P3 as-randomised analysis, mean LDL and HDL increased similarly from baseline (108–110 and 56–59 mg/dL, respectively) to W52 (119–130 and 59–71 mg/dL, respectively).Conclusion:No increases in statin-induced AEs such as muscle or liver toxicities occurred with statins and filgotinib coadministration; results are supported by a drug-drug interaction study.4 Mean LDL and HDL increased at W52 in all treatment arms.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.[4]Anderson et al. EULAR 2021 abstract.Disclosure of Interests:Peter C. Taylor Consultant of: AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer, Roche, BMS, Sanofi, Celltrion, and UCB, Grant/research support from: Celgene, Eli Lilly, Galapagos, and Gilead, Christina Charles-Schoeman Consultant of: Gilead, Pfizer, and Regeneron-Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Muhsen Alani Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Mona Trivedi Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Vanessa Castellano Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Sander Strengholt Shareholder of: Galapagos BV, Employee of: Galapagos BV, Michael Nurmohamed Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Roche, and Sanofi, Consultant of: AbbVie, Celgene, Celltrion, Eli Lilly, Janssen, and Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Mundipharma, Novartis, Pfizer, Roche, and Sanofi, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Pfizer, and Gilead Sciences, Inc., Consultant of: AbbVie, Eli Lilly, Pfizer, and Gilead Sciences, Inc.

Background:The consequences of the COVID-19 outbreak are unprecedented and have been felt by everyone around the world, including people with rheumatic and musculoskeletal diseases (RMDs). With the development of vaccines, the future is becoming brighter. Vaccines are a key pillar of public health and have been proven to prevent many serious diseases. However, vaccination also raises questions, especially for patients with inflammatory RMDs and/or treated with drugs that influence their immune system.Objectives:Our aim was to collect safety data among RMD patients receiving COVID-19 vaccines.Methods:The EULAR COVID-19 Vaccination (COVAX) Registry is an observational registry launched on 5 February 2021. Data are entered voluntarily by clinicians or associated healthcare staff; patients are eligible for inclusion if they have an RMD and have been vaccinated against SARS-CoV-2. Descriptive statistics are presented.Results:As of 27 April 2021, 1519 patients were reported to the registry. The majority were female (68%) and above the age of 60 (57%). Mean age was 63 years (SD 16), ranging from 15 to 97 years. A total of 28 countries contributed to the registry, with France (60%) and Italy (13%) as the highest contributors. The majority (91%) had inflammatory RMDs. Inflammatory joint diseases accounted for 51% of cases, connective tissue diseases 19%, vasculitis 16%, other immune mediated inflammatory diseases 4%, and non-inflammatory/mechanical RMDs 9%. The most frequent individual diagnoses were rheumatoid arthritis (30%), axial spondyloarthritis (8%), psoriatic arthritis (8%), systemic lupus erythematosus (SLE, 7%) and polymyalgia rheumatica (6%). At the time of vaccination, 45% were taking conventional synthetic DMARDs, 36% biological DMARDs, 31% systemic glucocorticoids, 6% other immunosuppressants (azathioprine; mycophenolate; cyclosporine; cyclophosphamide; tacrolimus), and 3% targeted synthetic DMARDs. The most frequent individual DMARDs were methotrexate (29%), TNF-inhibitors (18%), antimalarials (10%) and rituximab (6%). The vaccines administered were: 78% Pfizer, 16% AstraZeneca, 5% Moderna and 1% other/unknown; 66% of cases received two doses and 34% one dose. Mean time from 1st and 2nd dose to case report was 41 days (SD 26) and 26 days (SD 23), respectively. COVID-19 diagnosis after vaccination was reported in 1% (18/1519) of cases. Mean time from first vaccination until COVID-19 diagnosis was 24 days (SD 17). Disease flares were reported by 5% (73/1375) of patients with inflammatory RMDs, with 1.2% (17/1375) classified as severe flares. Mean time from closest vaccination date to inflammatory RMD flare was 5 days (SD 5). The most common flare types were arthritis (35/1375=2.5%), arthralgia (29/1375=2.1%), cutaneous flare (11/1375=0.8%) and increase in fatigue (11/1375=0.8%). Potential vaccine side effects were reported by 31% of patients (467/1519). The majority were typical early adverse events within 7 days of vaccination, namely pain at the site of injection (281/1519=19%), fatigue (171/1519=11%) and headache (103/1519=7%). Organ/system adverse events were reported by 2% (33/1519) but only 0.1% (2/1519) reported severe adverse events, namely a case of hemiparesis in a patient with systemic sclerosis/SLE overlap syndrome (ongoing at the time of reporting), and a case of giant cell arteritis in a patient with osteoarthritis (recovered/resolved without sequelae).Conclusion:The safety profiles for COVID-19 vaccines in RMD patients was reassuring. Most adverse events were the same as in the general population, they were non-serious and involved short term local and systemic symptoms. The overwhelming majority of patients tolerated their vaccination well with rare reports of inflammatory RMD flare (5%; 1.2% severe) and very rare reports of severe adverse events (0.1%). These initial findings should provide reassurance to rheumatologists and vaccine recipients, and promote confidence in COVID-19 vaccine safety in RMD patients, namely those with inflammatory RMDs and/or taking treatments that influence their immune system.Acknowledgements:EULAR COVID-19 Task Force; European Reference Network on rare and Complex Connective Tissue and Musculoskeletal Diseases; European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases Network; all rheumatologists contributing to the EULAR COVAX Registry.Disclosure of Interests:Pedro M Machado Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript., Grant/research support from: Orphazyme, unrelated to this manuscript., Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript., Saskia Lawson-Tovey: None declared, Kimme Hyrich Grant/research support from: BMS, UCB, and Pfizer, all unrelated to this manuscript., Speakers bureau: Abbvie, Loreto Carmona Consultant of: her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, S.A., Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal GmbH, and UCB Pharma, all unrelated to this manuscript., Laure Gossec Grant/research support from: AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, UCB, all unrelated to this manuscript., Speakers bureau: Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi, Galapagos, all unrelated to this manuscript., Elsa Mateus Grant/research support from: LPCDR received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal S.A., MSD, Celgene, Medac, Pharmakern, GAfPA; grants and non-financial support from Pfizer; non-financial support from Grünenthal GmbH, outside the submitted work., Anja Strangfeld Speakers bureau: AbbVie, MSD, Roche, BMS, and Pfizer, all unrelated with this manuscript., BERND RAFFEINER: None declared, Tiphaine Goulenok: None declared, Olilvier Brocq: None declared, Martina Cornalba: None declared, José A Gómez-Puerta Speakers bureau: AbbVie, BMS, GSK, Janssen, Lilly, MSD, Roche and Sanofi., Eric Veillard: None declared, Ludovic Trefond: None declared, Jacques-Eric Gottenberg: None declared, Julien Henry: None declared, Patrick Durez: None declared, Gerd Rüdiger Burmester: None declared, Marta Mosca: None declared, Eric Hachulla: None declared, Hans Bijlsma: None declared, Iain McInnes: None declared, Xavier Mariette Consultant of: BMS, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sanofi-Aventis, UCB, and grant from Ose, all unrelated to this manuscript.

Background:Psoriatic arthritis (PsA) is a heterogeneous disease with multiple musculoskeletal and dermatological manifestations. Due to this multifaceted clinical appearance, international guidelines do not provide a clear recommendation for one specific score to assess disease activity in PsA [1]. The Disease Activity Index for Psoriatic Arthritis (DAPSA), a validated, unidimensional score focusing on joint involvement, is one of the recommended options [1]. However, routine determination of C-reactive protein (CRP) to calculate DAPSA values takes hours to days. In contrast, quick quantitative CRP (qCRP) tests require only a few minutes and might facilitate regular assessment of the DAPSA (as Q-DAPSA) in clinical routine.Objectives:To validate the Q-DAPSA in a prospective, multicenter study of PsA patients. Since the Disease Activity Score 28 (DAS28) is not only used in rheumatoid arthritis, but also in PsA patients, the study also investigated the performance of a qCRP based DAS28 (DAS28-qCRP) in a PsA cohort.Methods:The study was conducted in five centers in Berlin, Germany. Consecutive adult (≥ 18 years) PsA patients were included. In addition to a rheumatological assessment, including patient reported outcomes (PROs), routine CRP and erythrocyte sedimentation rate (ESR) were measured in the local labs. Additionally, a qCRP testing with the „QuikRead go instrument“ (Aidian Oy, Finland) was performed locally at the study center (measurement range 0.5 - 200 mg/l for hematocrit concentrations of 40 – 45%). Statistical analysis included descriptive statistics, cross tabulation and weighted Cohen´s kappa comparing disease activity categories, Bland-Altman plots and intraclass correlation coefficient (ICC) for DAPSA, Q-DAPSA, DAS28-CRP and DAS28-qCRP.Results:In this study 104 patients were included between January and October 2020 (mean age: 51.2 years, mean disease duration: 7.1 years, 49 patients (47.1%) were male). 53 patients (51.0%) were treated with a bDMARD and 37 patients (35.6%) with csDMARDs. CRP and qCRP showed mean values of 5.20 and 6.17 mg/l, respectively. With the Q-DAPSA, 103 patients (99.0%) were assigned to the same disease activity category when compared to DAPSA (Table 1). Weighted Cohen´s kappa was 0.990 (95%CI 0.970; 1.000). ICC for numerical values of DAPSA and Q-DAPSA was 1.000 (95%CI 0.999; 1.000). The agreement of Q-DAPSA and DAPSA is shown in a Bland-Altman plot (Figure 1). DAS28-CRP and -qCRP were available for 103 patients; 101 patients (98.1%) showed the same disease activity category in the DAS28-qCRP and weighted Cohen´s kappa was 0.951 (95%CI 0.886; 1.000).Conclusion:The Q-DAPSA and DAPSA showed an almost perfect agreement on the assignment to disease activity categories (99%) with the important advantage of time. With Q-DAPSA, rheumatologists could base their clinical decision-making on a disease activity measurement by using a composite score immediately. Consequently, Q-DAPSA can be integrated in clinical routine and clinical trials and could be implemented into the treat-to-target concept in PsA patients. For rheumatologists who prefer DAS28-CRP for assessing disease activity in PsA patients, DAS28-qCRP may serve as a suitable alternative.References:[1]Smolen JS, et al. Ann Rheum Dis. 2018 Jan; 77(1):3-17.Table 1.Disease activity categories by Q-DAPSA vs. DAPASQ-DAPSA (n = 104)Remission (≤ 4)Low Disease Activity (> 4 and ≤ 14)High Disease Activity (> 14 and≤ 28)Very high Disease Activity (> 28)DAPSARemission (≤ 4)36 (34.6%)1 (1.0%)Low Disease Activity (> 4 and ≤ 14)39 (37.5%)High Disease Activity (> 14 and ≤ 28)22 (21.2%)Very high Disease Activity (> 28)6 (5.8%)The fields highlighted in red indicate that disease activity categories do not match. DAPSA = Disease activity index for Psoriatic Arthritis, Q-DAPSA = DAPSA calculated based on a quick quantitative CRPFigure 1.Bland-Altman plot for Q-DAPSA and DAPSAAcknowledgements:The authors would like to deeply thank Braun T, Doerwald C, Deter N, Höppner C, Lackinger J, Lorenz C, Lunkwitz K, Mandt B, Sron S and Zernicke J for their practical support and coordinating the study.Funding statement:The AQUA study was supported by an unrestricted research grant from Novartis. Testing kits were provided free of charge from Aidian Oy, Finland.Disclosure of Interests:None declared.

Background:Glucocorticoid (GC) therapy has strong anti-inflammatory effects and helps slow radiographic progression in RA1; however, GCs can be associated with adverse events (AEs) such as infection, especially with long-term use and higher doses.Objectives:To evaluate the impact of baseline GCs on the efficacy and safety of upadacitinib (UPA) with or without concomitant conventional synthetic DMARDs (csDMARDs).Methods:In this ad hoc analysis of three Phase 3 studies, patients with inadequate response to MTX (MTX-IR) receiving UPA 15 mg once daily (QD) or placebo (PBO) + csDMARDs in SELECT-NEXT, and MTX-IR/MTX-naïve patients receiving UPA 15 mg QD monotherapy or MTX monotherapy in SELECT-MONOTHERAPY/SELECT-EARLY, respectively, were included. Efficacy outcomes, including measures of remission and low disease activity (LDA) determined by DAS in 28 joints using CRP (DAS28[CRP]; Results:Of 1,506 patients included in the analysis, 737 (48.9%) were receiving baseline GCs (mean dose 6.2 mg/day). Baseline characteristics were broadly similar across treatment groups; SELECT-EARLY, which enrolled MTX-naïve patients, generally had the shortest duration of RA and higher CRP levels. Across UPA treatment groups, concomitant GCs generally did not influence the proportions of patients achieving remission (Figure 1). In SELECT-NEXT, clinical responses with UPA 15 mg in combination with csDMARDs were similar irrespective of concomitant GC use (Figure 1). Within SELECT-MONOTHERAPY, responses in patients receiving UPA 15 mg without concomitant csDMARDs or GCs were higher than those in patients receiving MTX alone, but were numerically lower than in those receiving UPA 15 mg with GCs (Figure 1). However, this was not observed within SELECT-EARLY, where clinical responses in patients receiving UPA 15 mg monotherapy without GCs were higher than in those patients receiving UPA 15 mg with GCs for both DAS28(CRP) table of safety data will be presented).Conclusion:UPA 15 mg in combination with csDMARDs or as monotherapy was effective in achieving remission and LDA, irrespective of concomitant GC use. Safety of UPA, including incidence of infection, appeared largely unaffected by concomitant GC use.References:[1]Kirwan JR, et al. Cochrane Database Syst Rev 2007;1:CD006356.Acknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing assistance was provided by Frances Smith, PhD, of 2 the Nth, which was funded by AbbVie.Disclosure of Interests:Bernard Combe Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche-Chugai, Sanofi, and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche-Chugai, Sanofi, and UCB Pharma, Frank Buttgereit Speakers bureau: AbbVie, Eli Lilly, Pfizer, and Roche, Andrew Ostor Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Novartis, Paradigm, Pfizer, Roche, and UCB Pharma., Ricardo Xavier Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB Pharma, Alain Saraux Speakers bureau: AbbVie, Bristol-Myers Squibb, Chugai, Eli Lilly, Nordic, Sanofi, and UCB Pharma, Consultant of: AbbVie, Bristol-Myers Squibb, Chugai, Eli Lilly, Nordic, Sanofi, and UCB Pharma, Capucine DARIDON Shareholder of: AbbVie, Employee of: AbbVie, Kirsten Famulla Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie, Employee of: AbbVie, Ivan Lagunes-Galindo Shareholder of: AbbVie, Employee of: AbbVie, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche, and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche, and UCB Pharma