SDAI Remission Research Articles

Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment

ObjectiveTo report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT)...

The double shared epitope: Its impact on clinical features and ultrasound findings in rheumatoid arthritis.

The link between the HLA-DRB1 locus and the risk of rheumatoid arthritis (RA) shown in genome-wide association studies strengthens the shared epitope (SE) hypothesis. We aimed to assess the impact of the double dose of the SE (double SE) on RA and explore its clinical associations, including the response to abatacept. We evaluated RA patients treated with csDMARDs or abatacept for HLA-DRB1 typing, clinical characteristics at baseline, and disease activity and ultrasound findings over 12 months. Patients with the double SE (n = 12) had significantly higher anti-citrullinated protein antibody (ACPA) titers, higher total grayscale (GS) score, and power Doppler (PD) score at baseline than patients without the double SE. Patients with the double SE exhibited reduced rates of SDAI remission and pronounced improvements in multiple disease activity between baseline and 12 months, including SDAI, CDAI, total GS score, and total PD score. When focusing on abatacept-treated patients, the decreases in SDAI, CDAI, and total PD score between baseline and 12 months were significantly larger in patients with the double SE. Patients with the double SE exhibited distinct characteristics, increased disease activity, and improved response to abatacept treatment.

Ultrasound versus clinical remission in patients with early rheumatoid arthritis: concordance and relationship with therapy discontinuation.

To evaluate prevalence of ultrasonographic remission (USR) and concordance with clinical remission in "drug-free" or "on-treatment" patients with early rheumatoid arthritis (RA). We carried out a cross-sectional study including consecutive early RA patients in SDAI remission ≥6 months in the period 06/2022 to 02/2023. CDAI, DAS28, DAS44 and Boolean remission were also evaluated. Patients underwent B-mode and Power Doppler (PD) assessments of 42 joints and 20 tendons. Synovitis, tenosynovitis and PD were graded semi-quantitatively (0-3) using standardised scores. Four definitions of USR were examined: USR1: absence of synovial hypertrophy (SH) and PD; USR2: SH≤1 and PD=0; USR3: SH≤1 and PD≤1; USR4: PD negative. Eighty patients were enrolled, of whom 12 drug-free. Overall remission rates were 100.0%, 83.7%, 91.2%, 96.2% and 80.0% for SDAI, CDIA, DAS28, DAS44 and ACR/EULAR Boolean criteria, respectively. 100% of drug-free patients were in remission according to all indices. The rate of USR in drug-free versus on-treatment remission was 58.3%, 66.7%, 66.7%, 83.3% versus 70.6%, 85.3%, 88.2%, 91.2% for USR1, USR2, USR3 and USR4, respectively. While clinical remission seems more frequent in drug-free patients, USR is more often observed on-treatment.

Biosimilars in rheumatoid arthritis in 2022 – data from the Romanian Registry of Rheumatic Diseases

Objective. The study aimed at determining whether RA patients starting or stopping biosimilars differ in any regard from those starting or stopping originals. Methods. Data on RA patients was obtained from the Romanian Registry of Rheumatic Diseases (RRBR) database between January 1st, 2022, and December 31st, 2022, encompassing all Romanian RA patients fulfilling the national criteria for bo/bsDMARD initiation, continuation or switching. Results. Etanercept and adalimumab predominated for initiations of biosimilars. Most entries on biosimilars originated from originals (including non-medical switches) and from bDMARDs without biosimilars. A historical effect of accumulation of patients was observed, manifested in the fact that originals still dominated the group of patients continuing their treatment, with the exception of infliximab, while biosimilars tended to be continued in younger patients and in patients with shorter disease duration. Cases categorized more severe by both patients, their doctors and their disease activity were preferably reserved for originals. In patients continuing their previous bDMARD, biosimilars exhibited higher DAS28 and SDAI remission rates. Conclusion. RRBR data from 2022 confirm the market rise of biosimilars in RA, but also physicians’ prudence in prescribing them to highly active cases. In the Romanian RA cohort, biosimilars are overall more effective in holding remission than originals.

P137 First-line tumour necrosis factor inhibitor (TNFi) treatment is associated with high multi-criteria remission early on compared to treat-to-target in a treatment naïve RA cohort

Abstract Background/Aims In rheumatoid arthritis (RA) disease assessment, SDAI and Boolean remission criteria are known to be more stringent in comparison to DAS28-ESR. Comparing remission rates across multiple assessment indices provides a more comprehensive evaluation of disease control. In an early RA trial cohort, we aimed to investigate stringent and multi-criteria remission (MCR) rates and evaluate their proportional change in response to treatment. Methods The ‘VEDERA’ trial randomised 120 treatment-naïve, new-onset RA patients to first-line etanercept+methotrexate (ETN+MTX) or methotrexate treat-to-target (MTX-TT) with escalation to ETN+MTX if not in DAS28-ESR remission at week24. Clinical assessments were completed at baseline, weeks12/24/48 (protocolised phase) up to week96 (standard-of-care). Remission cut-points included: DAS28-ESR ≤2.6, SDAI ≤3.3 and Boolean score for individual components≤1. MCR was defined as patients who were in DAS28-ESR, SDAI and Boolean remission concurrently. Descriptive analyses were undertaken to address the above aims. Results Overall, at week12, 26%(31/120) were in SDAI and 13%(16/120) in Boolean remission. This increased to 41%(49/120) and 23%(28/120) respectively by week48. In the ETN+MTX group at week12, 30%(18/60) were in SDAI and 17%(10/60) in Boolean remission. This increased to 43% (26/60) and 32%(19/60) respectively by week48. Stringent remission rates were lower in MTX-TT compared to ETN+MTX and significantly different for Boolean at week48 (15% vs 32%, odds ratio 2.6, 95% confidence interval 1.1 to 6.5, nominal p < 0.05) (Table 1). Of those in remission by the three different criteria, 36%(14/39) were in MCR at week12, with a greater proportion in ETN+MTX group [42%(10/24) compared to 27%(4/15) in MTX-TT]. MCR remained unchanged up to week48 but improved with treatment by week 96 to 45%(27/60). MCR rates did not converge between the 2 treatment groups at week 96 (ETN+MTX 55%; MTX-TT 38%). Conclusion First-line ETN+MTX is associated with higher rates of stringent remission from week 12 compared to MTX-TT, with improvement gradually over time with both strategies. Significantly higher proportion of patients treated with first line ETN+MTX compared to MTX-TT achieved Boolean and MCR. Early TNFi treatment associates with more complete and better cumulative disease activity profile. Patients not meeting MCR early following treat-to-target approach should be considered for more aggressive treatment strategies. Disclosure R. Shukla: None. D. Plant: None. P. Emery: None. M.H. Buch: None.

P107 Long-term efficacy of baricitinib in patients with rheumatoid arthritis with inadequate response to bDMARDs: results from RA-BEYOND up to 6.9-years of treatment

Abstract Background/Aims Baricitinib (BARI), an oral selective Janus kinase 1/2 inhibitor, is approved for treatment of adults with moderately-to-severely active rheumatoid arthritis (RA). BARI demonstrated efficacy in patients (pts) with RA who have inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) in a 24-week (wk) phase 3 study, RA-BEACON. BARI efficacy was evaluated up to 3 years (yrs) of treatment in a long-term extension (LTE) study, RA-BEYOND. This analysis reports long-term efficacy of BARI 4 mg and 2 mg in bDMARD-IR pts in the completed study RA-BEYOND. Methods In RA-BEACON, pts were randomized 1:1:1 to BARI 4 mg, 2 mg, or PBO; pts with no response could be rescued after wk 16. Completers to wk 24 could enter with BARI 4 or 2mg RA-BEYOND for up to 360 wks (6.9 yrs). LTE data were analysed by treatment assigned at baseline in RA-BEACON as observed up to time of stepdown (if applicable), study discontinuation, or study completion, whichever occurred earlier. Efficacy response rates (RR) were assessed as proportions of pts with observed data up to wk 360 for low-disease activity (LDA) (SDAI ≤ 11, DAS28-hsCRP ≤ 3.2, CDAI ≤ 10), remission (REM) (SDAI ≤ 3.3, DAS28-hsCRP < 2.6, CDAI ≤ 2.8, Boolean), and physical functioning (HAQ-DI ≤ 0.5). No formal statistical comparisons were conducted. Results 156, 152, and 140 pts entered the LTE (4 mg, 2 mg, and PBO, respectively). Pts in BARI 4 and 2 mg arms had higher LDA and REM RR vs PBO at LTE entry (wk 24). PBO-treated pts achieved comparable RR to pts in the BARI 4 mg arm by wk 48 (24 wks after switch to BARI 4 mg) and up to wk 360. Of pts enrolled to RA-BEYOND, approx. 50% in BARI 4 mg, 65% in 2 mg and 61% in PBO remained active at wk 156; 17%, 26% and 26% at wk 360, respectively. SDAI LDA RR were 47%/70% and 61%/74% for pts treated with BARI 4 mg and 2 mg, at wk 156 (yr 3)/ 360 (yr 6.9), respectively; SDAI REM RR were 15%/26% and 26%/26% for BARI 4 mg and 2 mg, at wk 156/360, respectively. SDAI and CDAI had comparable RR. DAS-28CRP LDA RR were similar to SDAI and CDAI, while REM RR were about twice those of SDAI and CDAI. HAQ-DI ≤ 0.5 RR was 15%/26% (BARI 4 mg), 21%/15% (BARI 2mg), and 9%/3% (PBO) at 3/6.9 yrs. Conclusion In observed data, BARI maintained efficacy and normative physical function bDMARD-IR population up to 6.9 yrs (360 wks). Disclosure R. Caporali: Consultancies; R. C. has been a consultant and/or speaker for: AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Fresenius Kabi, Galapagos NV, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, and UCB Pharma. D. Aletaha: Grants/research support; D. A. has been a speaker for and/or received research support from: AbbVie, Amgen, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Sobi. R. Sanmartí: Grants/research support; R. S. has been a speaker for and received research support from: Eli Lilly and Company. T. Takeuchi: Grants/research support; T. T. has been a consultant and/or speaker for and/or received research support from: AbbVie, Asahi Kasei Pharma, Astellas, AYUMI Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, DNA Chip Research, Eisai, Eli Lilly Japan K.K., Gilead Sciences, Janssen, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, and UCB Pharma. D. Mo: Shareholder/stock ownership; D. M. is an employee and shareholder of: Eli Lilly and Company. E. Haladyj: Shareholder/stock ownership; E. H. is an employee and shareholder of: Eli Lilly and Company. L. Zaremba-Pechmann: Other; L. Z-P. is a contractor for: HaaPACS GmbH. P.C. Taylor: Grants/research support; P. C. T. has been a consultant for and/or received research support from: AbbVie, Biogen, Celgene, Eli Lilly and Company, Fresenius Kabi, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer, Roche, and Sanofi.

Factors Associated With Maintenance of Remission Following Change From Combination Therapy to Monotherapy in Patients With Rheumatoid Arthritis.

Some patients with rheumatoid arthritis (RA) who persist in remission may decide to stop their therapy. We evaluated baseline characteristics associated with remaining in remission or low disease activity (LDA) following medication withdrawal. The Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis (SEAM-RA) was a phase III, multicenter, randomized withdrawal, double-blind, controlled study in patients with RA on methotrexate (MTX) + etanercept (ETN). If remission (Simplified Disease Activity Index [SDAI] ≤ 3.3) was sustained through a 24-week run-in period, patients then entered a 48-week double-blind period and were randomized 2:2:1 to receive MTX monotherapy, ETN monotherapy, or continue combination therapy. Multivariate logistic regression analysis was performed to identify baseline factors associated with remission or LDA at the end of both periods. Of 371 patients enrolled, 253 entered the double-blind period. After adjusting for other factors, covariates associated with achieving SDAI remission at the end of the run-in period included younger age, longer duration of MTX treatment, and less severe clinical disease variables. Covariates associated with maintaining remission/LDA at the end of the 48-week double-blind period included lower patient global assessment of disease activity (PtGA), lower C-reactive protein, rheumatoid factor (RF) negativity, longer RA duration in the MTX arm, shorter duration of ETN treatment, and lower magnesium. These findings indicate patients with overall lower disease activity are more likely to remain in SDAI remission/LDA after switching from combination therapy to monotherapy. RF-negative status and lower PtGA scores were strongly associated with increased likelihood of remaining in remission/LDA with MTX or ETN monotherapy. (SEAM-RA; ClinicalTrials.gov: NCT02373813).

Comparison of Efficacy and Safety of Original and Biosimilar Adalimumab in Active Rheumatoid Arthritis in a Real-World National Cohort.

Background and Objectives: Real-world evidence should reflect the evidence obtained from controlled trials; therefore, the study aimed to compare biosimilar adalimumab (bADA) to original adalimumab (oADA) in terms of efficacy and safety in a real-life national cohort of rheumatoid arthritis (RA) patients. Materials and Methods: The following study is a prospective observational study in which we analyzed patients treated with reimbursed biologics from the Romanian Registry of Rheumatic Diseases (RRBR). RA cases must fulfill the 2010 classification criteria, as well as specific inclusion and exclusion criteria. The RRBR database was queried for all RA patients starting oADA or bADA (FKB327, GP2017, MSB11022, SB5 available) from 2 May 2019 (the first bADA initiation) until 26 March 2022 (study search date). Results: The study included 441 patients who started oADA (48.3%) or bADA (51.7%) in the same time period. At baseline, patients starting bADA had a significantly higher mean age and lower prevalence of women. After the first six months of treatment, there were no significant differences between the oADA and bADA regarding rates of Boolean (15.0% vs. 12.3%, p = 0.401), DAS28-CRP (32.4% vs. 34.2%, p = 0.686) and SDAI (16.4% vs. 14.0%, p = 0.483) remission rates. There were 107 cases of adverse events (AE): 81.3% on oADA and 18.7% on bADA. Notably, 51.4% of AE were infections. Regarding severity, 49.5% of AEs were mild, 34.6% were moderate, and 15.9% were severe. Conclusion: Biosimilar adalimumab showed similar efficacy and safety to original adalimumab after the first six months of treatment in RA patients from a national registry.

American College of Rheumatology/EULAR Remission Criteria for Rheumatoid Arthritis: 2022 Revision.

In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean- and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the 2 sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. We used data from 4 randomized trials comparing biologic disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared to the original threshold of 1 cm (Boolean1.0). We analyzed agreement between the Boolean- and index-based criteria (Simplified Disease Activity Index [SDAI] and Clinical Disease Activity Index [CDAI]) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire [HAQ] score ≤0.5) and radiographic nonprogression. Data from 2,048 trial participants, 1,101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared to Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes. Using the Boolean 2.0 criteria classifies more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardizing predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

Impact of Treat-to-Target Therapy on Bone Mineral Density Loss in Patients With Rheumatoid Arthritis: A Prospective Cohort Study.

BackgroundOsteoporosis is a common comorbidity of rheumatoid arthritis (RA). Although RA disease activity has been demonstrated to be associated with bone loss in previous studies, most of them were cross-sectional studies and not in the context of treat-to-target (T2T) strategies.ObjectivesThis study aimed to evaluate the association of disease activity with bone mineral density (BMD) changes in the context of T2T strategies in a prospective RA cohort.MethodsRA patients were enrolled from a prospective CENTRA cohort of Peking University First Hospital. The follow-ups have been scheduled every 3 to 6 months. BMD was repeated at baseline, 1 year, and then every other year. Demographics, baseline clinical features, laboratory data, and medications at each visit were recorded. Time-adjusted mean disease activity scores were adopted to reflect the overall disease activity during follow-up. The influence of univariable associations between predictors and BMD was investigated using linear regression.ResultsA total of 268 patients were included in our analysis. Their mean age was 50 (12.9) years, and 224 (83.6%) were women. The median (IQR) disease duration was 48.7 (107.6) months. Osteoporosis in the lumbar spine was observed in 23.1% of patients and 9.3% in the femoral neck at enrollment. Older age, higher SDAI score, and lower BMI were associated with osteoporosis at baseline. The proportion of patients who achieved DAS28-ESR, CDAI, and SDAI remission or LDA at the end of the first year was 71.5%, 68.8%, and 67.4%, respectively. Reevaluations of BMD at 1 year were applied to 144 patients. Mean decreases of BMDs were 1.75% at the lumbar spine and 1.40% at the femoral neck at 1 year from baseline, respectively. Patients who achieved remission had less yearly bone loss in the lumbar spine (p = 0.036). Female gender was identified as a risk factor in the multiple linear regression analyses, and lower disease activity and bisphosphonates were protective factors of continuous bone loss.ConclusionDisease activity is associated with bone loss in RA patients in the context of T2T strategies, and those who achieved remission had less yearly bone loss.

Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study.

IntroductionTo evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD).MethodsData from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population.ResultsIn RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports.ConclusionsLong-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated.Trial registrationClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

POS0086 ANALYSIS OF DISEASE ACTIVITY MEASURES IN THE CONTEXT OF A METHOTREXATE WITHDRAWAL STUDY AMONG PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOFACITINIB 11 MG ONCE DAILY + METHOTREXATE: POST HOC ANALYSIS OF DATA FROM ORAL SHIFT

Background:The Phase 3b/4 study ORAL Shift demonstrated sustained efficacy and safety of tofacitinib modified-release (MR) 11 mg once daily (QD) following methotrexate (MTX) withdrawal that was non-inferior to continued tofacitinib + MTX use (per DAS28-4[ESR]), in patients (pts) with rheumatoid arthritis (RA) who achieved CDAI-defined low disease activity (LDA) with tofacitinib + MTX at Week (W)24.1Objectives:To assess the performance of alternative disease activity measures at W24 (randomisation) and W48 (study endpoint) in ORAL Shift.Methods:ORAL Shift (NCT02831855) enrolled pts aged ≥18 years with moderate to severe RA and an inadequate response to MTX. Pts received open-label tofacitinib MR 11 mg QD + MTX for 24 weeks. Achievement of CDAI LDA (≤10) at W24 was set as the criteria for entry to the 24-week double-blind MTX withdrawal phase, with pts randomised 1:1 to receive tofacitinib MR 11 mg QD + placebo (PBO) (ie blinded MTX withdrawal) or continue tofacitinib + MTX. In this post hoc analysis, efficacy analyses were performed in 8 subgroups defined by achievement of various disease activity criteria at W24: DAS28-4(ESR) remission (<2.6) or LDA (≤3.2); DAS28-4(CRP) <2.6 or ≤3.2; RAPID3 remission (≤3) or LDA (≤6); CDAI remission (≤2.8); and SDAI remission (≤3.3). For each subgroup, the proportion of pts who achieved the corresponding disease activity criterion at W48 was calculated, with a 95% confidence interval (CI) estimated using the normal approximation to the binomial distribution. The change (Δ) from W24 to W48 in least squares (LS) mean DAS28-4(ESR) and DAS28-4(CRP) was also calculated in each subgroup, with a 95% CI for the difference between treatment groups estimated using a mixed model with repeated measures. Nominal p values were calculated and are presented with no formal statistical hypothesis testing formulated.Results:Overall, 694 pts entered the open-label phase of ORAL Shift, and 530 were randomised and received treatment in the double-blind phase; 264 and 266 pts received tofacitinib + PBO and tofacitinib + MTX, respectively (Figure 1a). Considering those pts who were randomised and treated, the proportion of pts achieving each disease activity criterion at W24 varied, but was similar between treatments within each subgroup (Figure 1a). Among pts who met each disease activity criterion at W24, generally the majority of pts in both treatment groups also met the same criterion at W48 (Figure 1b). Numerically more pts receiving tofacitinib + MTX vs tofacitinib + PBO continued to meet the corresponding criterion at W48. Regardless of the disease activity criterion met at W24, differences between treatment groups in LS mean ΔDAS28-4(ESR) (Figure 1c) and ΔDAS28-4(CRP) (data not shown) from W24 to W48 favoured tofacitinib + MTX vs tofacitinib + PBO.Conclusion:This post hoc analysis of data from pts randomised and treated in ORAL Shift demonstrated that, regardless of the disease activity state criterion met at W24, generally a majority of pts receiving tofacitinib maintained achievement of the corresponding disease activity criterion at W48, with or without continued MTX. Differences between treatment groups in LS mean ΔDAS28-4(ESR) from W24 to W48, as defined by achievement of LDA or remission with a variety of disease activity measures, were less than a change of 1.2, which is considered to be the threshold for a minimal clinically important improvement.2

Comparable long-term outcomes between DAS28-ESR remission criteria and ACR/EULAR definitions in patients with established rheumatoid arthritis.

To compare long-term clinical, immunological, and radiographic outcomes between five sets of remission criteria (four clinical and one ultrasound (US)-based) in a cohort of RA patients in a clinical care setting. RA patients in remission (DAS28-ESR <2.6) were selected. HandUS assessments were made, and serum levels of inflammation/angiogenesis biomarkers were determined at baseline. Changes in baseline treatment and radiographic progression, defined as the variation in the modified Sharp van der Heijde score (mSHS) at 5 years, were analyzed. Five concepts were used to define remission: DAS28-ESR<2.6, SDAI<3.3, CDAI<2.8, Boolean criteria and Power Doppler score (PD)=0. Eighty-seven patients with DAS28-ESR<2.6 were included. One-third fulfilled SDAI (33.3%), CDAI (31%), and Boolean (35.6%) remission criteria, and 25.3% had no PD signal in the US evaluation. 26 patients (29.9%) changed therapy, ranging from 13.6% (PD remission) to 33.3% (CDAI remission) (p=0.11). Serum levels of ANG (p=0.015) and TNFa (p=0.025) were significantly lower in patients with Boolean remission, whereas IL-18 levels were significantly lower in those with PD remission (p=0.049). Patients without PD in the US assessment had significantly-lower mSHS erosion progression (p=0.014) at 5 years. Patients with established RA in DAS28-ESR remission had comparable clinical and radiographic outcomes in SDAI, CDAI, and Boolean definitions in a clinical care setting. US remission remained the closest to structural damage abrogation. Key Points • This study provides real world data on long-term outcomes of five clinical and imaging remission criteria in rheumatoid arthritis. • DAS28-ESR remission criteria had comparable radiographic progression and clinical prognosis than more stringent criteria in clinical practice. • US-based remission was closest to structural damage abolishment.

Effectiveness and safety of baricitinib in rheumatoid arthritis: a monocentric, longitudinal, real-life experience

Baricitinib is a Janus-kinase (JAK) 1/2 inhibitor, approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). We report the first real-life experience with baricitinib in a monocentric cohort of unselected RA patients. We enrolled consecutive RA patients starting baricitinib. At baseline and after 4, 12, 24 and 48 weeks we assessed the disease activity by composite indices (SDAI, CDAI and DAS28CRP) and ultrasonography, and we recorded any adverse events. The primary endpoint was the percentage of patients achieving SDAI remission at week 4. We enrolled 59 patients [(F:M = 50:9, median age 58.1 years (IQR 12.8), median disease duration 144 (IQR 150) months] treated with baricitinib in combination with a csDMARD (52.5%) or monotherapy (47.5%) for a median follow-up of 24 weeks (IQR 36). The 12-month drug retention rate was 74%. At weeks 4, 12, 24 and 48 we observed a significant reduction of DAS28, CDAI and SDAI, global health and pain (p<0.001 for all). After 4 weeks of treatment, 12% of patients achieved SDAI remission. Concomitant csDMARDs, previous biological DMARDs, gender, seropositivity and BMI did not affect the efficacy of baricitinib. Baricitinib allowed a significant reduction in prednisone dose after 12 and 24 weeks and a rapid and sustained ultrasound improvement. No serious adverse events, serious infections or cardiovascular events were recorded. Our study confirms the efficacy and safety profile and rapid onset of the effect of baricitinib in RA patients in a real-life setting.

A Matching-Adjusted Indirect Comparison of Upadacitinib Versus Tofacitinib in Adults with Moderate-to-Severe Rheumatoid Arthritis.

IntroductionUpadacitinib and tofacitinib are Janus kinase inhibitors approved for moderate-to-severe rheumatoid arthritis (RA). In the absence of head-to-head trials comparing their effectiveness, this study assessed the efficacy of upadacitinib 15 mg once-daily monotherapy/combination therapy against tofacitinib 5 mg twice-daily combination therapy among patients with RA using matching-adjusted indirect comparisons (MAICs).MethodsThe first of two MAICs used individual patient data (IPD) from the 14-week SELECT-MONOTHERAPY trial (upadacitinib [n = 217] vs. methotrexate [n = 216]) and published data from the ORAL Standard trial (tofacitinib + methotrexate [n = 204] vs. methotrexate [n = 108]). The second MAIC used IPD from the 26-week SELECT-COMPARE trial (upadacitinib + methotrexate [n = 647] vs. adalimumab + methotrexate [n = 324]) and published data from ORAL Strategy (tofacitinib + methotrexate [n = 376] vs. adalimumab + methotrexate [n = 386]). Data from patients in the upadacitinib trials were re-weighted based on age, sex, race, swollen joint count 66/28, tender joint count 68/28, C-reactive protein (CRP), and patients’ global assessments to match the patient characteristics in tofacitinib trials. After matching, ACR20/50/70 and clinical remission (SDAI[CRP] ≤ 3.3, CDAI ≤ 2.8, DAS28-ESR/CRP < 2.6) were compared for upadacitinib vs. tofacitinib + methotrexate at month 3 and upadacitinib + methotrexate vs. tofacitinib + methotrexate at months 3 and 6 using Wald tests.ResultsAt month 3, upadacitinib monotherapy patients experienced significantly larger improvement in ACR70 compared to tofacitinib + methotrexate (mean difference in difference [DID]: 9.9%; p = 0.019), while upadacitinib + methotrexate was associated with higher ACR50 compared to tofacitinib + methotrexate (DID: 12.9%; p = 0.011). At month 6, upadacitinib + methotrexate patients experienced significantly larger improvement in SDAI/CDAI/DAS28-ESR clinical remission compared to tofacitinib + methotrexate, with DIDs of 9.1% (p = 0.011), 7.5% (p = 0.038), and 11.3% (p = 0.002), respectively.ConclusionsCompared to tofacitinib combination therapy, treatment with upadacitinib monotherapy and combination therapy were associated with improved outcomes at 3/6 months (monotherapy: ACR70; combination: ACR50, SDAI, CDAI, and DAS28-ESR remission).Electronic supplementary materialThe online version of this article (10.1007/s40744-020-00257-w) contains supplementary material, which is available to authorized users.

Contributing factors of clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis patients with tightly controlled disease activity in clinical practice: a retrospective study

Objectives To determine whether specific parameters contribute to clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis (RA) patients under the ‘treat-to-target’ strategy in clinical practice. Methods We retrospectively analyzed 125 RA patients selected according to the following criteria; the patients’ symptom duration was ≤6 months, and none had experience with DMARDs. We evaluated the patients’ clinical disease activity at baseline and 1 year of treatment and the musculoskeletal ultrasound (MSUS)-detected synovitis activity at baseline. We performed an analysis to identify parameters that contribute to SDAI remission and the use of biologic/targeted synthetic (b/ts) DMARDs at 1 year post-diagnosis. Results Forty-seven patients received b/tsDMARDs therapy, and 58 patients achieved SDAI remission at 1 year post-diagnosis. Rheumatoid factor positivity, low patient’s/evaluator’s global assessment at baseline, and methotrexate use at 1 year post-diagnosis were associated with SDAI remission. The baseline clinical disease activity and MSUS scores were not associated with SDAI remission. Anti-cyclic citrullinated peptide antibody positivity/high titer and high swollen joint counts or the presence of severe synovial hypertrophy at baseline were associated with the use of b/tsDMARDs therapy. Conclusion The value of the expected poor-prognosis factors may be diminished by intensive therapy within the ‘windows of opportunity’.

SAT0104 MAINTENANCE OF SDAI REMISSION AND PATIENT-REPORTED OUTCOMES (PROS) FOLLOWING DOSE DE-ESCALATION OF ABATACEPT IN MTX-NAÏVE, ANTI-CITRULLINATED PROTEIN ANTIBODY (ACPA)+ PATIENTS WITH EARLY RA: RESULTS FROM AVERT-2, A RANDOMISED PHASE IIIB STUDY

Background:The Phase IIIbAssessingVeryEarlyRATreatment (AVERT)-2 trial (NCT02504268) evaluated SC abatacept (ABA) + MTX vs ABA placebo (PBO) + MTX in ACPA+ patients (pts) with early, active RA.1Results from the 56-wk induction period (IP) showed a significantly greater proportion of pts treated with ABA + MTX (vs MTX alone) reported clinically meaningful improvements in HAQ-DI, global disease activity and pain, which were sustained at 52 wks.2Objectives:To report maintenance of SDAI remission and PROs from the AVERT-2 de-escalation (D-E) period.Methods:Pts received blinded SC ABA (125 mg once wkly [QW]) + MTX or ABA PBO + MTX induction treatment for 56 wks. In this analysis, pts who completed induction with ABA + MTX and had sustained SDAI remission (≤3.3 at Wks 40 and 52) were re-randomised 1:1:1 to ABA QW + MTX, stepwise D-E (ABA every other wk + MTX for 24 wks then ABA PBO + MTX for 24 wks), or ABA QW + MTX PBO for 48 wks in the D-E period. PROs included physical function (HAQ-DI [0–3; decrease=improvement] and Short-Form 36 [SF-36] v2.0 Physical Functioning Scale [PFS]; 0–100; increase=improvement), and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] score; 0–52; decrease=improvement). Endpoints included: proportion of pts in SDAI remission and pts with HAQ-DI response (decrease from IP Day [D]1 in HAQ-DI ≥0.30); adjusted mean change (adMC) from D-E D1 in HAQ-DI, SF-36 PFS or FACIT-F to D-E Wk 48. adMCs were estimated using a mixed effect model with repeated measures.Results:147 ABA + MTX-treated pts were re-randomised in the D-E period. Across re-randomised arms, the range of mean scores was 1.87–2.52 for SDAI and 0.18–0.30 for HAQ-DI at entry into D-E period (D-E D1). 74% of pts receiving ABA QW + MTX maintained SDAI remission at D-E Wk 48 (Fig 1); this proportion was higher than in the ABA withdrawal and ABA QW + MTX PBO arms. Pts continuing ABA QW + MTX maintained HAQ-DI response during D-E (Fig 1), but by D-E Wk 48 the proportion of pts with HAQ-DI response in the ABA withdrawal arm declined by 30%. At D-E Wk 48, a small numerical decrease (adMC –0.04) in HAQ-DI was observed in the ABA QW + MTX arm; increases were seen in the withdrawal (adMC 0.26) and ABA QW + MTX PBO arms (adMC 0.16). By D-E Wk 48, SF-36 PFS increased (adMC 1.68) in the ABA QW + MTX arm but decreased in the withdrawal (adMC –3.34) and ABA QW + MTX PBO (adMC –1.45) arms. FACIT-F score increased during D-E in all arms, but the increase at D-E Wk 48 was lower in the ABA QW + MTX arm (adMC 0.79) vs the withdrawal (adMC 4.12) and ABA QW + MTX PBO (adMC 2.41) arms. Similar trends were seen for other PROs including Work Productivity and Activity Impairment-RA; while activity impairment remained stable in the ABA QW + MTX arm, there was a trend for worsening in the withdrawal arm.Conclusion:In the AVERT-2 D-E period, continued combination therapy (abatacept + MTX) resulted in maintenance of benefits on PROs, particularly physical functioning, in seropositive pts with early RA. D-E of abatacept followed by complete withdrawal was associated with the greatest loss of remission as well as worsening of PROs. The PRO results corresponded well to the maintenance of clinical (SDAI) remission.

THU0095 IMPACT OF BASELINE EROSION SCORE ON RESPONSE TO TREATMENT AND FUTURE RADIOLOGICAL DAMAGE IN AVERT-2, A RANDOMISED PHASE IIIB STUDY OF ABATACEPT IN MTX-NAÏVE, ANTI-CITRULLINATED PROTEIN ANTIBODY–POSITIVE (ACPA+) PATIENTS WITH EARLY RA

Background: Bone erosions are associated with poor prognosis in patients (pts) with RA. They can be associated with subclinical inflammation and independently predict future radiological damage.1 The Phase IIIb Assessing Very Early RA Treatment (AVERT)-2 (NCT02504268) trial evaluated abatacept (ABA)+MTX in MTX-naive, ACPA+ pts with early RA.2 Objectives: To explore the impact of baseline (BL) X-ray erosion scores (ES) on clinical response and future radiological damage over 1 yr in different groups of pts from AVERT-2. Methods: BL and Wk 52 X-ray data were evaluated using Sharp/van der Heijde score. SDAI remission rates (RRs; ≤3.3), unadjusted mean changes from BL (CfB) and duration of/time to sustained remission over 52 wks were evaluated. Radiographic progression was assessed at Wk 52 using CfB in ES. A range of BL ES cut-offs were evaluated to highlight key findings through comparison of pts with low and high ES. Results: Of 994 pts in the study, 964 (97%) had BL (median 2.0, interquartile range [IQR] 0.5–5.1) and 792 (80%) had BL and Wk 52 (median 2.5, IQR 1.0–6.5) ES. Results in Table 1 are based on ES cut-offs of 2 and 5, resulting in 53% and 75%, respectively, of pts in low ES groups. In pts who received ABA+MTX, those with low ES had higher SDAI RRs over 52 wks vs pts with high ES. The relationship was more pronounced for higher cut-offs. This was not observed with ABA placebo+MTX (MTX). Greater reduction of mean CfB in SDAI was achieved in pts with high vs low ES who received ABA+MTX. This was not observed with MTX. Pts who received ABA+MTX had longer duration and shorter time to sustained SDAI remission vs MTX. With ABA+MTX, pts with low ES had longer duration and shorter time to sustained SDAI remission vs high ES. This was not observed with MTX. Mean CfB in ES at Wk 52 was lower in the ABA+MTX arm vs the MTX arm. ABA seemed to equally protect pts with low and high ES; with MTX, pts with high ES had higher mean CfB in ES at Wk 52 than pts with low ES. Conclusion: This erosion-based stratification of the AVERT-2 early seropositive RA population emphasizes the importance of treating pts prior to the accumulation of erosive disease. Abatacept+MTX led to higher SDAI RRs in pts with low vs high ES and provided further protection vs MTX alone against future radiological damage in pts with high ES. Additional statistical modelling and adjustment for confounding factors at BL is warranted.

THU0163 USE OF BIOLOGICAL AGENT IN MONOTHERAPY IN RHEUMATOID ARTHRITIS IN COMPARISON TO THE ASSOCIATIONS WITH D(ISEASE) M(ODIFIING) A(NTI) R(HEUMATIC) D(RUGS): REVIEW OF LITERATURE AND META-ANALYSIS OF RANDOMIZED TRIALS.

Background:Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis (RA) patients with suboptimal response or intolerance to conventional synthetic DMARDs (CsDMARDs). Currently, 9 biologic agents are approved in the RA treatment: and among them, three anti TNF agents are also approved in monotherapy (adalimumab, certolizumab and etanercept), but also abatacept, anakinra and tocilizumab. Registries of routine clinical practice treatment indicate that approximately one third of RA patients are being treated with a bDMARD in monotherapy and analyses from health care claims suggest that when methotrexate (MTX) is prescribed in combination with a bDMARD, more than half of the patients do not collect the MTX prescription and overall patients seem to taper MTX intake over time. So it is important to evaluate the benefit and harm associated with use of biological agents as monotherapy, and not only the traditional combination therapy strategies.Objectives:To compare the efficacy and safety of the individual biological agents used in monotherapy in patients with RA than the combination therapy strategy with CsDMARD + bDMARD.Methods:We used The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and MEDLINE in order to carry out our research, for published reports from inception of each database through December 2019. Search results were limited to randomised controlled trials (RCTs), with our two arms: biological agent in monotherapy and combination strategie (with any CsDMARDs). Major outcome was the ACR 20 reponse criteria at 24 week. The secondary outcomes were: the ACR 20 at 52 week, ACR 50, 70, 90 reponse criteria, the DAS 28 remission (with CRP and/or ESR), the score sharps modified non progressor, the proportion of patients who withdrawals the study due to adverse events, the proportion of patients who withdrawals the study due to lack of efficacy, the HAQ improvement &gt; 0,22, CDAI and SDAI remission at week 24 and 52 if the data were available. The study of tolerance was also made. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in R (version 3.6.1) using fixed and random-effects.Results:The systematic review identified 2566 citations. The analysis comprises 22 trials (6358 patients), including six biological agents approved for RA (abatacept, adalimumab, etanercept, golimumab, rituximab and tocilizumab) as well as two other molecules: Clazakizumab, a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine and Anbainuo, recombinant human TNFRII:Fc fusion protein. No study satisfyies our search criteria for anakinra, certolizumab and infliximab. Compared to combination therapy with CsDMARD+bDMARD, bDMARD monotherapy has less probability to give a ACR20 response at 24 weeks (RR: 0,92 [0,89 – 0,96]) in fixed or random effect model and this result is similar at 52 weeks (RR: 0,94 [0,89 – 0,99]). For all other outcome mesures, we can see an increased of ACR50–70 and 90 responses, an improve of the DAS 28 remission score, an increase of the proportion of sharp’s score non progressors (&lt;0,5) as well as a decrease of withdrawals for inefficacy without increase of withdrawals for toxicity.Conclusion:Evidence from this meta-analysis suggests that combinaison strategy with bDMARD+CsDMARD remains the most efficacious option, being more effective than the use of biologics in monotherapy. The interest from this point of view is to sensitize prescribers to the use of other CsDMARDs when there is a contraindication or intolerance to MTX, but also to make patients aware of the superiority of the association of biological agents with CsDMARDs.figureDisclosure of Interests:Célia DELPECH: None declared, François-Xavier LABORNE: None declared, Pascal Hilliquin Consultant of: BMS, MSD, Novartis, Roche-Shugai.

Dynamics of lymphocyte subpopulations, CD4+CD25+CD127- T regulatory cells in patients with rheumatoid arthritis during therapy with the rituximab biosimilar Acellbia

Objective: to evaluate the effect of the rituximab (RTM) biosimilar Acellbia on the peripheral blood levels of CD3+, CD3+CD4+, CD3+CD8+, CD16+CD56+, CD19+, and CD4+CD25+CD127- lymphocytes in patients with rheumatoid arthritis (RA).Patients and methods. Examinations were made in 20 RA patients who received 2 RTM infusions at a total dose of 1200 mg. The levels of C-reactive protein, IgM rheumatoid factor, IgG, IgM, and IgA were measured by a nephelometric method. The relative and absolute contents of CD3+, CD3+CD4+, CD3+CD8+, CD16+CD56+, CD19+, CD4+CD25+CD127- T regulatory cells (Tregs) were estimated by multicolor flow cytofluorometry.Results and discussion. At week 24 of RTM therapy, there was a good/satisfactory effect according to EULAR criteria in 17 (85%) patients; DAS28 remission in 4 (20%), and SDAI remission in 2 (10%). The use of RTM was accompanied by a significant increase in the relative content of CD4+CD25+CD127- T lymphocytes, the median of which at weeks 12 and 24 after therapy initiation increased from 6.8 [5.2; 7.6]% to 7.3 [6.1; 8.3] and 6.97 [6.4; 8.2]%, respectively (p&lt;0.05). The absolute peripheral blood count of Tregs tended to increase at weeks 12 after the first infusion of the drug (up to 0.05 [0.04; 0.075] ⋅ 109 /l; p=0.05). At week 24 follow-up, the patients who achieved SDAI remission/low disease activity had significantly higher baseline relative Tregs levels (7.35 [6.8; 7.97]% than those with the moderate activity of the pathological process (5.8 [4.3; 7.22] %; p&lt;0.05).Conclusion. The use of the RTM biosimilar is accompanied by the development of complete depletion of CD19+ lymphocytes and by an increase in CD3+ and CD3+CD4+ lymphocytes and Tregs. The larger baseline number of CD4+CD25+CD127- lymphocytes is associated with the higher efficiency of RTM therapy.