Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with rheumatoid arthritis: Results from RA-BEYOND

Objective To evaluate the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active rheumatoid arthritis (RA). Methods Patients completed 1 of 3 phase 3 baricitinib trials (NCT01711359, NCT01710358, NCT01721057) and entered the long-term extension RA-BEYOND (NCT01885078), in which patients received once-daily 4 mg or 2 mg baricitinib. Across these trials, patients initially receiving methotrexate (MTX) or adalimumab switched to baricitinib 4 mg at week 52. Patients initially receiving placebo switched to baricitinib 4 mg at week 24. Radiographs were scored at baseline and years 2, 3, 4, and 5. Change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS) was computed. Results Overall, 2125/2573 (82.6%) randomized patients entered RA-BEYOND; 1837/2125 (86.4%) entered this analysis. From years 3 to 5, higher proportions of DMARD-naïve patients on initial baricitinib (monotherapy; +MTX) had no progression versus initial MTX (ΔmTSS≤0, year 5: 59.6% baricitinib 4 mg; 66.2% baricitinib 4 mg+MTX; 40.7% MTX). Higher proportions of patients with inadequate response (IR) to MTX on initial baricitinib or adalimumab versus placebo had no progression (ΔmTSS≤0, year 5: 54.8% baricitinib 4 mg; 55.0% adalimumab; 50.3% placebo). Higher proportions of patients with conventional synthetic (cs)DMARD-IR on initial baricitinib 4 mg had less progression versus initial placebo or baricitinib 2 mg (ΔmTSS≤0, year 5: 66.7% baricitinib 4 mg; 58.2% baricitinib 2 mg; 60.0% placebo). Conclusion Oral baricitinib maintained lower levels of radiographic progression than initial csDMARD or placebo through 5 years in patients with active RA.

AB0187 PREVALENCE, RISK FACTORS, AND TREATMENT MODALITIES OF ATLANTOAXIAL DISLOCATION IN RHEUMATOID ARTHRITIS

Background:Cervical spine involvement is common in patients with rheumatoid arthritis (RA). The most common abnormality is atlantoaxial dislocation (AAD). It may lead to severe neurological symptoms and even death. Currently, there is a lack of consensus on the best approach to treatment.Objectives:We investigated the prevalence of and risk factors for AAD in patients with RA, as well as its relationship to treatment modalities.Methods:We conducted a cross-sectional study including 224 patients with RA. All patients fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism RA classification criteria. Radiographs of the cervical spine included lateral views taken in flexion, extension, neutral position of the neck, anteroposterior and odontoid projection view. Patients were divided into two groups: (G1) a group with AAD and (G2) without ADD. We compared clinical, radiological, and laboratory findings between the two groups, as well as the treatments used: Steroid therapy, classic and biologic disease-modifying anti-rheumatic drugs (DMARDs). Structural joint damage was assessed with the Sharp/van der Heijde radiographic method. Functional impairment was assessed using the Health Assessment Questionnaire (HAQ). We used Statistical Package for Social Sciences (SPSS) 22.0 to analyze the results. The level of statistical significance was set at 0.05.Results:ADD was present in 16% of the cases (n=36). Female predominance was noted, with a sex ratio of 0.25 (p=0.530). The mean age was 58±12 years, with no significant difference between groups (p=0.146). The mean disease duration was significantly higher in G1 (11.5 ± 10.5 years versus 5.9 ± 6.3, p=0.004). A noticeable relationship between AAD and immunopositivity was found: rheumatoid factor (RF) was present in 86.1% of the cases in G1 versus 67.5% in G2 (p=0.025). Anti-citrullinated protein antibodies (ACPA) were present in 86.1% of the cases in G1 versus 64.8% in G2 (p=0.012). We found a significant difference between AAD and disease activity assessed by DAS28-VS (5.8±1.3 in G1 versus 5.3±1.6 in G2,p=0.027). AAD was significantly associated with more structural joint damage: erosions (121.1±60.9 in G1 versus 61.8±56.5 in G2,p<10-3), joints space narrowing (77.4±47.4 in G1 versus 38.7±40 in G2, p<10-3), Sharp/van der Heijde radiographic score (190.2±103.1 in G1 versus 100.1±90.6 in G2, p<10-3). Hip involvement was more frequent in G1 (22.2% versus 9.4% in G2, p=0.038).HAQ score was higher in G1 (1.8±0.7 versus 1.2±1, p=0.002).Seventy-five percent of patients in G1 had received methotrexate versus 82.3% in G2 (p=0.301). The mean duration of methotrexate therapy was longer in G1 (24.6±23.5 versus18±24 months, p=0.015). G1 patients received a higher mean dose and cumulative dose of methotrexate: 13.2±3.5 g/week versus 11.8±4.4 g/week (p=0.048), and 6.5±6.8 versus 4.8±8.5 (p=0.025), respectively.Thirty-five percent of patients in G1 had received corticosteroids versus 25% in G2 (p=0.217). Patients in G1 had a significantly longer duration of steroid therapy: 17.8 + 20.2 versus 13.3 + 24.3 months (p=0.22). The mean dose of corticosteroids was similar between the two groups: 6.9±4.3 mg/day versus 5.7±4.6 mg/day (p=0.132). The total cumulative dose was significantly higher in G1: 6.5±6.8 mg/day versus 4.8±8.5 mg/day (p=0.025).There was no significant difference in using other DMARDs: Sulfasalazine (p=0.182) and leflunomide (p=0.276).No significant difference was observed with patients under biologic DMARDs: 24.1% in G1 versus 17% in G2 (p=0.725).Conclusion:Cervical spine involvement is common in RA and may be asymptomatic. Immunopositive patients seem to have more frequently ADD, as well as those with high disease activity and severe structural joint damage. The treatment modalities do not appear to be affected by AAD; however, patients with ADD seem to have higher cumulative doses of corticosteroids and methotrexate. Given the cross-sectional nature of our study, it is difficult to confirm the connection between the two. Further studies are needed.Disclosure of Interests:None declared

P134 Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with RA: results from RA-BEYOND

Background/Aims Baricitinib (BARI) is an oral, reversible, selective JAK1/2 inhibitor. Treatment with once-daily oral BARI resulted in low rates of radiographic progression for up to 2 years in patients with rheumatoid arthritis (RA). Here, we evaluate the radiographic progression of structural joint damage in patients with RA over 5 years of treatment with BARI. Methods This included patients who completed three Phase 3 trials, RA-BEGIN (DMARD-naive), RA-BUILD (csDMARD-IR), or RA-BEAM (MTX-IR), and enrolled in long-term extension study, RA-BEYOND. Patients receiving blinded BARI at the conclusion of Phase 3 trials remained on that dose (2mg/4mg, once daily) in RA-BEYOND. At 52 weeks, DMARD-naive patients receiving methotrexate(MTX) or combination therapy(BARI 4mg+MTX) were switched to BARI 4mg monotherapy; MTX-IR patients receiving adalimumab(ADA) were switched to BARI 4mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo(PBO) were switched to BARI 4mg on background csDMARD. Analysis population included patients who had baseline and at least one radiograph collected after 2 years. Radiographic progression of structural joint damage (Years 3-5) was determined by changes from baseline in van der Heijdemodified Total Sharp Score(ΔmTSS), erosion score, and joint space narrowing. Proportion of patients showing no progression was assessed based on change from baseline mTSS(ΔmTSS) from originating study, using thresholds of 0.5 or smallest detectable change(SDC). Mixedmodel repeatedmeasures and logistic regression models were used to analyze continuous variables and categorical variables, respectively; linear extrapolation was used for imputation of missing data(maximum of 1 year). Results 82.6% (2125/2573) of patients entered long-term extension study. Among DMARD-naive patients, those on initial BARI monotherapy or in combination with MTX had significantly slower radiographic progression(ΔmTSS) versus those on initial MTX at Years 3, 4, 5 (p ≤ 0.05). They had significantly fewer erosions at these time points (p ≤ 0.05). A greater proportion of patients who received initial BARI therapy and BARI+MTX had no radiographic progression versus initial MTX monotherapy using thresholds of 0.5 (p ≤ 0.05). Among MTX-IR patients, those on initial BARI treatment had slower radiographic progression compared to PBO and results were comparable to those on initial ADA treatment at Years 3, 4, 5. A greater proportion of patients who received initial BARI therapy had no radiographic progression versus initial PBO using thresholds of SDC (p ≤ 0.05). Among csDMARD-IR patients, although differences between groups were small, patients on initial BARI 4mg had slowest radiographic progression compared to initial PBO and initial BARI 2mg. At least 74% of the structure data used in the analyses are based on observed data. Conclusion Treatment with once-daily oral BARI maintained low rates of radiographic progression for up to 5 years in different patient populations with RA. Disclosure D.M.F.M. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma. C.E. Kartman: Shareholder/stock ownership; Eli Lilly and Company. L. Xie: Shareholder/stock ownership; Eli Lilly and Company. S. Beattie: Shareholder/stock ownership; Eli Lilly and Company. D.E. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, and Sanofi. Y. Tanaka: Member of speakers’ bureau; AbbVie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB, and YL Biologics. Grants/research support; AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, and Taisho-Toyama and Takeda. R. Fleischmann: Consultancies; AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB.

Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis—a comprehensive review

Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.

SAT0145 EFFICACY AND SAFETY OF UPADACITINIB MONOTHERAPY IN MTX-NAÏVE PATIENTS WITH EARLY ACTIVE RA RECEIVING TREATMENT WITHIN 3 MONTHS OF DIAGNOSIS: A POST-HOC ANALYSIS OF THE SELECT-EARLY

Background:Early treatment of RA within the therapeutic window(0-3 months from symptom onset), has been associated with improved clinical outcomes and physical function. However, ≤42% of RA patients(pts) visit a rheumatologist within 90 days of symptom onset1,2.Objectives:To assess safety and efficacy of Upadacitinib(UPA), an oral, reversible, potent JAK-1 selective inhibitor3, in pts with moderate to severely active RA who were MTX-naïve or had an inadequate response to csDMARDs/bDMARDs4-6.Methods:In SELECT–EARLY, MTX-naïve pts with active RA and poor prognosis were randomized 1:1:1 to once-daily UPA monotherapy at 15 or 30 mg or weekly MTX (titrated up to 20 mg/week through Week 8). Efficacy (including ACR, DAS28(CRP), CDAI responses and change in mTSS) and safety outcomes from a post-hoc analysis of patients who received treatment within 90 days from diagnosis are reported here. The statistical significance defined asp<0.05was exploratory in nature.Results:A total of 270 pts commenced treatment within 90 days from RA diagnosis (median: 44 days [11, 89]). Pts in each arm were mostly female (70%), had moderately to severely active RA with mean DAS28(CRP) =5.9±1.02, had structural joint damage (mean mTSS =7.7±21.5) and were seropositive for both ACPA and RF at baseline (72%)4. At Week 24, compared to MTX, significantly greater proportions of pts receiving UPA 15 or 30 mg monotherapy achieved efficacy outcomes including ACR20, 50 and 70 responses, DAS28CRP<2.6, CDAI≤2.8 or Boolean remission. Improvements in physical function (HAQ-DI) and decrease in pain were also significantly greater in pts receiving UPA 15 and 30 mg vs MTX at Week 24. Treatment with UPA was also associated with a greater inhibition of structural joint damage compared with MTX (Figure 1). Safety outcomes were consistent with the full study and the integrated safety analysis (all phase 3 studies of UPA). Compared to MTX, higher frequencies of serious infections and herpes zoster were reported in both UPA groups. There were 2 deaths in total (UPA 30 mg: 1 due to cardiovascular death and 1 due to pneumonia and sepsis) (Figure 2).Conclusion:In RA pts, early initiation of treatment with UPA 15 mg and 30 mg monotherapy within 3 months from diagnosis was associated with clinically meaningful improvements in efficacy, including remission and inhibition of progression of structural joint damage compared to MTX. The safety profile was consistent with the overall study and the integrated phase 3 safety analysis7. UPA seems to be a promising treatment option for more patients to reach their treatment targets of remission or low disease activity when treated within 3 months of diagnosis.References:[1]Raza K et al. Ann Rheum Dis. 2011;70(10):1822-5.[2]Stack RJ et al. BMJ Open. 2019;9:e024361.[3]Parmentier et al. BMC Rheumatol. 2018;2:23.[4]van Vollenhoven R et al, Arth Rheumatol. 2018; 70 (s10) [Abs ACR2018].[5]Burmester GR et al. Lancet 2018;391:2503-12.[6]Genovese MC et al, Lancet 2018;391:2513-24.[7]Cohen S et al, Ann Rheum Dis [Abs EULAR2019].Disclosure of Interests:Meliha C Kapetanovic: None declared, Maria Andersson Shareholder of: AbbVie, Employee of: AbbVie, Alan Friedman Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Tim Shaw Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Ulf Müller-Ladner Speakers bureau: Biogen, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB

THU0211 RADIOGRAPHIC OUTCOMES IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING UPADACITINIB AS MONOTHERAPY OR IN COMBINATION WITH METHOTREXATE: RESULTS AT 2 YEARS FROM THE SELECT-COMPARE AND SELECT-EARLY STUDIES

Background:For patients with rheumatoid arthritis (RA), long-term prevention of structural joint damage is a key treatment goal.1In the SELECT-EARLY and SELECT-COMPARE trials, upadacitinib (UPA), an oral JAK inhibitor, inhibited the progression of structural joint damage at 6 months and 1 year when used either as monotherapy or in combination with methotrexate (MTX) in patients (pts) with active RA.2Objectives:To describe the radiographic progression up to 2 years (96 wks) among pts with RA receiving UPA either as monotherapy or in combination with MTX.Methods:Both the SELECT-EARLY and SELECT-COMPARE phase 3, randomized controlled trials enrolled pts at high risk for progressive structural damage with baseline (BL) erosive joint damage and/or seropositivity.3,4In SELECT-EARLY, MTX-naïve pts (N=945) were randomized to UPA 15 mg or 30 mg once daily (QD) or MTX monotherapy. In SELECT-COMPARE, pts with an inadequate response to MTX (N=1629) were randomized to UPA 15 mg, placebo (PBO), or adalimumab (ADA) 40 mg every other wk, with all pts continuing background MTX; at wk 26, all pts receiving PBO were switched to UPA 15 mg, regardless of response. In both trials, mean changes from BL in modified Total Sharp Score (mTSS), joint space narrowing, and joint erosion as well as the proportion of pts with no radiographic progression (change in mTSS ≤0) were evaluated based on X-rays taken at wks 24/26, 48, and 96 for those patients in whom wk 96 X-rays were available. Data are reported as observed (AO).Results:BL demographics have been reported previously.3,4In the SELECT-EARLY study, at wk 96 UPA monotherapy (15 mg and 30 mg doses) significantly inhibited radiographic progression compared with MTX as measured by mean change in mTSS and by the proportion of patients with no radiographic progression (Figures 1 and 2). When patients who were rescued (MTX added to UPA or UPA added to MTX) were removed from the analysis, changes in mTSS from baseline remained similar. By the same measures, in SELECT-COMPARE, the degree of inhibition of structural progression observed was comparable between UPA and ADA. Following the switch of all PBO patients to UPA, the rate of progression slowed and was comparable to that observed in pts receiving UPA from BL. Among pts from both studies that had no radiographic progression at wk 24/26, >90% remained without radiographic progression at wk 48 and 96.Conclusion:UPA was effective in inhibiting the progression of structural joint damage through 2 years both in MTX-naïve patients receiving UPA monotherapy and MTX-inadequate responder patients receiving UPA in combination with MTX.References:[1]Smolen, et al.Ann Rheum Dis2017;76(6):960-77.[2]Peterfy, et al.Ann Rheum Dis2019;78(suppl 2):369-370.[3]Fleischmann, et al.Arthritis Rheumatol2019;71(11):1788-1800.[4]Van Vollenhoven, et al.Arthritis Rheumatol2018;70(suppl 10).Disclosure of Interests: :Charles Peterfy Consultant of: AbbVie, Acerta, Amgen, AstraZeneca, Bristol Myers Squibb, Centrexion, Daiichi Sankyo, Five Prime Therapeutics, Genentech, Gilead, Hoffman-La Roche, Janssen, Lilly USA, MedImmune, Merck, Myriad, Novartis, Plexxikon, Pfizer, Sanofi, Salix Santarus, Samsung, Samumed, Setpoint, Sorrento, UCB, Vorso, Employee of: founder and CEO of Spire Sciences, which provides imaging services to multiple pharmaceutical companies, Speakers bureau: Amgen, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Alan Friedman Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Jose Jeffrey Enejosa Shareholder of: AbbVie, Employee of: AbbVie, Stephen Hall Grant/research support from: Abbvie, UCB, Janssen, Merck, Eduardo Mysler Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer., Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer, Patrick Durez Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Pfizer, Sanofi, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Tim Shaw Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc.