Progression Of Structural Joint Damage Research Articles

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Earlier clinical response predicts low rates of radiographic progression in biologic-naïve patients with active psoriatic arthritis receiving guselkumab treatment

ObjectiveAssess relationship between earlier clinical improvement and radiographic progression (RP) over 2 years in guselkumab-treated patients with active psoriatic arthritis (PsA).MethodPost hoc analyses combined data from DISCOVER-2 biologic-naïve adults with active PsA randomized to either guselkumab 100 mg every 4 weeks (Q4W) or guselkumab at W0, W4, then Q8W. Correlations (Spearman’s coefficient) between baseline disease parameters and total PsA-modified van der Heijde-Sharp (vdH-S) score were examined. Repeated-measures mixed models, adjusted for known RP risk factors, assessed the relationship between Disease Activity Index in PsA (DAPSA) improvement, DAPSA improvement exceeding the median or the minimal clinically important difference (MCID), or DAPSA low disease activity (LDA) at W8 and RP rate, assessed by change from baseline in vdH-S score through W100.ResultsBaseline age, PsA duration, CRP level, and swollen joint count, but not psoriasis duration/severity, weakly correlated with baseline vdH-S score. Elevated baseline CRP (parameter estimate [β] = 0.17–0.18, p < 0.03) and vdH-S score (β = 0.02, p < 0.0001) significantly associated with greater RP through W100. Greater improvement in DAPSA (β = -0.03, p = 0.0096), achievement of DAPSA improvement > median (least squares mean [LSM] difference: -0.66, p = 0.0405) or > MCID (-0.67, p = 0.0610), or DAPSA LDA (-1.44, p = 0.0151) by W8 with guselkumab significantly associated with less RP through W100. The effect of W8 DAPSA LDA on future RP was strengthened over time among achievers vs. non-achievers (LSM difference enhanced from -1.05 [p = 0.0267] at W52 to -1.84 [p = 0.0154] at W100).ConclusionsIn guselkumab-treated patients with active PsA, earlier improvement in joint symptoms significantly associated with lower RP rates through 2 years, indicating blockade of the IL-23 pathway may modify long-term disease course and prevent further joint damage.Key Points• Greater improvement in DAPSA at Week 8 of guselkumab treatment was significantly associated with less progression of structural joint damage at 2 years in patients with active psoriatic arthritis (PsA).• Early control of peripheral joint disease activity with blockade of the IL-23 pathway may modify long-term PsA trajectory and prevent further joint damage.

Efficacy and safety of ixekizumab in patients with active psoriatic arthritis with and without concomitant conventional disease-modifying antirheumatic drugs: SPIRIT-P1 and SPIRIT-P2 3-year results

Introduction/objectivesTo evaluate the three-year efficacy and safety of ixekizumab with and without concomitant conventional synthetic disease-modifying antirheumatic drug (csDMARD) use in patients with active psoriatic arthritis (PsA).MethodPatients with PsA who were biologic-naïve (SPIRIT-P1, NCT01695239) or had prior inadequate response to tumor necrosis factor inhibitors (SPIRIT-P2, NCT02349295) were randomized to receive 80-mg ixekizumab every four weeks after receiving 160-mg ixekizumab at baseline. Efficacy, safety, and immunogenicity were evaluated in this post-hoc analysis in three subgroups: (1) ixekizumab monotherapy, (2) ixekizumab and methotrexate (MTX), (3) ixekizumab and any csDMARD (including MTX). Missing data were imputed using multiple imputation for continuous variables and modified non-responder imputation for categorical variables.ResultsEfficacy was similar across the three subgroups with 59.1%, 67.0%, and 66.1% of ixekizumab-treated patients achieving 20% improvement in the American College of Rheumatology scale score at week 156. Radiographic progression of structural joint damage (SPIRIT-P1 only) was similarly inhibited across the three subgroups with several outliers. No new safety signals were reported, and 91.0%, 84.1%, and 83.2% in the three subgroups reported ≥ 1 treatment-emergent adverse event. At week 156, 15.9%, 13.1%, and 11.0% in the three subgroups had antidrug antibodies; most had low titer status.ConclusionsIxekizumab showed sustained efficacy in treating patients with PsA for up to three years in monotherapy or in combination with MTX or any csDMARD. The three subgroups had similar safety and immunogenicity profiles, which supports that the use of concomitant MTX or csDMARDs does not seem to impact the benefit/risk profile of ixekizumab.Key Points• Ixekizumab treatment led to improved clinical responses over time when used as monotherapy or in combination with concomitant MTX or any concomitant csDMARD (including MTX) in patients with active PsA.• Ixekizumab monotherapy has similar radiographic efficacy as ixekizumab with MTX or ixekizumab with other csDMARDs (including MTX); similar inhibition of radiographic progression was observed between the subgroups of patients receiving ixekizumab monotherapy or ixekizumab with MTX or other csDMARDs.• The long-term safety profile of ixekizumab used as monotherapy or in combination with MTX or any other csDMARDs is consistent with what has been previously reported. The addition of MTX or any csDMARD to ixekizumab treatment did not negatively impact the favorable long-term safety profile of ixekizumab.

Inhibition of structural joint damage progression with upadacitinib in rheumatoid arthritis: 1-year outcomes from the SELECT phase 3 program

ObjectivesTo evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active RA receiving upadacitinib as monotherapy or in combination with MTX.MethodsRadiographic progression was assessed in two phase 3 randomized controlled trials. MTX-naïve patients were randomized to upadacitinib 15 or 30 mg once daily or MTX monotherapy (SELECT-EARLY, n = 945), while MTX inadequate responders (IRs) were randomized to upadacitinib 15 mg once daily or adalimumab 40 mg every other week or placebo added to background MTX (SELECT-COMPARE, n = 1629). The mean changes from baseline in modified total Sharp score (mTSS), joint space narrowing and erosion scores were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as observed.ResultsIn patients naïve or with limited exposure to MTX (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg and 1.00 for MTX based on linear extrapolation (P < 0.001 for both upadacitinib doses vs MTX). Among patients with an inadequate response to MTX (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus MTX group vs placebo plus MTX (0.28 vs 1.73; P < 0.001). The mean change from baseline in the adalimumab plus MTX group was 0.39.ConclusionUpadacitinib monotherapy or in combination with background MTX was effective in inhibiting the progression of structural joint damage through week 48 in MTX-naïve and MTX-IR patients with RA.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov), NCT02706873 and NCT02629159

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

Abstract 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 &amp; 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.

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&lt;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&lt;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.

P225 Inhibition of structural joint damage with upadacitinib as monotherapy or in combination with MTX in patrients with RA: one-year outcomes from the select Phase 3 programme

Abstract Background Long-term prevention of structural joint damage is a key treatment goal in the management of RA. Upadacitinib (UPA), a JAK1-selective inhibitor, inhibited the progression of structural joint damage at 6 months as monotherapy in methotrexate (MTX)-naïve RA patients and in combination with MTX in patients with inadequate response (IR) to MTX. Objectives: To evaluate the progression of structural joint damage (radiographic) through Week 48 in patients with moderately to severely active RA treated with UPA monotherapy or in combination with MTX. Methods Radiographic progression was assessed in 2 phase 3 randomized controlled trials (RCTs). MTX-naïve patients were randomized to UPA 15 or 30mg QD or MTX monotherapy [SELECT-EARLY, N = 945], while MTX-IR patients were randomized to UPA 15mg QD or adalimumab (ADA) 40 mg eow or placebo (PBO), with continuous background MTX [SELECT-COMPARE, N = 1629]. Both RCTs specifically enrolled patients at high risk for progression of joint damage (high disease activity including elevated hsCRP, presence of baseline erosions and ACPA and/or RF positivity). The mean changes (D) from baseline (BL) in modified Total Sharp Score (mTSS), joint space narrowing (JSN), and erosion scores (ES) as well as the proportion of patients with no radiographic progression (ΔmTSS ≤0) at Weeks 24/26 and 48 were determined in both RCTs. Data were analyzed by linear extrapolation (LE) for missing data imputation and treatment switching, and as observed (AO). Results BL demographics have been reported previously. At Weeks 24/26, UPA as monotherapy and in combination with background MTX significantly inhibited radiographic progression measured by mean DmTSS and the proportion of patients with no radiographic progression vs MTX and PBO, respectively. The significant inhibition of radiographic progression with UPA was maintained through Week 48 vs MTX (LE and AO) in EARLY and vs PBO (LE) in COMPARE. Following the switch of all PBO patients to UPA in COMPARE by Week 26, no further change in mean mTSS was observed through Week 48. The inhibition of radiographic progression vs comparators was not only observed for the overall mTSS scores but also its components - the JSN and ES in both RCTs (LE and AO). Conclusion UPA both as monotherapy, and in combination with background MTX, was effective in inhibiting the progression of structural joint damage through Week 48 in MTX-naïve, and MTX-IR patients, respectively. Disclosures C. Peterfy: Consultancies; AbbVie, Acerta, Amgen, AstraZeneca, Bristol-Myers Squibb, Centrexion, Daiichi Sankyu, Five Prime Therapeutics, Genentech, Hoffmann-La Roche, Janssen, Lilly USA, MedImmune, Merck, Novartis, Plexxikon, Pfizer, Sanofi, Salix-Santarus, Samsung. M.C. Genovese: Consultancies; Consultant for and has received grants from AbbVie Inc, Lilly, Pfizer, Galapagos, and Gilead. I. Song: Corporate appointments; Employee of AbbVie. A. Friedman: Corporate appointments; Employee of AbbVie. S. Hall: Consultancies; Received research grants and consultancy fees from AbbVie Inc, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis. E. Mysler: Grants/research support; Received research grants and speaker’s bureau fees from Bristol-Myers Squibb, Roche, Eli Lilly, AbbVie, Novartis, Janssen, and Pfizer. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Samsung, Pfizer, UCB, Mundipharma, Hospira, and Eli Lilly. X. Baraliakos: Grants/research support; AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer Inc, Roche and UCB. J. Enejosa: Corporate appointments; Employee of AbbVie. T. Shaw: Corporate appointments; Employee of AbbVie. Y. Li: Corporate appointments; Employee of AbbVie. S. Chen: Corporate appointments; Employee of AbbVie. V. Strand: Consultancies; Consultant for AbbVie, Amgen, AstraZeneca, BMS, Celltrion, Celgene, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sanofi, and UCB.

Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis

ObjectivesTo evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)–naïve or had an inadequate...

Role of reproductive and menopausal factors in functional and structural progression of rheumatoid arthritis: results from the SCQM cohort.

To study the relationship between female reproductive and menopausal factors on functional and structural joint damage progression in women with RA. This is an observational cohort study of RA patients enrolled in the Swiss Clinical Quality Management Program for Rheumatoid Arthritis. Information about female hormonal factors, such as pregnancies, menopause and hormonal therapy, were retrospectively retrieved using a specific questionnaire. The primary outcome was functional disability progression (HAQ) and the secondary outcome radiographic joint damage progression. We compared the functional progression between pre- and post-menopausal women using a multilevel regression model for longitudinal data, adjusting for potential confounders, such as baseline age, years of education, disease duration, seropositivity, DAS28 and treatment. A total of 1667 women were analysed, of whom 1025 (61%) were post-menopausal. Participants had a median of 6 HAQ assessments (interquartile range 3-10) during 5.1 (interquartile range 2.2-9.8) years of follow-up. At baseline, post-menopausal women had higher HAQ and erosion scores than pre-menopausal women. The evolution of HAQ scores over time differed between pre- and post-menopausal women (P < 0.001), with a less favourable evolution in post-menopausal women, particularly with earlier age at menopause. Erosion progression did not differ between pre- and post-menopausal women. In women with RA, functional disability progression differed between pre- and post-menopausal women. The more favourable evolution of function in pre-menopausal women was not explained by disease duration, age or radiographic damage.

Effects of baricitinib on radiographic progression of structural joint damage at 1 year in patients with rheumatoid arthritis and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs

BackgroundBaricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD).ObjectivesTo evaluate...

Radiographic Progression of Structural Joint Damage in Patients with Active Psoriatic Arthritis Treated with Ixekizumab over 52 Weeks

Abstract not available. Disclosures: Study sponsored by Eli Lilly and Company. Copyright 2018 SKIN

AC-CUTE: An Open-Label Study to Evaluate Progression of Structural Joint Damage and Inflammation in Subjects with Moderate to Severe Rheumatoid Arthritis.

Aim Examine the efficacy of once-weekly subcutaneous tocilizumab (SC-TCZ) on joint damage at 24 weeks based on radiography of the hands and feet and magnetic resonance imaging (MRI) of the hand in subjects with moderate to severe rheumatoid arthritis (RA). Methods In this Australian open-label, multicentre, prospective, single-arm study, subjects received 162 mg SC-TCZ weekly. Primary endpoint was change in radiographic Genant-modified Total Sharp Score (TSS) between baseline and Week 24. Secondary endpoints included change from baseline to Week 24 in RA MRI scoring (RAMRIS) of erosions, synovitis, and osteitis and Cartilage Loss Score (CARLOS) in the dominant hand and disease activity score 28 (DAS28). Results 52 subjects were enrolled (80% female, mean (SD) age 57 (12) years). Radiography showed mild but not significant progression of joint damage (mean (SD) change in TSS 0.46 (1.29)). Synovitis reduced significantly on MRI; however, osteitis, erosion, and cartilage loss did not change significantly. DAS28 improved significantly by Week 24; 78% of subjects achieved DAS28 remission. SC-TCZ was generally well tolerated. Conclusion Synovitis and DAS28 decreased significantly; however, no significant change in osteitis or joint damage was observed at Week 24. Trial registration This trial is registered with Clinicaltrials.gov registration number NCT01951170 (ML28703).

Radiographic Progression of Structural Joint Damage in Patients with Active Psoriatic Arthritis Treated with Ixekizumab over 52 Weeks

Abstract Not Available

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study

BackgroundBaricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.MethodsIn this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate...

Have radiographic progression rates in early rheumatoid arthritis changed? A systematic review and meta-analysis of long-term cohorts.

To evaluate, firstly, all published data on baseline and annual progression rates of radiographic damage from all longitudinal observational cohorts, and secondly, the association of standard clinical and laboratory parameters with long-term radiographic joint damage. A comprehensive search of the literature from 1975 to 2014, using PubMed, SCOPUS and Cochrane databases, identified a total of 28 studies that investigated long-term radiographic progression, and 41 studies investigating predictors of long-term radiographic progression. This was submitted and approved by PROSPERO in February 2014 (Registration Number: CRD42014007589). Meta-analysis indicated an overall baseline rate of 2.02%, and a yearly increase of 1.08% of maximum damage. Stratified analysis found that baseline radiographic scores did not differ significantly between cohorts recruiting patients pre- and post-1990 (2.01% vs 2.03%; P > 0.01); however, the annual rate of progression was significantly reduced in the post-1990 cohorts (0.68% vs 1.50%; P < 0.05). High levels of acute phase markers, baseline radiographic damage, anti-CCP and RF positivity remain consistently predictive of long-term radiographic joint damage. Critical changes in treatment practices over the last three decades are likely to explain the reduction in the long-term progression of structural joint damage. Acute phase markers and presence of RF/anti-CCP are strongly associated with increased radiographic progression.

Tofacitinib versus Methotrexate in Rheumatoid Arthritis

BackgroundMethotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate.MethodsWe randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician).ResultsMean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels.ConclusionsIn patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.)

AB1000 Assessing the Impact of Subcutaneous Abatacept in Inhibiting Structural Damage in Rheumatoid Arthritis by Low Field Magnetic Resonance Imaging and X-Ray

BackgroundRheumatoid arthritis (RA) treatment has shifted from reducing symptoms to earlier inhibition of disease progression, thus preventing irreversible structural damage and disability. Detection of synovitis (SYN), osteitis (OST), and erosions...

Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis: Meeting Rheumatologists’ Requirements in Routine Clinical Practice

Certolizumab pegol, a pegylated Fab' anti-tumour necrosis factor (TNF)-α agent, has shown efficacy in patients with rheumatoid arthritis (RA) unresponsive to previous treatment. In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease-modifying antirheumatic drug (DMARD), the efficacy of certolizumab pegol, as monotherapy or with methotrexate, was similar to that reported in other anti-TNF clinical studies, with 60% or fewer of patients achieving American College of Rheumatology 20% improvement in RA. Rapid clinical response was also seen, with significant differences evident at week 1, and efficacy maintained at study end and in open-label extensions. Adding certolizumab pegol to non-biological DMARDs is efficacious in other RA populations. In the CERTAIN study, certolizumab increased remission rates, prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA. In the REALISTIC study, rapid and consistent clinical responses were observed in a diverse group of anti-TNF-eligible RA patients representing those seen in clinical practice. In the RAPID studies, rapid and sustained reduction in RA signs and symptoms, inhibition of structural joint damage progression, and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate. Certolizumab pegol was generally well-tolerated in clinical trials, although long-term observational data are not yet available. Current data suggest that certolizumab pegol suits a 'treat to target' approach, providing rapid and sustained improvements in RA signs and symptoms, and beneficial effects on workplace and home productivity in patients with RA.

The effects of tocilizumab on osteitis, synovitis and erosion progression in rheumatoid arthritis: results from the ACT-RAY MRI substudy

ObjectiveTo examine the imaging-detected mechanism of reduction of structural joint damage progression by tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) using MRI.MethodsIn a substudy of a randomised, double-blind, phase...

THU0199 Week 12 Clinical Response to Certolizumab Pegol Predicts Long-Term Outcomes Regardless of Concomitant Medications and Baseline Disease Characteristics in Japanese Patients with Active Rheumatoid Arthritis

BackgroundEarly response to certolizumab pegol (CZP), a PEGylated Fc-free anti-TNF, has been shown to predict long-term probability of low disease activity and inhibition of progression of structural joint damage in...