Erosions on T1-Weighted Magnetic Resonance Imaging Versus Radiography of Sacroiliac Joints in Recent-Onset Axial Spondyloarthritis: 2-Year Data (EMBARK Trial and DESIR Cohort).

OBJECTIVE: (1) To compare the capacity to detect sacroiliac joint (SIJ) erosions and baseline-to-week 104 change in erosions between magnetic resonance imaging (MRI) and radiographs in recent-onset axial spondyloarthritis (axSpA); and (2) to compare treatment-discriminatory capacities of MRI and radiographic scores for erosion detection in patients receiving etanercept in the Effect of Etanercept on Symptoms and Objective Inflammation in Nonradiographic axSpA (EMBARK) trial vs controls in the DESIR (Devenir des Spondylarthropathies Indifférenciées Récentes) cohort. METHODS: Anonymized SIJ MRI and radiographs were assessed at patient and joint surface levels. Three readers evaluated MRI; 3 different readers evaluated radiographs. Final scores for comparison of radiographs and MRI for detection of erosions were assigned based on agreement of ≥ 2 of 3 readers' assessments. RESULTS: At baseline, discordance in erosion detection between imaging methods was more frequent for MRI erosions in the absence of radiographic erosions (48/224 [21.4%] patients) than for radiographic erosions in the absence of MRI erosions (14/224 [6.3%] patients; P < 0.001). After 104 weeks, a decrease in erosions was observed on MRI but not radiographs in 49/221 (22.2%) patients, and on radiographs but not MRI in 6/221 (2.7%) patients (P < 0.001). In the treatment-discriminant capacity analysis, the largest standardized differences between etanercept and control cohorts at week 104 were changes in Spondyloarthritis Research Consortium of Canada MRI erosion discrete score, changes in erosion average score, and meeting the modified New York criteria on radiographs, with unadjusted/adjusted Hedges G effect sizes of 0.40/0.50, 0.40/0.56, and 0.40/0.43, respectively. CONCLUSION: In recent-onset axSpA, SIJ erosions and erosion change were observed more frequently on MRI than radiography. The significance of interval improvement of MRI erosions warrants further research. [ClinicalTrials.gov: NCT01258738, NCT01648907].

Structural changes in the sacroiliac joint on MRI and relationship to ASDAS inactive disease in axial spondyloarthritis: a 2-year study comparing treatment with etanercept in EMBARK to a contemporary control cohort in DESIR.

BACKGROUND: Limited information is available on the impact of treatment with a tumor necrosis factor inhibitor (TNFi) on structural lesions in patients with recent-onset axial spondyloarthritis (axSpA). We compared 2-year structural lesion changes on magnetic resonance imaging (MRI) in the sacroiliac joints (SIJ) of patients with recent-onset axSpA receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). We also evaluated the relationship between the Ankylosing Spondylitis Disease Activity Score (ASDAS) and change in MRI structural parameters. METHODS: The difference between etanercept (EMBARK) and control (DESIR) in the net percentage of patients with structural lesion change was determined using the SpondyloArthritis Research Consortium of Canada SIJ Structural Score, with and without adjustment for baseline covariates. The relationship between sustained ASDAS inactive disease, defined as the presence of ASDAS < 1.3 for at least 2 consecutive time points 6 months apart, and structural lesion change was evaluated. RESULTS: This study included 163 patients from the EMBARK trial and 76 from DESIR. The net percentage of patients with erosion decrease was significantly greater for etanercept vs control: unadjusted: 23.9% vs 5.3%; P = 0.01, adjusted: 23.1% vs 2.9%; P = 0.01. For the patients attaining sustained ASDAS inactive disease on etanercept, erosion decrease was evident in significantly more than erosion increase: 34/104 (32.7%) vs 5/104 (4.8%); P < 0.001. A higher proportion had erosion decrease and backfill increase than patients in other ASDAS status categories. However, the trend across ASDAS categories was not significant and decrease in erosion was observed even in patients without a sustained ASDAS response. CONCLUSIONS: These data show that a greater proportion of patients achieved regression of erosion with versus without etanercept. However, the link between achieving sustained ASDAS inactive disease and structural lesion change on MRI could not be clearly established. TRIAL REGISTRATION: EMBARK: ClinicalTrials.gov identifier: NCT01258738 , Registered 13 December 2010; DESIR: ClinicalTrials.gov identifier: NCT01648907 , Registered 24 July 2012.

Radiographic and clinical effects of 10 mg and 25 mg twice-weekly etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis.

OBJECTIVES: To compare the radiographic and clinical effects of 25 versus 10 mg twice-weekly (BIW) etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis (RA). METHODS: This was a post-hoc analysis of a Phase 3 study where Japanese patients with active RA were randomized to receive BIW etanercept 25 mg (n = 182), etanercept 10 mg (n = 192), or methotrexate (n = 176) for 52 weeks (NCT00445770). This analysis included assessments of week-24 and week-52 disease activity, week-52 radiographic progression, and the relationship between baseline characteristics and week 52 clinical outcomes with clinically relevant radiographic progression (CRRP) at week 52. RESULTS: At week 52, there were no significant differences between 25 and 10 mg etanercept in terms of achieving low disease activity or remission. CRRP was observed in 36% and 32% of patients in the 10 and 25 mg groups, respectively. Predictor analysis suggested that worse background disease status, treatment with methotrexate rather than etanercept, and poorer clinical outcomes at week 52 were associated with CRRP. CONCLUSIONS: The 25 mg BIW etanercept dosage does not appear to be significantly more efficacious than 10 mg in Japanese patients with RA. Further studies evaluating the optimal etanercept dosing regimen in this patient population may be merited. NCT: NCT00445770.

Relationship between disease activity status or clinical response and patient-reported outcomes in patients with non-radiographic axial spondyloarthritis: 104-week results from the randomized controlled EMBARK study.

BACKGROUND: We assessed the external validity of composite indices Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Assessment in SpondyloArthritis international Society (ASAS) 40 response (ASAS40) by evaluating the correlations between the changes in some patient reported outcomes (PROs) for patients with non-radiographic axial spondyloarthritis (nr-axSpA) and the changes in the scores of the composite indices. METHODS: This was a post-hoc analysis of data from the EMBARK study in patients with nr-axSpA treated with etanercept. PROs were grouped according to ASDAS status (inactive [< 1.3], low [≥ 1.3 to < 2.1], high [≥ 2.1 to ≤3.5], and very high [> 3.5]), patient achievement of > 50% improvement in BASDAI (BASDAI50 responders), and > 40% improvement in ASAS (ASAS40 responders) at 104 weeks. Analyses were conducted on observed cases available at Week 104. Changes in PROs from Baseline to Week 104 were assessed using analysis of covariance with adjustment for baseline with linear contrast. RESULTS: Higher ASDAS disease activity at 104 weeks was associated with lower long-term improvement from baseline in PROs (e.g., total back pain [visual analog scale, cm (95% confidence interval): - 4.58 (- 4.95, - 4.21), - 3.86 (- 4.28, - 3.43), - 2.15 (- 2.68, - 1.61), and 1.30 (- 0.51, 3.12) for inactive, low, high, and very high ASDAS disease activity, respectively; Multidimensional Fatigue Inventory (MFI) general fatigue: - 4.77 (- 5.70, - 3.84), - 2.96 (- 4.04, - 1.87), - 1.00 (- 2.32, 0.31), and 2.14 (- 2.10, 6.38); all p < 0.001)]. BASDAI50 non-responders had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: - 1.61 (- 2.05, - 1.18) vs. -4.43 (- 4.69, - 4.18); MFI general fatigue: - 0.01 (- 1.12, 1.09) vs. -4.30 (- 4.98, - 3.62); all p < 0.001). ASAS40 non-responders also had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: - 1.91 (- 2.30, - 1.52) vs. -4.75 (- 5.05, - 4.46); MFI general fatigue: - 0.63 (- 1.56, 0.30) vs. -4.64 (- 5.37, - 3.91); all p < 0.001). CONCLUSION: Composite indices are valid for monitoring treatment response and adequately reflect treatment-related changes experienced by patients with nr-axSpA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01258738. Registered 9 December 2010.

An Analysis of Real-World Data on the Safety of Etanercept in Older Patients with Rheumatoid Arthritis.

OBJECTIVE: The aim of this study was to use real-world data to evaluate potential interactions between age, treatment, and the risk of developing four adverse events (AEs) common in the elderly: congestive heart failure, serious infections, non-melanoma skin cancer, and interstitial lung disease. These AEs were identified as important in a prior age-based analysis (≤ 65 vs > 65 years) of etanercept- or placebo-treated patients with rheumatoid arthritis (RA) in controlled clinical trials. METHODS: Real-world data (1 January 2013 to 31 January 2018) were obtained from the IBM Watson Health MarketScan® Database. Patients were included if aged ≥ 18 years, enrolled for ≥ 1 year prior to RA diagnosis, and without any of the four AEs of interest prior to RA diagnosis or between RA diagnosis and first etanercept exposure. Logistic regression analysis was applied following propensity matching of patients receiving or not receiving etanercept based on age at diagnosis, age status at the beginning of observation (> 65 years or not), sex, geographic region, and follow-up duration. RESULTS: The overall cohort comprised 403,689 patients. The absolute risk of each of the four AEs increased with age. In propensity-matched cohorts, etanercept was associated with significantly higher odds of developing each of the four AEs (p < 0.001 for all). However, the relative risk of experiencing the four AEs in patients who received etanercept versus those who did not was similar between patients ≤ 65 years of age and those > 65 years of age. CONCLUSIONS: In patients with RA, the relative increase in etanercept-associated risk of experiencing congestive heart failure, serious infection, non-melanoma skin cancer, or interstitial lung disease was similar between elderly and non-elderly.

Radiographic and clinical outcomes following etanercept monotherapy in Japanese methotrexate-naïve patients with active rheumatoid arthritis.

Objectives: Compare outcomes with methotrexate (MTX) or etanercept (ETN) monotherapy in Japanese patients with active rheumatoid arthritis (RA) who were MTX-naïve or with intolerance or inadequate response to prior MTX (MTX-IR).Methods: Post hoc analysis of a phase 3 study comparing MTX, ETN 10 mg twice weekly, and ETN 25 mg twice weekly in Japanese patients with RA. Disease activity was evaluated using American College of Rheumatology (ACR) scores and 28-joint Disease Activity Score (DAS28), radiographic progression evaluated using van der Heijde's modified Total Sharp Score (mTSS), and functional status evaluated using Health Assessment Questionnaire Disability Index (HAQ-DI).Results: Among MTX-naïve and MTX-IR patients, greater proportions of those randomized to either ETN group achieved ACR20, ACR50, ACR70, DAS28 ≤3.2 or <2.6, clinically relevant inhibition of mTSS changes, and reductions in HAQ-DI compared with MTX at the majority of time points. There were very few clinically meaningful differences between ETN groups for any of the variables evaluated.Conclusion: ETN monotherapy was more effective than MTX in both MTX-naïve and MTX-IR patients, with very few clinically meaningful differences between ETN 10 mg and ETN 25 mg when given twice weekly. The relative benefits of ETN were greater in MTX-naïve patients than MTX-IR patients.ClinicalTrials.gov identifierNCT00445770.

Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials.

BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC. METHODS: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events. RESULTS: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2-12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1-0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5). CONCLUSIONS: In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

A single-arm, open-label study to assess the immunogenicity, safety, and efficacy of etanercept manufactured using the serum-free, high-capacity manufacturing process administered to patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of etanercept (ETN) manufactured using the serum-free, high-capacity manufacturing (SFHCM) process in patients with rheumatoid arthritis (RA). METHODS: In this global, multicenter, open-label, single-arm study (NCT02378506), 187 adult patients with moderate to severe RA received ETN 50 mg once weekly for 24 weeks manufactured using the SFHCM process. Immunogenicity (presence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)) was assessed at 12 and 24 weeks. Safety and efficacy were evaluated at 4, 12, and 24 weeks. RESULTS: Eight (4.5%) patients tested positive for ADA, and there were no NAbs detected at any time throughout the study. Ninety (48.1%) patients reported treatment-emergent adverse events (AEs), of which 27 (14.4%) reported injection-site reactions, and 43 (23.0%) reported infections. The majority of AEs were mild or moderate in severity, and the drug was well tolerated. Throughout the duration of the study (week 4 to week 24), there was a progressive increase in the American College of Rheumatology (ACR)-defined responses (ACR20: 55.9%-82.0%, ACR50: 16.1%-57.8%, and ACR70: 3.2%-26.7%) from baseline and the proportion of patients achieving low disease activity and remission, with a corresponding decrease in measures of disease activity. CONCLUSION: The immunogenicity, safety, and efficacy of ETN manufactured using the SFHCM process were similar to the current approved ETN formulation. ClinicalTrials.gov registration: NCT02378506.

Maintenance of low disease activity and remission with etanercept-disease-modifying antirheumatic drug (DMARD) combination therapy compared with treatment with DMARDs alone in Latin American patients with active rheumatoid arthritis: Subset analysis of a randomized trial.

BACKGROUND: Current guidelines on the treatment of rheumatoid arthritis (RA) recommend early therapy targeting the achievement of low disease activity (LDA) or clinical remission. Little published information is available on the success of this treatment strategy in Latin America. In a subset analysis of patients from Latin America, we compared efficacy maintenance with etanercept 50 mg once weekly (ETN50) versus placebo (PBO), on a background of methotrexate (MTX) ±â€Šother non-biologic, disease-modifying antirheumatic drugs, in patients with moderate-to-severe RA who had achieved LDA with ETN50. METHODS: In the Treat-to-Target trial, adult patients with active RA nonresponsive to MTX were treated with ETN50 for 24 weeks (Period 1). Patients achieving LDA were randomized to receive ETN50 or PBO for 28 additional weeks (Period 2). The proportion of patients maintaining LDA at week 52 and other efficacy and quality-of-life measures were assessed. Descriptive statistics are presented using last observation carried forward imputation of data. RESULTS: Of the 64 patients from Latin America treated in Period 1, 61 (95.3%) achieved LDA. Among patients receiving ETN50, 13/34 remained in LDA and 6/14 maintained remission at week 52 versus 6/27 and 4/10 patients receiving PBO. The median time to flare was 113 days and 33 days for the ETN50 and PBO groups, respectively. In the overall population, adverse events were reported in 37% and 43%, serious adverse events in 1% and 4%, and serious infections in 0% and 2% of patients in the ETN50 and PBO groups, respectively. CONCLUSIONS: In patients with RA from Latin America, continuing treatment with ETN50 after achieving LDA appears to result in a higher proportion of patients maintaining LDA and remission compared with switching to PBO. CLINICALTRIALS. GOV REGISTRATION: NCT01578850.

The Prevalence of Non-radiographic Axial Spondyloarthritis Among Patients with Inflammatory Back Pain from Northwest and South Africa: Data from a Noninterventional, Cross-Sectional Study.

INTRODUCTION: Information is limited on the prevalence and clinical characteristics of nonradiographic axial spondyloarthritis (nr-axSpA) among patients with inflammatory back pain (IBP) in African countries. A global study estimated the prevalence of nr-axSpA among patients with IBP from 19 countries in Latin America, Europe, Asia, and Africa. This post hoc subset analysis focused on estimating prevalence of nr-axSpA and clinical characteristics among patients with IBP from Northwest Africa (Morocco and Algeria) and South Africa. METHODS: Patients from Northwest Africa and South Africa diagnosed with nr-axSpA according to protocol completed patient-reported outcome measures to assess disease activity and functional limitations, including Ankylosing Spondylitis Disease Activity Score (ASDAS). RESULTS: Of the 206 patients with IBP from Africa (n = 168, Northwest Africa and n = 38, South Africa), 33 (16.0%) were diagnosed with nr-axSpA (n = 26, Northwest Africa and n = 7, South Africa), corresponding to prevalence rates of 15.5% and 18.4%, respectively. Disease activity per region, measured as mean ASDAS, was 2.4 ± 1.4 and 2.4 ± 0.9, respectively, based on erythrocyte sedimentation rate and 2.4 ± 1.3 and 2.7 ± 0.7 based on C-reactive protein. CONCLUSIONS: Although the number of patients available for the analysis was low, it appears that the prevalence of nr-axSpA among patients with IBP is similar between Northwest and South Africa, and the disease burden is substantial. Limited access to magnetic resonance imaging may hinder early detection in these areas, thereby affecting the assessment of prevalence. FUNDING: Pfizer.

Maintenance of Remission with Etanercept-DMARD Combination Therapy Compared with DMARDs Alone in African and Middle Eastern Patients with Active Rheumatoid Arthritis.

INTRODUCTION: To compare etanercept (ETN) and placebo (PBO) for maintaining low disease activity (LDA) achieved with ETN in patients with rheumatoid arthritis (RA) from Africa and the Middle East. METHODS: In this subset analysis of the Treat-to-Target trial (ClinicalTrials.gov identifier NCT01981473), 53 adult patients with moderate-to-severe RA nonresponsive to methotrexate were treated with 50 mg ETN/week for 24 weeks (Period 1). Patients achieving LDA were randomized to continue ETN treatment or switched to PBO for an additional 28 weeks (Period 2). The proportion of patients maintaining LDA or remission in each arm at the end of Period 2 was determined. Additional efficacy and patient-reported outcomes (PROs) were also evaluated. RESULTS: During Period 1, 51 patients achieved LDA according to the disease activity score-28 joints-erythrocyte sedimentation rate (DAS28-ESR LDA) and 30 achieved remission. At week 52, nine of 22 and eight of 29 in the ETN and PBO groups, respectively, remained in DAS28-ESR LDA without experiencing a flare. Additionally, six of 14 and five of 16 in the ETN and PBO groups, respectively, remained in remission. Among patients experiencing a flare during Period 2, 13 of 22 and 21 of 29 received ETN or PBO, respectively. The median time to flare was 193 and 87 days in the ETN and PBO groups, respectively. At week 52, consistently more patients in the ETN group than in the PBO group achieved predetermined efficacy and PRO endpoints. CONCLUSIONS: These data suggest continuing ETN maintenance therapy is beneficial to patients after they have achieved their treatment target. However, this subset analysis is limited by the small patient population and must be interpreted with caution. FUNDING: Pfizer. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT0198147.

Tuberculosis and viral hepatitis infection in Eastern Europe, Asia, and Latin America: impact of tumor necrosis factor-α inhibitors in clinical practice.

Tumor necrosis factor-α (TNF-α) inhibitors are increasingly becoming the standard of care for treating a number of inflammatory diseases. However, treatment with TNF-α inhibitors carries an inherent risk of compromising the immune system, resulting in an increased susceptibility to infections and malignancies. This increased risk of infection is of particular concern in Asia, Eastern Europe, and Latin America where tuberculosis (TB) and viral hepatitis are endemic. In this brief review, we examine the literature and review the impact of TNF-α inhibitors on the incidence and the reactivation of latent disease with respect to TB, hepatitis C infection, and hepatitis B infection. Our findings show that TNF-α inhibitors are generally safe, if used with caution. Patients should be screened prior to the initiation of TNF-α inhibitor treatment and given prophylactic treatment if needed. In addition, patients should be monitored during treatment with TNF-α inhibitors and after treatment has stopped to ensure that infections, if detected, are treated promptly and effectively. Our analysis is consistent with other reports and guidelines.

Modification of structural lesions on MRI of the sacroiliac joints by etanercept in the EMBARK trial: a 12-week randomised placebo-controlled trial in patients with non-radiographic axial spondyloarthritis.

OBJECTIVE: To evaluate the impact on structural lesions observed on MRI in the sacroiliac joints (SIJ) at 12 weeks in patients with non-radiographic axial spondyloarthritis (nr-axSpA) receiving etanercept or placebo in EMBARK (Effect of Etanercept on Symptoms and Objective Inflammation in nr-axSpA, a 104 week study). METHODS: Patients were randomised to double-blind etanercept 50 mg/week or placebo for 12 weeks. Structural lesions at baseline and 12 weeks were scored by two independent readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural score (SSS) on T1-weighted MRI. Change in SPARCC SSS and correlation with improvement in clinical outcomes was evaluated. RESULTS: MRI scans from 185 patients (etanercept, n=88; placebo, n=97) were reviewed. At baseline, there were no significant differences in mean SPARCC SSS between etanercept and placebo. From baseline to 12 weeks, change in mean SPARCC SSS was significantly greater for etanercept than placebo for erosion (-0.57 vs -0.08, respectively, adjusted p value=0.017) and backfill (0.36 vs 0.06, adjusted p value=0.022). A treatment difference was also present for the subgroup of patients with SIJ inflammation on MRI (SPARCC bone marrow oedema ≥2): erosion: -0.81 versus -0.13 for etanercept versus placebo, respectively, p=0.007; backfill: 0.48 versus 0.08, respectively, p=0.032. Decrease in erosion and increase in backfill correlated with improvement in more clinical outcomes for etanercept than placebo. CONCLUSION: Treatment with etanercept was associated with significantly greater reduction in erosions and increase in backfill at 12 weeks compared with placebo, consistent with a very early reparative response to antitumour necrosis factor therapy. The impact on disease progression in spondyloarthritis should be studied further. TRIAL REGISTRATION NUMBER: NCT01258738; Post-results.

Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis.

OBJECTIVE: To compare 2 years of radiographic sacroiliac joint (SIJ) changes in patients with recent onset axial spondyloarthritis (axSpA) receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). METHODS: Endpoints were changes at week 104 per the modified New York (mNY) grading system in total SIJ score (primary endpoint) and net percentage of patients with progression defined three ways. Treatment effect was analysed with and without adjustment for baseline covariates. RESULTS: At 104 weeks, total SIJ score improved in the etanercept group (n=154, adjusted least-squares mean change: -0.14) and worsened in the control group (n=182, change: 0.08). The adjusted difference between groups (etanercept minus control) was -0.22 (95% CI -0.38 to -0.06), p=0.008. The net percentage of patients with progression was significantly lower in the etanercept versus the control group for two of three binary endpoints: -1.9% versus 1.6% (adjusted difference for etanercept minus control: -4.7%,95% CI -9.9 to 0.5, p=0.07) for change in mNY criteria; -1.9% versus 7.8% (adjusted difference: -18.2%,95% CI -30.9 to -5.6, p=0.005) for change ≥1 grade in ≥1 SIJ; and -0.6% versus 6.7% (adjusted difference: -16.4%,95% CI -27.9 to -5.0, p=0.005) for change ≥1 grade in ≥1 SIJ, with shift from 0 to 1 or 1 to 0 considered no change. CONCLUSION: Despite the slow radiographic SIJ progression rate over 2 years in axSpA, this study suggests a lower rate of progression in the SIJ with etanercept than without anti-tumour necrosis factor therapy. TRIAL REGISTRATION NUMBERS: NCT01258738, NCT01648907; Post-results.

Incidence of Antidrug Antibodies in Rheumatoid Arthritis Patients From Argentina Treated With Adalimumab, Etanercept, or Infliximab in a Real-World Setting.

BACKGROUND: Biologic agents may induce immune responses that could impact drug action. OBJECTIVES: The aims of this study were to assess antidrug antibodies (ADAs) in patients with rheumatoid arthritis (RA) from Argentina treated with etanercept, adalimumab, or infliximab at a single visit and correlate it with efficacy outcomes. METHODS: In this subset analysis of a noninterventional, multinational, cross-sectional study (NCT01981473), adult patients with RA treated continuously for 6 to 24 months with etanercept, adalimumab, or infliximab were evaluated for ADAs and trough drug concentrations of 2 days or less prior to the next scheduled dose. Efficacy measurements included Disease Activity Score based on a 28-joint count-erythrocyte sedimentation rate, low disease activity, and Health Assessment Questionnaire-Disability Index. Targeted medical history of injection site/infusion reactions, serum sickness, and thromboembolic events were reported. RESULTS: Baseline demographics, disease characteristics, and duration of treatment of the 119 patients (etanercept: n = 54, adalimumab: n = 52, infliximab: n = 13) were similar across all groups. No etanercept-treated patient tested positive for ADAs compared with 19 (36.5%) of 52 patients and 4 (30.8%) of 13 patients treated with adalimumab and infliximab, respectively. In adalimumab- and infliximab-treated patients, ADA presence correlated negatively with trough drug levels. A greater proportion of ADA-negative patients achieved Health Assessment Questionnaire-Disability Index of 0.5 or less and had better composite efficacy measures compared with ADA-positive patients. The rate of targeted medical events reported was low. CONCLUSIONS: In this subset analysis, RA patients from Argentina treated with adalimumab or infliximab, but not etanercept, tested positive for ADAs. Antidrug antibody-negative patients showed a tendency toward better clinical outcomes compared with ADA-positive patients.

Correction: The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study.

[This corrects the article DOI: 10.1371/journal.pone.0175207.].

Effects of Long-Term Etanercept Treatment on Clinical Outcomes and Objective Signs of Inflammation in Early Nonradiographic Axial Spondyloarthritis: 104-Week Results From a Randomized, Placebo-Controlled Study.

OBJECTIVE: To evaluate the long-term clinical and imaging efficacy of etanercept in patients with early, active nonradiographic axial spondyloarthritis (SpA). METHODS: Adult patients who satisfied the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA (but not the modified New York radiographic criteria), with symptom duration >3 months to <5 years, and who were unresponsive to ≥2 nonsteroidal antirheumatic drugs (NSAIDs) received double-blind etanercept 50 mg/week or placebo for 12 weeks, followed by open-label etanercept 50 mg/week to week 104. Clinical, magnetic resonance imaging (MRI; Spondyloarthritis Research Consortium of Canada [SPARCC] scores), and safety outcomes at 104 weeks were analyzed. RESULTS: Of 215 randomized patients (etanercept: n = 106; placebo: n = 109), 205 entered the study (etanercept/etanercept: n = 100; placebo/etanercept: n = 105) and 169 completed the open-label period (etanercept/etanercept: n = 83; placebo/etanercept: n = 86). At week 104, 61 of 81 (75%), 49 of 81 (61%), 48 of 80 (60%), and 57 of 81 (70%) patients who received etanercept throughout the trial achieved ASAS20, ASAS40, Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease, and Bath Ankylosing Spondylitis Disease Activity Index criteria for 50% improvement (BASDAI 50) scores, respectively (observed). From baseline to week 104, continued improvements in clinical outcomes (ASDAS-C-reactive protein: -1.5 and -1.7; BASDAI: -3.3 and -3.8 [last observation carried forward]), and SPARCC MRI scores (sacroiliac joint: -6.0 and -3.4; spinal: -2.1 and -0.8 [observed]) were seen in patients receiving etanercept/etanercept and placebo/etanercept. During the study, 8% in the etanercept/etanercept group and 7% in the placebo/etanercept group had serious adverse events; no new safety signals were seen. CONCLUSION: Patients with early, active nonradiographic axial SpA and an inadequate response to at least 2 NSAIDs demonstrated improvement in clinical and imaging outcomes that were sustained through 104 weeks of etanercept treatment.

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study.

OBJECTIVE: To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. METHODS: This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. RESULTS: Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. CONCLUSION: ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. TRIAL REGISTRATION: This study was registered on www.ClinicalTrials.gov (NCT01981473).