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].

Does psoriatic axial spondyloarthritis phenotype correlate with imaging morphotype?

OBJECTIVES: To compare the magnetic resonance imaging (MRI) morphology of inflammatory and chronic lesions in the sacroiliac joints (SIJs) and spine between patients with non-psoriatic and psoriatic non-radiographic axial spondyloarthritis (axSpA and p-axSpA, respectively). METHODS: Patients from the EMBARK trial (NCT01258738) with axSpA (n=179) and p-axSpA (n=24) who had MRI data available were compared in terms of baseline demographics, clinical characteristics, and the frequency (n/N [%]) and distribution of inflammatory and structural SIJ and spinal lesions. RESULTS: Patients with p-axSpA were on average older (35.1 years vs. 31.7 years, p=0.047), had a higher occurrence of asymmetric sacroiliitis (54.2% vs. 29.6%, p=0.042), and a lower occurrence of human leukocyte antigen (HLA)-B27 positivity (41.7% vs. 73.7%, p=0.010) than patients with axSpA. There were no significant differences in the frequency of lesions in any of the SIJ or spinal quadrants between the two subgroups. CONCLUSIONS: These data suggest that differences between axSpA and p-axSpA extend beyond presence of psoriasis, and include age, SI symmetry, and HLAB27 status. These findings may help explain the morphotype-phenotype relationship across axSpA, similar to those described in older radiographic studies.

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.

Evaluation of whether extremely high enthesitis or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores suggest fibromyalgia and confound the anti-TNF response in early non-radiographic axial spondyloarthritis.

OBJECTIVES: Differentiating between pain from spondyloarthritis (SpA) and pain from fibromyalgia is challenging. We evaluated patients with non-radiographic axial SpA (nr-axSpA) to determine the percentage of patients with extremely high enthesitis and/or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, the relationship between extreme scores and depression, and the effect of extreme scores on treatment outcomes with etanercept. METHODS: Patients with nr-axSpA received double-blind etanercept 50 mg or placebo weekly and were divided into those who did vs did not have extreme scores at baseline. Extreme scores were defined as the highest quintile for enthesitis score (≥6), and/or scores ≥8 on three of five BASDAI items (excluding morning stiffness duration). Depression was assessed with the Hospital Anxiety and Depression Scale, depression subscale (HADS-D) and medication use. Week 12 outcomes included Assessment of SpondyloArthritis (ASAS) 40 and ASAS partial remission. RESULTS: At baseline, 35/213 (16.4%) patients met extreme enthesitis criteria, 31 (14.6%) met extreme BASDAI criteria, 12 (5.6%) met both, and 135 (63.4%) met neither. More patients with extreme scores than without met the HADS-D definition of depression: 35/68 (51.5%) vs. 27/118 (22.9%), p<0.0001. For patients with vs. without extreme scores who received etanercept, no significant difference existed in week 12 ASAS 40: 13/41 (31.7%) vs. 21/60 (35.0%), respectively, or ASAS partial remission: 8/41 (19.5%) vs. 19/60 (31.7%). CONCLUSIONS: Extreme enthesitis and/or BASDAI scores were associated with measurements of depression, but did not affect week 12 ASAS 40 or ASAS partial remission.

Limited association between scalp psoriasis and psoriatic arthritis severity and treatment response.

OBJECTIVES: We evaluated whether scalp psoriasis (PsO) is associated with psoriatic arthritis (PsA) severity and/or with treatment response to etanercept. METHODS: Patients with moderate-to-severe PsO and active PsA received etanercept 50 mg once weekly for 24 weeks. Patients were stratified according to whether scalp PsO was present at baseline. Demographics and disease characteristics were compared at baseline and after 12 and 24 weeks of treatment with etanercept. RESULTS: Scalp PsO was present in 273/373 (73.2%) patients; they were significantly younger and a higher proportion were male versus those without scalp PsO. At baseline, the patient global assessment psoriasis score was significantly higher for patients with scalp PsO versus without (67.0 vs. 57.9, p<0.01); tender joint count was significantly higher for patients without scalp PsO (6.0 vs. 5.0, p<0.05). A higher proportion of patients without versus with scalp PsO achieved enthesitis ≤1 at Week 12 (91.5% vs. 81.7%, p<0.05) and dactylitis ≤1 at week 24 (93.9% vs. 85.6%, p<0.05). Patients with scalp PsO showed significantly greater improvements in fatigue and joint pain at weeks 12 and 24, and a greater proportion achieved a score ≤0.5 in the health assessment questionnaire at week 12 (65.2% vs. 53.0%, p<0.05). CONCLUSIONS: Scalp PsO was not clearly associated with PsA severity, and it did not affect treatment response. Patients without scalp PsO exhibited greater improvements in objective joint outcomes, whereas patients with scalp PsO experienced better outcomes in patient-reported outcomes.

Assessment of clinical efficacy and safety in a randomized double-blind study of etanercept and sulfasalazine in patients with ankylosing spondylitis from Eastern/Central Europe, Latin America, and Asia.

Despite the demonstrated efficacy of etanercept for the treatment of ankylosing spondylitis (AS), sulfasalazine is often prescribed, especially in countries with limited access to biologic agents. The objective of this subset analysis of the ASCEND trial was to compare the efficacy of etanercept and sulfasalazine in treating patients with AS from Asia, Eastern/Central Europe, and Latin America. A total of 287 patients, 190 receiving etanercept 50 mg once weekly and 97 receiving sulfasalazine 3 g daily, from eight countries were included in this subset analysis. Differences in disease activity and patient-reported outcomes assessing health-related quality-of-life (HRQoL) parameters in response to treatment were analyzed using the Cochran-Mantel-Haenszel test for categorical efficacy endpoints and analysis of covariance model for continuous variables. At week 16, a significantly greater proportion of patients receiving etanercept achieved ASAS20 (79.0 %) compared with patients receiving sulfasalazine (61.9 %; p = 0.002). At week 16, treatment with etanercept also resulted in significantly better responses than sulfasalazine for ASAS40 (64.7 vs. 35.1 %; p < 0.001), ASAS5/6 (48.1 vs. 26.3 %; p < 0.001), proportion of patients achieving 50 % response in Bath AS Disease Activity Index (65.8 vs. 42.3 %; p < 0.001), partial remission (35.3 vs. 17.5 %; p = 0.002), and all HRQoL parameters. Both treatments were well tolerated. Etanercept was significantly more effective than sulfasalazine in the treatment of patients with AS from Asia, Central/Eastern Europe, and Latin America.

How much does Disease Activity Score in 28 joints ESR and CRP calculations underestimate disease activity compared with the Simplified Disease Activity Index?

OBJECTIVES: Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) is used instead of erythrocyte sedimentation rate (DAS28-ESR) to assess rheumatoid arthritis disease activity; however, values for remission and low disease activity (LDA) for DAS28-CRP have not been validated. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guidelines suggest remission should be calculated by Simplified Disease Activity Index (SDAI) rather than DAS28-ESR. We examined values of remission and LDA of DAS28-CRP that correspond to the respective cut-off points for DAS28-ESR and SDAI from five clinical trials. METHODS: DAS28-CRP cut-offs that best correspond to DAS28-ESR remission <2.6 and LDA ≤3.2 were obtained by cumulative distribution plots, receiver operating curves and maximum concordance and averaged for each approach, treatment group and study. Level of agreement between DAS28-CRP and DAS28-ESR remission and LDA cut-offs was compared against each other and versus SDAI remission ≤3.3 and LDA ≤11. RESULTS: Percentage of patients who achieved remission and LDA by DAS28-ESR cut-offs was greater for DAS28-CRP versus DAS28-ESR regardless of patient population or treatment group. Discordance between CRP and ESR cut-offs ranged from 4%-26% and 8%-23% for remission and LDA, respectively, and 19%-40% and 6%-11% for DAS28-CRP versus SDAI, respectively. Estimated (range) remission and LDA thresholds were 2.4 (2.2-2.6) and 2.9 (2.6-3.3), 1.9 (1.6-2.2) and 3.1 (3.1-3.3) and 2.2 (1.1-2.9) and 3.6 (3.4-4.0) for DAS28-CRP versus DAS28-ESR, DAS28-CRP versus SDAI and DAS28-ESR versus SDAI, respectively. CONCLUSIONS: DAS28-CRP underestimates disease activity when using cut-off points validated for DAS28-ESR; therefore, DAS28-ESR cut-off values should not be applied to DAS28-CRP. Although DAS28-CRP and DAS28-ESR cut-offs for LDA ≤3.2 correspond to SDAI LDA, neither corresponds well to SDAI remission.

Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.

BACKGROUND: Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. METHODS: In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3.2 and ≤5.1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15-25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. FINDINGS: 604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5-49.1%; p<0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0-44.8%; p<0.0001). INTERPRETATION: Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. FUNDING: Pfizer.

Short-term efficacy of etanercept plus methotrexate vs combinations of disease-modifying anti-rheumatic drugs with methotrexate in established rheumatoid arthritis.

OBJECTIVES: The aims of this study were to investigate the short-term benefit of etanercept (ETN) + MTX vs conventional synthetic DMARDs (csDMARDs; HCQ, LEF or SSZ) + MTX in subjects with established RA. The effect of disease duration (≤2 years vs >2 years) and severity (moderate vs severe) on treatment outcomes was also assessed. Methods. Data from Asian and Latin American subjects with inadequate response to MTX were pooled from the APPEAL (ETN 25 mg biweekly + MTX or csDMARD + MTX; NCT00422227) and Latin RA (ETN 50 mg/week + MTX or csDMARD + MTX; NCT00848354) studies. Endpoints included the 28-joint DAS with ESR (DAS28-ESR) low disease activity (LDA; ≤3.2), DAS28 remission (<2.6) and HAQ score ≤0.5. RESULTS: Four hundred seventy-eight subjects received ETN + MTX, 245 subjects received csDMARD + MTX [HCQ + MTX (n = 81), LEF + MTX (n = 69), SSZ + MTX (n = 95)]. At week 16, significantly more subjects receiving ETN + MTX vs subjects on csDMARDs + MTX achieved DAS28-ESR LDA (39% vs 18%, P < 0.001), remission (18% vs 7%, P < 0.001) and HAQ ≤0.5 (48% vs 34%, P < 0.001). For both treatment arms, these endpoints were achieved by a greater proportion of subjects with ≤2 years vs >2 years disease duration and with moderate vs severe disease activity. CONCLUSION: Overall, ETN + MTX was more effective in treating subjects with established RA than csDMARDs + MTX at 16 weeks. More subjects with shorter disease duration and moderate disease activity achieved optimal response regardless of treatment regimen. TRIAL REGISTRATION: clinicaltrials.gov, NCT00422227 and NCT00848354.

Long-term Etanercept Response for Patients with Radiographic Axial Spondyloarthritis Based on Achievement of Early, Intermediate, or Late Responses During Index Studies.

INTRODUCTION: Short-term placebo (PBO)- or active-controlled clinical studies have demonstrated that etanercept (ETN) is effective and well tolerated in patients with radiographic axial spondyloarthritis (r-axSpA) with long-term efficacy and safety continuing for up to 7 years after treatment start. Short-term randomized controlled trials (RCTs) have shown the efficacy of ETN after 12-24 weeks, with statistically significant improvements as early as week 2. This post hoc analysis investigated the timeframe (i.e., temporal responses) in which patients with r-axSpA achieved their first clinical response with ETN and how patients responded over a longer period according to different temporal responses in index studies. METHODS: Data were analyzed from three phase 3/4 PBO- or sulfasalazine-controlled RCTs of ETN for the treatment of r-axSpA (index studies). Long-term open-label extension (OLE) studies assessed how patients responded over a longer period according to different temporal responses ("Early," "Intermediate," "Late," or "Non-response") in their corresponding index studies. RESULTS: Within each index study, patient responses differed significantly between ETN and control arms for achievement of Assessment in SpondyloArthritis international Society (ASAS) 20 and other measures of treatment response. In general, the proportion of responders in the OLE studies was high for those with "Early" and "Intermediate" responses as defined in the index studies. Despite patients being considered non-responders in the index studies, a large proportion achieved response on continued treatment in the OLE studies over the longer term, including through 48 weeks. CONCLUSIONS: Response in the index studies was maintained in the long term, and continued treatment was warranted in a large proportion of patients despite initial non-response. Absence of an early response in index studies did not predict non-response over the long term, and early response to treatment was not always a predictor for later response. TRIAL REGISTRATION: NCT00421915; NCT00247962; NCT00356356; NCT00421980; NCT00410046.

Female patients with ankylosing spondylitis: analysis of the impact of gender across treatment studies.

OBJECTIVES: To examine the impact (if any) of gender on the clinical, functional and patient-reported outcomes of treatment using data pooled from four controlled clinical trials. METHODS: Study data were pooled from four clinical control trials in which 1283 adult patients with active ankylosing spondylitis (AS) were treated with etanercept, sulfasalazine or placebo. Patients were stratified by gender and analysed for differences/similarities in baseline demographics, disease characteristics, and efficacy in AS outcome measures and safety and discontinuation rates after 12 weeks of therapy. RESULTS: Significant baseline differences were observed between 326 female patients compared with 957 male patients. Female patients had an older mean age of disease onset (35.0 vs 31.2 years; p<0.001), shorter mean time of disease duration (7.4 vs 9.5 years; p<0.001) and lower mean baseline C-reactive protein (13.1 vs 20.9 mg/l; p<0.001); a lower proportion was HLA-B27 positive (76.3% vs 85.2%; p<0.001) compared with male patients. Women had significantly (p<0.001) smaller differences in all week 12 efficacy assessments including AS disease activity score (0.87 vs -1.08), Bath AS disease activity index (-19.22 vs -23.41) and Bath AS functional index (-13.89 vs -16.88) relative to men. A similar relationship was observed between women and men in the adjusted mean difference of nocturnal back pain (4.04, 95% CI 0.77 to 7.32; p<0.05), total back pain (3.80, 95% CI 0.77 to 7.32; p<0.05) and patient global assessment (4.79, 95% CI 1.51 to 8.08; p<0.01). CONCLUSIONS: Women had a higher burden of disease and less improvement in AS outcome measures compared with men. This was observed despite women having a later disease onset of shorter duration; the mechanism behind this observation is unclear. Additional research is necessary to better understand female patients with AS and the burden of disease in this population.

Comparison of disease activity index for psoriatic arthritis (DAPSA) and minimal disease activity (MDA) targets for patients with psoriatic arthritis: A post hoc analysis of data from phase 3 tofacitinib studies.

OBJECTIVE: To compare achievement of Disease Activity Index in Psoriatic Arthritis (DAPSA) remission (REM)/low disease activity (LDA) with very low disease activity (VLDA)/minimal disease activity (MDA) targets in tofacitinib-treated patients with psoriatic arthritis (PsA). METHODS: In this post hoc analysis, data were pooled from two phase 3 studies (6 months' [NCT01882439] and 12 months' [NCT01877668] duration) of patients with PsA receiving tofacitinib 5 or 10 mg twice daily. Cut-offs for DAPSA targets: ≤4 for clinical REM and >4-≤14 for LDA. VLDA and MDA were defined as meeting 7 or ≥5, respectively, of 7 criteria. An ordered logistic regression model was performed to evaluate associations between baseline characteristics and achievement of DAPSA targets as well as VLDA/MDA at month 3. Agreement between achieving DAPSA and VLDA/MDA targets at months 1-6 was assessed via kappa tests. Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 Health Survey (SF-36) Physical Component Summary (PCS) scores (month 6), modified Total Sharp Score (mTSS) and proportion of radiographic non-progressors (mTSS ≤0.5) at month 12 (NCT01877668 only) were compared across DAPSA and VLDA/MDA targets. RESULTS: Increased disease activity at baseline was associated with reduced likelihood of achieving DAPSA-REM/DAPSA-LDA or VLDA/MDA at month 3. There was moderate agreement (kappa values 0.41-0.60) between DAPSA-REM and VLDA, and DAPSA-LDA and MDA, from months 1 to 6, although over half of patients achieving DAPSA-REM and over two thirds of patients achieving DAPSA-LDA, respectively, were not captured by VLDA and MDA. Achieving DAPSA-REM/DAPSA-LDA or VLDA/MDA was associated with improved HAQ-DI and SF-36 PCS scores at month 6, and slightly reduced radiographic progression at month 12. CONCLUSION: This analysis of data from tofacitinib-treated patients with PsA demonstrated moderate agreement between the DAPSA and VLDA/MDA composite instruments. In agreement with previous studies, VLDA and MDA may be more difficult to achieve than DAPSA-REM and DAPSA-LDA, respectively. However, the clinical and prognostic relevance of this finding should be determined. These data support DAPSA and VLDA/MDA as useful tools for evaluating disease activity and treatment response in PsA. CLINICALTRIALS: GOV: NCT01882439; NCT01877668.

Sensitivity and discriminatory ability of the Ankylosing Spondylitis Disease Activity Score in patients treated with etanercept or sulphasalazine in the ASCEND trial.

OBJECTIVES: The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a new composite clinical tool combining subjective and objective measures. Using data from the randomized double-blind Ankylosing Spondylitis Study Comparing Enbrel with Sulfasalazine Dosed Weekly (ASCEND) trial, we tested ASDAS validity and assessed its capacity to discriminate between treatment effects and change-from-baseline improvements. METHOD: These post hoc analyses were conducted in patients who received etanercept (50 mg/week) or SSZ (≤ 3 g/day) for 16 weeks. The ASDAS was tested for its capacity to discriminate between those who achieved and did not achieve Assessment of Spondyloarthritis International Society (ASAS) partial remission and ASAS20. Week 16 adjusted treatment differences and effect sizes of improvement from baseline of 42 outcomes were calculated. RESULTS: Means for ASDAS were less than half in patients with ASAS partial remission compared with patients without partial remission across the entire study population (1.2 vs 2.6; P<0.0001). Patients who achieved ASAS20 had greater mean changes from baseline in ASDAS than those who did not (-1.8 vs -0.3; P<0.0001). ASDAS was consistently shown to have one of the highest discriminatory capacities compared with other measurements (including subjective measurements) regardless of normal vs high CRP, presence or absence of peripheral arthritis and high vs very high ASDAS at baseline. As a dichotomous variable using different thresholds for improvement and disease severity, ASDAS had slightly better discriminatory capacity than all corresponding ASAS measures. CONCLUSION: ASDAS is a validated and highly discriminatory tool for the detection of significant differences between treatments for AS as well as for detecting a significant improvement from baseline with etanercept and SSZ.

Simplified Ankylosing Spondylitis Disease Activity Score (SASDAS) Versus ASDAS: A Post Hoc Analysis of a Randomized Controlled Trial.

OBJECTIVE: To compare the Simplified Ankylosing Spondylitis Disease Activity Score (SASDAS) against the Ankylosing Spondylitis Disease Activity Score (ASDAS) for measuring and categorizing disease activity using data from the EMBARK trial (ClinicalTrials.gov: NCT01258738), a randomized controlled trial of etanercept (ETN) for axial spondyloarthritis (axSpA). METHODS: Patients with early active axSpA received ETN 50 mg once weekly (n = 106) or placebo (PBO; n = 109) for 12 weeks in a double-blind manner; they then received open-label ETN for 92 weeks. For this analysis, ASDAS-C-reactive protein (CRP) and SASDAS-CRP were calculated at baseline, week 12, and week 24. The SASDAS was calculated by the linear addition of the ASDAS components without adjustment. RESULTS: A very strong correlation, as determined by the Spearman correlation coefficient, was observed between the ASDAS and SASDAS for continuous variables at baseline and during treatment. For pooled categorical data at baseline, the SASDAS placed 69.9% of patients in the same disease categories as the ASDAS but overestimated for 17.8% of patients and underestimated for 12.2% of patients. A similar pattern was seen postbaseline. Cohen weighted [Formula: see text] statistics for all individual and pooled treatments and timepoints (0.54-0.73) reflected moderate to substantial agreement. The capacity to differentiate between treatments (ie, ETN and PBO/ETN) was higher with the ASDAS (effect size -0.74, 95% CI -1.03 to -0.46) compared with the SASDAS (effect size -0.51, 95% CI -0.79 to -0.23), but sensitivity to change was generally similar. CONCLUSION: A very strong correlation between the SASDAS and ASDAS was observed when considering continuous variables; however, moderate to substantial agreement was observed for categorical data, and the SASDAS classified a lower proportion of patients as being in the inactive and low disease activity categories.

Frequency and Duration of Early Non-serious Adverse Events in Patients with Rheumatoid Arthritis and Psoriatic Arthritis Treated with Tofacitinib.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This post hoc analysis assessed frequency or duration of early select non-serious adverse events (AEs; excluding infections), and their impact on treatment discontinuation, in patients with RA or PsA treated with tofacitinib 5 or 10 mg twice daily, or placebo. METHODS: Data were pooled from five phase 3 and one phase 3b/4 studies in patients with moderate-to-severe RA, and two phase 3 studies in patients with active PsA. Select all-causality, non-serious AEs, reported to month 3 (placebo-controlled period), were headache, diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal discomfort or pain); incidence rates (unique patients with events per 100 patient-years of follow-up), duration of, and discontinuations due to these non-serious AEs were reported. RESULTS: We analyzed 3871 and 710 patients with RA and PsA, respectively. Incidence of non-serious AEs to month 3 was generally similar with tofacitinib and placebo. The most frequent non-serious AEs were headache and diarrhea with tofacitinib, and dyspepsia, nausea, and headache with placebo. Most events were mild or moderate in severity, lasting ≤ 4 weeks. Permanent discontinuations due to non-serious AEs were not observed in patients with PsA, and were < 1.0% in patients with RA across treatment groups. The most frequent cause of temporary discontinuation across all groups was gastric discomfort (0.3-0.8%). CONCLUSIONS: Non-serious AE incidence was generally similar in patients with RA or PsA receiving tofacitinib or placebo. Most events were mild or moderate and generally resolved within 4 weeks. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01877668; NCT01882439; NCT02187055.

Tofacitinib is a medicine that can be taken by patients to treat rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Serious side effects that might occur in patients taking tofacitinib are more frequently discussed than the mild, non-serious side effects that patients might consider to be more of a 'nuisance', which often occur shortly (< 3 months) after starting treatment. Here we looked at patients with RA or PsA who were taking tofacitinib or placebo (no medicine) during clinical trials, to find out how often they had certain non-serious side effects, how long they lasted, and whether they caused the patients to stop taking their medication. A similar number of patients with RA or PsA taking tofacitinib or placebo had non-serious side effects. The most common non-serious side effects in patients taking tofacitinib were a headache and diarrhea. The most common non-serious side effects in patients taking placebo (no medicine) were indigestion, a feeling of sickness, and/or headache. Most non-serious side effects were mild or moderate and stopped within about 4 weeks. Fewer than one in every 100 patients with RA, and no patients with PsA, stopped taking their medication because of non-serious side effects. Most patients who stopped taking their medication did so due to a feeling of gastrointestinal (stomach) discomfort.

Predictors of response to etanercept-methotrexate treatment: a post hoc logistic regression analysis of a randomized, open-label study in Latin American patients with rheumatoid arthritis.

BACKGROUND: Determining potential predictors of clinical response would allow a more personalized rheumatoid arthritis (RA) treatment approach in heterogeneous populations such as Latin American (LA) patients. METHODS: Post hoc analysis to identify baseline characteristics predictive of clinical remission in response to treatment with etanercept (ETN) plus methotrexate (MTX) in LA patients with moderate to severe MTX-resistant RA. We report data from the group of patients who received ETN 50 mg/week plus MTX (ETN + MTX, n = 281) in a clinical trial consisting of an initial 24-week open-label phase, followed by a 104-week extension. Remission was defined as 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) score < 2.6. Cutoff values to dichotomize baseline variables maximizing the detection of remission were obtained from Receiver Operator Curve analyses. Baseline dichotomized and categorical variables were analyzed altogether in a stepwise logistic regression model. Odds of attaining response at Weeks 24 and 128 were estimated for each significant predictor. RESULTS: At Week 24 and Week 128, 27% (66/241) and 42% (91/219) of patients in the ETN + MTX group achieved remission. On average, patients achieving remission were younger and had lower baseline ESR, lower Physician Global Assessment (PGA) scores, lower total Health Assessment Questionnaire (HAQ) scores, and lower visual analog scale (VAS) Pain scores compared with patients who did not achieve remission. The best subset of baseline variables predicting Week 24 remission in the stepwise regression model were age ≤ 49 years (odds ratio [OR] 2.93), body mass index (BMI) > 28.5 kg/m2 (OR 3.24), disease duration > 3.7 years (OR 2.22), ESR ≤ 42 mm/h (OR 2.72), PGA ≤ 6 (OR 3.21), tender joint count ≤ 14 (OR 2.25), and total HAQ score ≤ 1.6 (OR 2.86). At Week 128, age ≤ 42 years (OR 2.21), SF-36 Mental Health Scale score > 39.6 (OR 2.16), White race (OR 4.07), > 18 swollen joints (OR 2.11), and VAS Pain ≤ 41 (OR 6.05) at baseline were the best subset of significant predictors of remission. CONCLUSIONS: In LA patients with RA, younger age, higher BMI, longer disease duration, higher SF-36 Mental Health Scale score, higher swollen joint count, and overall lower disease activity predicted clinical response to ETN + MTX therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00848354.

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.

Visit-to-visit blood pressure variation and outcomes in heart failure with reduced ejection fraction: findings from the Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms trial.

BACKGROUND: Visit-to-visit office blood pressure (BP) variability (BPV) has been associated with morbidity and mortality outcomes in several cardiovascular conditions. The aim of this study was to evaluate the association between BPV and outcomes in patients with heart failure and reduced ejection fraction and the effect of eplerenone on BPV. METHODS AND RESULTS: We evaluated the associations between BPV, calculated as SBP coefficient of variation (SBP-CoV = SD/mean × 100%), and the primary composite endpoint of cardiovascular mortality or heart failure hospitalization (HFH), and its components, in 2549 patients from the Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms trial. Lower SBP-CoV was independently associated with a higher risk of all the studied outcomes, while higher as well as lower SBP-CoV were associated with a higher risk of cardiovascular death. After a median follow-up period of 21 months the risk of the composite outcome of cardiovascular death or HFH was almost double in the lower SBP-CoV tertile as compared with the intermediate tertile [adjusted hazard ratio: 2.01, 95% confidence interval (1.62-2.51), P < 0.001]. The relationship between SBP-CoV and outcomes was not modified by eplerenone (P value for interaction = 0.48). An interaction was detected between mean SBP and SBP-CoV for the primary outcome (P = 0.048) and for HFH (P = 0.018). The effect modification was slight, but lower SBP-CoV was associated with worse outcomes in patients with both low and high SBP, while this interaction was less clear for patients with SBP in the 'normal' range. CONCLUSION: In our patients with heart failure and reduced ejection fraction and mild symptoms, both a lower and higher SBP-CoV were associated with worse outcomes. SBP-CoV did not modify the benefit of eplerenone. Further studies are warranted to clarify the role of BPV in heart failure. CLINICALTRIALS. GOV IDENTIFIER: NCT00232180.