A. Szumski

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.

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.

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.

Resilience as a predictor of treatment response in patients with posttraumatic stress disorder treated with venlafaxine extended release or placebo

This post-hoc analysis evaluated resilience as a predictor of treatment response in patients with posttraumatic stress disorder (PTSD). Data were pooled from two randomized, double-blind studies conducted with adult outpatients treated with flexible doses of venlafaxine extended release (ER) 37.5 to 300 mg/day or placebo. The 17-item Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS-SX17) was the primary outcome measure. Baseline Connor–Davidson Resilience Scale (CD-RISC) scores for the 25-, 10-, and 2-item versions were used to predict changes in PTSD symptom severity at week 12 and symptomatic remission (CAPS-SX17 ≤ 20). Analyses were conducted for the overall population and separately for the individual treatment groups. In total, pretreatment resilience predicted a positive treatment response. For the overall population, all versions of the CD-RISC predicted CAPS-SX17 change scores and remission after controlling for variables such as treatment group and baseline symptom severity. For venlafaxine ER-treated patients, all versions of the CD-RISC were predictive of remission, but only the 10-item version was predictive of CAPS-SX17 change score. Our results suggest that higher pretreatment resilience is generally associated with a positive treatment response. Future research may be warranted to explore the relationship between response to active treatment and the spectrum of resiliency.

Cardiometabolic profile, clinical features, quality of life and treatment outcomes in patients with moderate-to-severe psoriasis and psoriatic arthritis

Abstract Cardiometabolic, clinical and quality-of-life (QoL) measures were assessed before and after etanercept treatment in patients who had moderate-to-severe plaque psoriasis with and without psoriatic arthritis (PsA) in the PRISTINE trial. Adult patients were randomized to receive etanercept 50 mg once weekly or twice weekly double-blind for 12 weeks; all patients subsequently received etanercept 50 mg once weekly open-label through week 24. Metabolic syndrome was identified in 44 and 41% of patients with and without PsA, elevated blood pressure in 73 and 56% (p < 0.05) and diabetes in 21 and 9% (p < 0.01), respectively. Significant improvements from baseline in Psoriasis Area Severity Index were observed with etanercept therapy at all time points over 24 weeks (p < 0.001) independent of PsA history. At baseline, patients with PsA had worse QoL than patients without PsA. After 24 weeks of etanercept, both groups had significant improvement from baseline in QoL, but the PsA group had greater improvement than that without PsA. Cardiovascular comorbidities were common in psoriasis patients with and without PsA, suggesting that clinicians need to be attentive to cardiometabolic parameters in this population. Worse QoL was demonstrated in PsA versus psoriasis alone. Regardless of patients’ PsA status, treatment with etanercept significantly improved skin symptoms and QoL measures.

A factor analysis of posttraumatic stress disorder symptoms using data pooled from two venlafaxine extended-release clinical trials

Confirmatory factor analysis (CFA) of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM‐IV) three‐factor posttraumatic stress disorder (PTSD) diagnostic criteria was conducted to determine fit for this patient population. An exploratory factor analysis (EFA) of alternate symptom structures was planned to identify symptoms that cluster in this population. The response of symptom factors to treatment with venlafaxine extended release (ER) was explored.

Predictors of Clinical Remission under Anti-tumor Necrosis Factor Treatment in Patients with Ankylosing Spondylitis: Pooled Analysis from Large Randomized Clinical Trials.

Objective. Investigate the role and relation of disease duration of different factors for achieving clinical remission with anti-tumor necrosis factor (TNF) treatment in patients with active ankylosing spondylitis (AS). Methods. Data pooled from 4 large (n = 1281) clinical trials were used to compare disease duration subgroups for placebo or sulfasalazine (SSZ) versus etanercept (ETN), which, in turn, were analyzed by age of diagnosis ≤ 40 versus > 40 years, HLA-B27 status, and baseline C-reactive protein (CRP) ≤ upper limit of normal (ULN) versus > ULN using chi-square tests, and ANCOVA. The primary efficacy measure was Assessments of SpondyloArthritis international Society (ASAS) partial remission (PR) after 12 weeks of treatment. Also analyzed were Bath AS Disease Activity Index and Functional Index, AS Disease Activity Scores, and ASAS response rates. Results. Overall, a larger percentage of patients achieved ASAS-PR with ETN versus SSZ or placebo. More patients with ≤ 2-year disease duration treated with ETN experienced partial remission (34%) versus longer disease duration (30%, 27%, and 22% for > 2–5, > 5–10, and > 10 yrs, respectively; all p < 0.05). In the subgroup of patients with both disease duration ≤ 2 years and aged ≤ 40 years at diagnosis, the treatment response was even more pronounced. Similar results were seen in HLA-B27–positive patients in the disease duration ≤ 2-year subgroup. Overall, patients with high CRP at baseline had better treatment responses compared with patients with normal CRP. Conclusion. Treatment response under anti-TNF treatment with ETN at 12 weeks was greatest among patients with disease duration ≤ 2 years and even more pronounced in subgroups of patients ≤ 40 years old or HLA-B27–positive at diagnosis.

DAS28-CRP and DAS28-ESR cut-offs for high disease activity in rheumatoid arthritis are not interchangeable

Background In most patients with rheumatoid arthritis (RA), Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) is lower than DAS28 erythrocyte sedimentation rate (DAS28-ESR), suggesting that use of the DAS28-ESR cut-off to assess high disease activity (HDA) with DAS28-CRP may underestimate the number of patients with HDA. We determined the DAS28-CRP value corresponding to the validated DAS28-ESR cut-off for HDA. Methods Baseline data were pooled from 2 clinical studies evaluating etanercept (ETN) plus methotrexate (MTX) or MTX in early RA; DAS28-CRP and DAS28-ESR were obtained, allowing the determination of the DAS28-CRP HDA value best corresponding to the DAS28-ESR cut-off of >5.1. Results At baseline, as expected, fewer patients had HDA by DAS28-CRP than DAS28-ESR; DAS28-CRP>5.1 and DAS28-ESR>5.1 had only modest agreement (κ coefficients 0.45–0.54). Mean DAS28-CRP and DAS28-ESR were 5.7 and 6.2, respectively, in the ETN+MTX group (n=571), and 6.0 and 6.5 in the MTX group (n=262). A DAS28-CRP cut-off of 4.6 corresponded to a DAS28-ESR cut-off of 5.1. Conclusions We have shown that a DAS28-CRP of 4.6 corresponds to 5.1 for DAS28-ESR. Since this is substantially lower than the DAS28-ESR cut-off of 5.1, using 5.1 as the cut-off for DAS28-CRP underestimates disease activity in RA. Trial registration number NCT00195494; NCT00913458.

Impact of early vs. late disease onset on treatment response to etanercept in patients with psoriasis

DEAR EDITOR, Early-onset psoriasis (EOP) has been characterized by onset age < 40 years, and accounts for > 75% of cases of psoriasis. By contrast, late-onset psoriasis (LOP) occurs after 40 years of age. Such a bimodal age of onset has since been identified in several large studies. However, little is known about the relative response of the two groups to treatment. In this analysis, we aimed to investigate the response to etanercept therapy in patients with psoriasis stratified by EOP vs. LOP. Data were combined from four clinical trials of etanercept for psoriasis – PRISTINE, PRESTA, 318 and CRYSTEL – to provide two dose groups: etanercept 25 mg twice weekly (BIW) or 50 mg once weekly and etanercept 50 mg BIW. Patients aged > 40 years at enrolment were stratified into EOP (≤ 40 years at diagnosis) vs. LOP (> 40 years at diagnosis). Patients aged < 40 years at enrolment were excluded to minimize the confounding effect of age. Efficacy analyses were based on patients who had at least one treatment dose and postbaseline data, analysed by last observation carried forward. Differences in baseline disease and demographic characteristics in the EOP and LOP subgroups were analysed using ANOVA for continuous parameters and chi-square-tests for categorical parameters. At week 12, age-of-diagnosis categories were analysed in ANCOVA models of week 12 efficacy outcomes adjusted for study and baseline of parameter. Week 12 adjusted odds ratios (ORs) for 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 12 were generated to compare the two age-of-diagnosis subgroups. PASI 75 was analysed by treatment group and adjusted for baseline and study in conditional logistic regression models. Age at enrolment was significantly different between EOP and LOP highand low-dose groups (both P < 0 001; Table 1), suggesting that age of enrolment and age of onset are highly correlated. At baseline, duration of psoriatic arthritis was significantly longer in patients with EOP than in those with LOP. Other baseline demographics were similar or were not consistently different between patients with EOP vs. LOP when stratified into lowand high-dose groups. Mean baseline PASI was significantly lower in patients with LOP than in those with EOP in both etanercept treatment arms (Table 2). To rule out the possibility that the association was due to disease duration and not age of diagnosis, Spearman correlations between disease duration and baseline PASI and between disease duration and week 12 PASI were obtained, and were shown to be very weakly correlated (R < 0 05) and nonsignificant. The week 12 mean PASI total score was significantly lower in patients with EOP vs. LOP in the etanercept 50-mg BIW group (Table 2). Achievement of PASI 75 among high-dose patients was greater in the EOP vs. LOP group [51% vs. 39%; OR 1 62; 95% confidence interval (CI) 1 05– 2 51]. The corresponding low-dose values were 34% vs. 39% (OR 0 79; 95% CI 0 54–1 16). Baseline body surface area (BSA) involvement was significantly higher for patients with EOP vs. LOP in the etanercept 50-mg BIW arm. In the high-dose etanercept group, BSA and Dermatology Life Quality Index at week 12 were significantly lower for patients with EOP than with LOP (P < 0 05 for both). It is notable that while the patients with EOP had higher baseline BSA, BSA in this group improved to a greater degree than in the LOP group, and surpassed the LOP group at week 12. Both the anxiety and depression subscales of the Hospital Anxiety and Depression Scale were lower at baseline for patients with EOP vs. LOP in both treatment arms, and the week 12 results were only slightly better for patients with EOP vs. LOP. In this retrospective analysis of combined data from four clinical trials, 77% of patients had EOP and 23% had LOP, which is in line with the known prevalence of the two groups. EOP at diagnosis was associated with higher baseline PASI and BSA than LOP, which is suggestive of the increased disease severity expected for this phenotype. Despite the differences in disease severity at baseline, patients with EOP responded better to etanercept 50-mg BIW treatment in terms of week 12 absolute PASI and achievement of PASI 75. Faster improvement in EOP vs. LOP in skin-disease activity parameters (e.g. PASI, BSA), despite the longer disease duration of EOP, is supportive of the distinctive nature of EOP. Overall, patients with EOP responded better to treatment with high-dose etanercept than did patients with LOP, but the effect was not apparent with low-dose etanercept. The reason for this is unclear but could indicate that high-dose etanercept is more effective at targeting tumour necrosis factor-a, which may exhibit different activity according to disease stage or phenotype. Unfortunately, studies directly investigating the effect of age of onset on treatment response in psoriasis are not available. Two recent studies investigated response to treatment with the

Cardiometabolic biomarkers in chronic plaque psoriasis before and after etanercept treatment

Abstract Objective: To assess cardiometabolic biomarkers in patients with psoriasis before and after etanercept treatment. Methods: Patients with moderate-to-severe plaque psoriasis were randomized to etanercept 50 mg once or twice weekly, double-blinded. Cardiometabolic biomarkers were assessed at baseline and after 12 weeks of treatment (n = 273). Results: At baseline, 42% of patients had metabolic syndrome. Etanercept was not associated with any clinically relevant adverse effects on cardiometabolic biomarkers. In the once-weekly subgroup, significant mean percentage changes from baseline (p < 0.05) were observed for the quantitative insulin-sensitivity check index (QUICKI; −2.2%), apolipoprotein (Apo) A1 (3.2%), Apo B:Apo A1 ratio (−3.5%), leptin (8.6%) and high-sensitivity C-reactive protein (hsCRP) (−65.5%); and in the twice-weekly subgroup for plasma insulin (15.9%), QUICKI (−2.7%), high-density lipoprotein cholesterol (HDL-C; 2.9%), apolipoprotein (Apo) A1 (2.8%), Apo B:Apo A1 (−4.6%) and hsCRP (−74.4%). Conclusion: Metabolic syndrome was common in these patients with moderate-to-severe psoriasis. Etanercept treatment may provide some potentially favorable modulation of insulin sensitivity, HDL-C, Apo A1 and Apo B:Apo A1 ratio.