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.

Open-label observation of addition of etanercept versus a conventional disease-modifying antirheumatic drug in subjects with active rheumatoid arthritis despite methotrexate therapy in the Latin American region.

BACKGROUND: Previous global studies examined etanercept (ETN) + methotrexate (MTX) for treatment of rheumatoid arthritis (RA), but included few subjects from Latin America. OBJECTIVE: The objective of this study was to compare the safety and efficacy of ETN + MTX versus a standard-of-care disease-modifying antirheumatic drug (DMARD) + MTX in Latin American subjects with moderate to severe active RA despite MTX therapy. METHODS: This open-label, active-comparator study (NCT00848354) randomized subjects 2:1 to ETN 50 mg/wk + MTX or investigator-selected DMARD (sulfasalazine or hydroxychloroquine) + MTX (ETN + MTX, n = 281; DMARD + MTX, n = 142). The primary end point was the proportion achieving American College of Rheumatology (ACR) 50 at week 24. Secondary end points included ACR20/70, disease activity score (DAS) 28 measures, and mean change in modified total Sharp score. Patient-reported outcomes were the Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment: RA (WPAI:RA), and Caregiver Burden and Resource Utilization. Statistical analyses were stratified by country; χ test and analysis of covariance were used. Adverse events were monitored. RESULTS: More subjects achieved ACR50 at week 24 with ETN + MTX versus DMARD + MTX (62% vs 23%, respectively), in addition to secondary end points (P < 0.0001 for all); mean change in modified total Sharp score was lower for the ETN + MTX group (0.4 vs 1.4, respectively; P = 0.0270). Improvements in patient-reported outcomes favored ETN + MTX for Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale for depression, WPAI:RA, and Caregiver Burden and Resource Utilization emergency department visits for RA (P < 0.01). Overall, adverse events were similar between the groups (69% vs 68%,); serious adverse events were also similar (4% vs 1%). The rate of overall infections was higher with ETN + MTX (38%) than DMARD + MTX (22%, P ≤ 0.001). CONCLUSIONS: Consistent with published global data among RA patients with inadequate response to MTX, adding ETN to MTX demonstrated better efficacy than adding one other conventional DMARD to MTX. No new safety issues were observed. ETN + MTX provided favorable benefit-risk profile among RA patients from LA region.

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.

Improved health outcomes with etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis.

BACKGROUND: Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied. METHODS: Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used. RESULTS: Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores. CONCLUSION: Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region. TRIAL REGISTRATION: clintrials.gov # NCT00422227.

Comparison of physician and patient global assessments over time in patients with rheumatoid arthritis: a retrospective analysis from the RADIUS cohort.

BACKGROUND: In rheumatoid arthritis (RA), there is discordance between patient and physician assessments of disease severity and treatment response. OBJECTIVE: This retrospective analysis of the RADIUS (RA Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) 1 cohort examined specific factors that influence differences in global assessments for therapeutic effectiveness of disease-modifying antirheumatic drugs made by physicians (physician global assessment [PhGA]) and patients (patient global assessment [PtGA]). METHODS: The RADIUS 1 cohort consisted of primarily community-based private practice patients with RA requiring either the addition of or a switch to a new biologic or nonbiologic disease-modifying antirheumatic drug and who were followed for up to 5 years by their rheumatologists. Periodic assessments included PhGA, PtGA, Health Assessment Questionnaire-Disability Index (HAQ-DI), 28-item tender/painful joint count (TJC28), swollen joint count (SJC28), pain Visual Analog Scale (VAS), and acute-phase reactants. RESULTS: Among 4359 patients (mean disease duration, 7.3 years), PhGA most highly correlated with TJC28 (0.6956; 95% confidence interval [CI], 0.6881-0.7030) and SJC28 (0.6757; 95% CI, 0.6678-0.6834). Moderate overall correlations were observed for PtGA with TJC28 (0.5000; 95% CI, 0.4890-0.5108) and less 50 with SJC28 (0.3754; 95% CI, 0.3628-0.3878). Patient global assessment most strongly correlated with pain VAS (0.8349; 95% CI, 0.8305-0.8392) and moderately correlated with HAQ-DI (0.5979; 95% CI, 0.5886-0.6071). Acute-phase reactants poorly correlated with PhGA and PtGA. CONCLUSIONS: Low correlations between PhGA and acute-phase reactants suggest that these measurements have a limited contribution compared with the physical examination when physicians make global assessments. These results also suggest that physicians should consider patients' assessments of their disease activity (HAQ, pain VAS, and PtGA) and put joint counts into proper context.

Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment.

OBJECTIVES: To compare health-related quality of life (HRQoL) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis using spydergram representations. METHODS: Data from randomised, controlled trials of etanercept in patients with RA, PsA and psoriasis were analysed. HRQoL was assessed by the medical outcomes survey short form 36 (SF-36) physical (PCS) and mental (MCS) component summary and domain scores. Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure. RESULTS: Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA, but near normative values in patients with psoriasis; MCS scores at baseline were near normal in PsA and psoriasis but low in RA. Treatment with etanercept resulted in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications. Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA; clinically meaningful improvements in SF-6D were observed in all three patient populations following treatment with etanercept. CONCLUSIONS: Patients with RA, PsA and psoriasis demonstrated unique HRQoL profiles at baseline. Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA, PsA and psoriasis.

Combination etanercept and methotrexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study.

OBJECTIVE: The objective of this post hoc analysis was to test the benefits of treating very early rheumatoid arthritis (VERA; ≤4 months) using COMET trial data. Treatment response in VERA and early rheumatoid arthritis (ERA; >4 months to 2 years) with combination etanercept+methotrexate (ETN+MTX) or MTX monotherapy was compared. METHODS: Data assessed at week 52 for baseline disease duration effect included remission (disease activity score (DAS)28 <2.6, SDAI ≤3.3, Boolean), low disease activity (LDA; DAS28 <3.2), Boolean components of remission and radiographic non-progression. Subjects who discontinued because of lack of efficacy were included as non-responders. RESULTS: Higher proportions of VERA subjects achieved LDA (79%) and DAS28 remission (70%) than ERA (62%, 48%, respectively, p<0.05) with ETN+MTX. Such high responses with MTX monotherapy were not observed (VERA, LDA=47%, DAS28 remission=35%; ERA, 47% and 32% respectively, p>0.70 for each). Regardless of disease duration, no radiographic progression was seen in 80% of subjects with ETN+MTX. In contrast, a higher proportion of VERA subjects showed no radiographic progression compared with ERA subjects treated with MTX (73.9% vs 50%, p=0.01). CONCLUSIONS: Treatment of VERA with ETN+MTX provides qualitatively improved clinical outcomes not seen with MTX monotherapy, supporting the pivotal role of TNF inhibition in early disease.

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.

Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial.

OBJECTIVE: Etanercept, a fully human tumor necrosis factor (TNF) receptor, is an effective treatment in patients with ankylosing spondylitis (AS). Sulfasalazine is frequently used for the treatment of both axial symptoms and peripheral symptoms of AS, and it has been the recommended therapy before the use of an anti-TNF agent when peripheral arthritis is present. Until now, no clinical trial has compared the efficacy and safety of a TNF blocker with that of sulfasalazine. This study was undertaken to compare the efficacy and safety of etanercept with that of sulfasalazine after 16 weeks of treatment in patients with axial and peripheral manifestations of AS. METHODS: In this randomized, double-blind study, patients received etanercept 50 mg once weekly (n=379) or sulfasalazine titrated to a maximum of 3 gm/day (n=187) for 16 weeks. The primary end point was the proportion of patients who achieved the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) at 16 weeks. Last observation carried forward was predefined for imputation of missing values. RESULTS: The mean age of the patients was 41 years, 74% were male, and the mean disease duration was 7.6 years. The proportion of ASAS20 responders at week 16 was greater among patients treated with etanercept compared with those treated with sulfasalazine (75.9% versus 52.9%; P<0.0001). As early as week 2 of treatment, etanercept was found to be more effective than sulfasalazine (P<0.0001) in ameliorating both the axial symptoms and peripheral manifestations. Serious adverse events rarely occurred, and the rate of serious adverse events did not differ between groups. CONCLUSION: In this population of patients with AS, etanercept was significantly more effective than sulfasalazine in improving the signs and symptoms of AS in the axial skeleton and peripheral joints.

Reduced risk of infections with the intravenous immunoglobulin, IgPro10, in patients at risk of secondary immunodeficiency-related infections.

Aim: Patients with secondary immunodeficiency (SID) are at increased risk of infections and may be treated with immunoglobulin replacement therapy (IgRT). Despite growing efficacy evidence for IgRT in infection prevention in SID, treatment guidelines are not aligned. Materials & methods: A retrospective database analysis was conducted to assess treatment patterns and infection rates in patients at risk of SID-related infections, with or without IgRT (IgPro10) exposure, to evaluate real-world effectiveness of IgRT in infection prevention. Results: Of 11,448 patients included, 222 received IgPro10. B-cell malignancies and solid organ transplants were the predominant underlying conditions. Despite being sicker at baseline, the IgPro10 cohort demonstrated fewer infections post-index than the non-IgRT cohort. Conclusion: IgPro10 may be an effective option for infection prevention in SID.

Secondary immunodeficiency (SID) occurs when the immune system is weakened by external factors, including certain medical treatments. It can leave a person with an increased risk of potentially serious or even fatal infections, as they no longer have adequate defenses against bacteria. Some patients with this condition require treatment to boost their immune system, including supplementation of their antibodies, known as immunoglobulin replacement therapy (IgRT). In this study, we explored whether: (1) patients with conditions that are at risk of SID and associated infections received IgRT; and (2) whether receiving the IgRT reduced the incidence of infections. We found that patients who had IgRT were much less likely to experience infections than those who did not receive IgRT, suggesting that IgRT may be an effective treatment option for preventing infections in patients with compromised immune systems caused by SID.

Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study.

OBJECTIVE: To evaluate how continuation of and alterations to initial year 1 combination etanercept-methotrexate (MTX) therapy and MTX monotherapy regimens affect long-term remission and radiographic progression in early, active rheumatoid arthritis. METHODS: Subjects were randomized at baseline for the entire 2-year period; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2. The original combination group either continued combination therapy (the EM/EM group; n = 111) or received etanercept monotherapy (the EM/E group; n = 111) in year 2; the original MTX monotherapy group either received combination therapy (the M/EM group; n = 90) or continued monotherapy (the M/M group; n = 99) in year 2. Efficacy end points included remission (a Disease Activity Score in 28 joints [DAS28] <2.6) and radiographic nonprogression (change in the modified Sharp/van der Heijde score < or = 0.5) at year 2. A last observation carried forward analysis from the modified intention-to-treat population (n = 398) and a post hoc nonresponder imputation (NRI) analysis (n = 528) were performed for remission. RESULTS: At year 2, DAS28 remission was achieved by 62/108, 54/108, 51/88, and 33/94 subjects in the EM/EM, EM/E, M/EM, and M/M groups, respectively (P < 0.01 for the EM/EM and M/EM groups versus the M/M group). This effect was corroborated by a more conservative post hoc 2-year NRI analysis, with remission observed in 59/131, 50/134, 48/133, and 29/130 of the same respective groups (P < 0.05 for each of the EM/EM, EM/E, and M/EM groups versus the M/M group). The proportions of subjects achieving radiographic nonprogression (n = 360) were 89/99, 74/99, 59/79, and 56/83 in the EM/EM (P < 0.01 versus each of the other groups), EM/E, M/EM, and M/M groups, respectively. No new safety signals or between-group differences in serious adverse events were seen. CONCLUSION: Early sustained combination etanercept-MTX therapy was consistently superior to MTX monotherapy. Combination therapy resulted in important clinical and radiographic benefits over 2 study years, without significant additional safety risk.

Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.

BACKGROUND: Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept. METHODS: 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3-24 months were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494). FINDINGS: 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44-56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23-33%) taking methotrexate alone (effect difference 22.05%, 95%CI 13.96-30.15%, p<0.0001). 487 evaluable patients had severe disease (DAS28>5.1). 196 of 246 (80%, 75-85%) and 135 of 230 (59%, 53-65%), respectively, achieved radiographic non-progression (20.98%, 12.97-29.09%, p<0.0001). Serious adverse events were similar between groups. INTERPRETATION: Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. FUNDING: Wyeth Research.

The role of C-reactive protein as a predictor of treatment response in patients with ankylosing spondylitis.

OBJECTIVES: To determine whether C-reactive protein (CRP) level is predictive of response to tumor necrosis factor-α blocker treatment in patients with ankylosing spondylitis (AS) and whether there is an optimal CRP range for treatment initiation. METHODS: In this post hoc analysis, data on etanercept-treated patients with AS were pooled from four randomized trials. Week 12 responses (ASAS20, ASAS50, ASDAS-CRP < 1.3, and ASDAS-CRP ∆ ≤ 1.1) were evaluated in relationship to baseline CRP levels (normal, defined as ≤ upper limit of normal [≤ ULN]; elevated, > ULN; high, > ULN and ≤ 3xULN; and very high, > 3xULN), baseline levels of patient-reported outcomes (PROs), and CRP levels at weeks 2, 4, and 8, using univariate and stepwise predictor analyses. In addition, relationships between baseline CRP and other baseline predictors were analyzed using stepwise models of response. RESULTS: Among 867 patients, baseline CRP levels were normal in 371 (43%) patients, high in 299 (34%), and very high in 197 (23%). Very high baseline CRP was a significant predictor for all four week-12 outcomes, compared with normal CRP. Conversely, normal CRP at weeks 2, 4, and 8 was a stronger predictor of week 12 response than elevated CRP. PROs were less consistent predictors of response. In addition, there was a significant association between higher baseline CRP and lower age of disease onset (< 40 years) and between normal CRP and lower disease burden. CONCLUSIONS: In patients with AS, both baseline and post-baseline CRP levels can be predictive of response to treatment at week 12, more consistently than PROs. CLINICAL TRIALS: NCT00421915, NCT00247962, NCT00418548, NCT00356356.

Predictors of remission with etanercept-methotrexate induction therapy and loss of remission with etanercept maintenance, reduction, or withdrawal in moderately active rheumatoid arthritis: results of the PRESERVE trial.

BACKGROUND: The aim was to analyze characteristics that predict remission induction and subsequent loss of remission in patients with moderately active rheumatoid arthritis (RA) who received full-dose combination etanercept plus methotrexate induction therapy followed by reduced-dose etanercept or etanercept withdrawal. METHODS: Patients with Disease Activity Score based on 28-joint count (DAS28) >3.2 and ≤5.1 received open-label etanercept 50 mg once weekly (QW) plus methotrexate for 36 weeks. Those who achieved DAS28 low disease activity by 36 weeks were randomized to double-blind treatment with etanercept 50 mg or 25 mg QW plus methotrexate or placebo plus methotrexate for 52 weeks. All analyses were adjusted for the continuous baseline variables of their respective remission outcomes. RESULTS: Younger age, body mass index (BMI) <30 kg/m2, and lower Health Assessment Questionnaire (HAQ) score at baseline were significant predictors of week-36 remission (P < 0.05) based on DAS28, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Baseline DAS28, SDAI, and CDAI were significantly predictive of all three remission endpoints (P < 0.05). For all three treatments, the strongest predictors of loss of DAS28 remission included failure to achieve sustained remission (DAS28 < 2.6 at weeks 12, 20, 28, and 36) with induction therapy, higher DAS28/SDAI/CDAI at randomization and at 1 month, increase in DAS28/SDAI/CDAI at 1 month, and increase in DAS28/CDAI/SDAI components and patient-reported outcomes (PROs) at 1 month. With the exception of not achieving sustained remission, very similar significant predictors were observed for loss of SDAI and CDAI remission. CONCLUSION: These findings suggest that patients with moderately active RA who are younger and have lower BMI, lower HAQ, and lower disease activity at baseline are most likely to achieve remission when receiving combination etanercept and methotrexate induction therapy. In addition, patients who fail to achieve sustained remission with induction therapy and those with worse disease activity and PROs at early time points after initiating maintenance therapy with a full-dose or reduced-dose etanercept-methotrexate regimen or methotrexate monotherapy are most likely to lose remission across all treatment arms. These findings may help guide clinicians' decision-making as they treat patients to remission and beyond. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00565409 . Registered on 28 November 2007.

Patient Preferences Associated with Therapies for Psoriatic Arthritis: A Conjoint Analysis.

BACKGROUND: As psoriatic arthritis (PsA) treatment choices continue to expand, it is important to consider patient preferences for treatment modalities for PsA. Involving patients in treatment decisions can influence adherence to treatment and outcomes of therapy. OBJECTIVE: To determine patient preferences for medication attributes prescribed for patients with PsA. METHODS: A choice-based conjoint survey was mailed to 2800 randomly selected patients with PsA who were enrolled in Humana Medicare and commercial plans. Patients had been diagnosed with PsA between January 1, 2012, and September 30, 2016. The medication attributes included in the survey were the medication route of administration, frequency of administration, ability to reduce daily joint pain and swelling, likelihood of serious infections, improvement in the patient's ability to perform daily activities, achieving clear or almost clear skin, and cost. Hierarchical Bayesian models were used to score patient preferences after adjusting for demographic and clinical characteristics. The mean attribute importance scores were used to rank patient preferences. RESULTS: A total of 468 patients (258 with a Medicare plan and 210 with a commercial plan) completed the survey. The top 3 medication attributes for patients in Medicare plans were route of administration, cost, and improvement in the ability to perform daily activities. For patients in commercial plans, the top 3 medication attributes were cost, route of administration, and frequency of administration. Within the top 2 attributes for patients in both plans, the oral route of administration and lower cost were most preferred. CONCLUSION: Medication route of administration and cost were the 2 most important considerations for patients diagnosed with PsA who were enrolled in Medicare or commercial plans with Humana. As PsA treatment choices continue to expand, considering patient preferences may improve patient adherence and treatment outcomes and should be considered when making treatment decisions for this patient population.

Clinical and demographic factors associated with change and maintenance of disease severity in a large registry of patients with rheumatoid arthritis.

BACKGROUND: We examined models to predict disease activity transitions from moderate to low or severe and associated factors in patients with rheumatoid arthritis (RA). METHODS: Data from RA patients enrolled in the Corrona registry (October 2001 to August 2014) were analyzed. Clinical Disease Activity Index (CDAI) definitions were used for low (≤10), moderate (>10 and ≤22), and severe (>22) disease activity states. A Markov model for repeated measures allowing for covariate dependence was used to model transitions between three (low, moderate, severe) states and estimate population transition probabilities. Mean sojourn times were calculated to compare length of time in particular states. Logistic regression models were used to examine impacts of covariates (time between visits, chronological year, disease duration, age) on disease states. RESULTS: Data from 29,853 patients (251,375 visits) and a sub-cohort of 9812 patients (46,534 visits) with regular visits (every 3-9 months) were analyzed. The probability of moving from moderate to low or severe disease by next visit was 47% and 18%, respectively. Patients stayed in moderate disease for mean 4.25 months (95% confidence interval: 4.18-4.32). Transition probabilities showed 20% of patients with low disease activity moved to moderate or severe disease within 6 months; >35% of patients with moderate disease remained in moderate disease after 6 months. Results were similar for the regular-visit sub-cohort. Significant interactions with prior disease state were seen with chronological year and disease duration. CONCLUSION: A substantial proportion of patients remain in moderate disease, emphasizing the need for treat-to-target strategies for RA patients.