Eustratios Bananis

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.

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.

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs

Objectives Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Methods Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. Results 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Conclusions Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. Trial registration numbers (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).

When is switching warranted among biologic therapies in rheumatoid arthritis

Switching among biologic therapies is common practice in patients with rheumatoid arthritis who have an inadequate response or intolerable adverse events. Evidence from observational studies and association guidelines supports the use of sequential biologic therapy for these reasons. Owing to recent economic pressures on healthcare budgets, patients with rheumatoid arthritis who are well controlled on and tolerant of their current biologic therapy may be switched to alternative biologics, despite limited evidence supporting this practice. Clinical research and experience suggest that TNF antagonists are not interchangeable, as meaningful differences have been observed in their efficacy and safety profiles. Additional research is needed to assess the risk:benefit ratio of specific sequences of biologic therapies and the validity of switching biologic therapies for nonclinical purposes.

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy

Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib.

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.

Relationship between clinical and patient-reported outcomes in a phase 3 trial of tofacitinib or MTX in MTX-naïve patients with rheumatoid arthritis

Objective To compare the relationship between clinical measures and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with tofacitinib or methotrexate (MTX). Methods In a phase 3 randomised controlled trial, patients (N=956) who were MTX-naïve or had received ≤3 doses were randomised and received tofacitinib 5 or 10 mg twice daily or MTX titrated to 20 mg/week. Outcomes included: per cent of patients achieving American College of Rheumatology 70% responses (ACR70), ACR50, low disease activity (LDA) by Simplified Disease Activity Index (SDAI ≤11) and Clinical Disease Activity Index (CDAI ≤10), remission by SDAI (≤3.3) and CDAI (≤2.8), patient-reported Health Assessment Questionnaire-Disability Index (HAQ-DI scores <0.5), pain and global assessment of disease activity. Results At month 6, most patients who achieved LDA/remission by one definition achieved LDA/remission with others; however, discordance between measures was greater with MTX than with tofacitinib. As expected, concordance between CDAI and SDAI responses was high. Overall, patients achieving LDA or ACR50 responses reported less improvement in PROs (HAQ-DI, pain and patient global assessment) compared with clinical measures (tender and swollen joint counts). Conclusions Variability in levels of responses between clinical outcomes and PROs should be considered when setting treat-to-target goals in patients with RA. Trial registration number NCT01039688; Post-results.

SAT0229 Herpes Zoster and Tofacitinib: The Risk of Concomitant Nonbiologic Therapy

Background Rheumatoid arthritis (RA) patients are at increased risk for herpes zoster (HZ), and treatment with tofacitinib, an oral janus kinase (JAK) inhibitor, appears to increase this risk.1 Prior analysis from the RA development programme for tofacitinib identified Japanese and Korean patients to be at increased risk within the clinical development programme.1 There is a need to understand whether patients using concomitant nonbiologic disease-modifying antirheumatic drugs (DMARDs; ie methotrexate [MTX]) are at higher risk than tofacitinib monotherapy patients. Objectives To evaluate the incidence of HZ in patients receiving tofacitinib and to investigate the incidence rates (IRs) among patients using tofacitinib monotherapy and those using concomitant nonbiologic DMARDs or corticosteroids. Methods We identified reports of serious and non-serious HZ from Phase (P)1/P2/P3 and long-term extension (LTE) studies of tofacitinib in RA patients (data cut April 2014), and calculated crude IRs for all HZ (serious and non-serious; unique patients with events per 100 patient-years [py]) with 95% CI. One of the LTE studies was ongoing at the time of the analysis (database not locked). Patients were censored at study withdrawal, development of HZ or death. In addition, within P3 studies where dose groups were balanced, we described HZ rates in stratified fashion according to concomitant nonbiologic DMARDs and baseline corticosteroid use. Results In pooled P1/P2/P3 and LTE studies (19 studies; 6192 patients; 16 839 py of exposure) HZ was reported in 636 tofacitinib-treated patients: IR 4.0 (3.7, 4.4). IRs for tofacitinib-associated HZ varied widely across regions of enrolment, being lowest in Eastern and Western Europe (2.4 [2.0, 2.9] and 3.3 [2.4, 4.40], respectively) and highest among patients enrolled in Japan/Korea: IR 8.1 (7.0, 9.4). Within P3 studies, HZ incidence varied according to tofacitinib dose and background therapy with nonbiologic DMARDs: tofacitinib 5 mg twice daily (BID) monotherapy, 14 cases (IR 2.0 [1.2, 3.3]); tofacitinib 10 mg BID monotherapy, 22 cases (IR 2.9 [1.9, 4.5]); tofacitinib 5 mg BID with nonbiologic DMARDs, 43 cases (IR 4.4 [3.2, 5.9]); tofacitinib 10 mg BID with nonbiologic DMARDs, 50 cases (IR 5.0 [3.8, 6.6]). Crude IRs for HZ in patients enrolled outside Japan/Korea were lower, but similar trends in rates, according to background nonbiologic DMARDs and tofacitinib dose, were observed. In addition, crude HZ IRs were higher in patients using corticosteroids vs those not using corticosteroids, although total exposure time for these groups was limited (Figure 1). Conclusions From univariate analysis within the P3 database of the tofacitinib RA clinical development programme, numerically higher crude IRs, with overlapping CIs, were observed for HZ in patients using higher dose of tofacitinib, combination nonbiologic DMARD therapy and corticosteroids. However, further analysis, including multivariable analysis, is necessary to thoroughly evaluate the risk of these and other factors for HZ development. References Winthrop KL, et al. Arthritis Rheumatol 2014; 66: 2675-84. Acknowledgements All aspects of this study were funded by Pfizer Inc. Editorial support was provided by Claire Cridland of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest K. Winthrop Grant/research support from: Pfizer Inc, S. Lindsey Speakers bureau: Pfizer Inc, H. Fan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gelone Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Mendelsohn Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Bananis Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Curtis Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc

THU0180 Relationship Between Different Clinical Measurements and Patient-Reported Outcomes: Results from a Phase 3 Study of Tofacitinib or Methotrexate in Methotrexate-Naïve Patients with Rheumatoid Arthritis

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives Here we compare the relationship between clinical measures and patient-reported outcomes (PROs) in patients (pts) with RA treated with tofacitinib or methotrexate (MTX). Methods MTX-naïve pts with RA from a double-blind, parallel group, Phase 3 trial (ORAL Start; NCT01039688) were randomised (2:2:1) and treated with tofacitinib 5 mg twice daily (BID) monotherapy (N=373), tofacitinib 10 mg BID monotherapy (N=397) or MTX titrated from 10 to 20 mg/week (N=186). Clinical measures included: the proportion of pts achieving ACR50 and ACR70 responses, the proportion achieving low disease activity (LDA) measured by Clinical Disease Activity Index (CDAI LDA, CDAI≤10) and Simplified Disease Activity Index (SDAI LDA, SDAI≤11), and the proportion achieving remission (REM) measured by CDAI REM (CDAI≤2.8) and SDAI REM (SDAI≤3.3). PROs included: proportion of pts achieving improvements in physical function measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, to normative values <0.5). Results At Month 6, a greater proportion of pts achieved ACR responses, LDA and REM with tofacitinib 5 mg or 10 mg BID than with MTX (Table 1). Most pts who achieved LDA and REM by one measure also achieved LDA and REM by other measures (Table 1); however, discordance was observed between different measures of LDA and REM, and appeared greater with MTX vs either tofacitinib dose (Table 1). As expected there was a high degree of concordance between CDAI LDA and SDAI LDA (Table 1) and CDAI REM and SDAI REM (Table 1). Overall, pts achieving LDA or ACR50 showed less improvement from baseline in patient-reported pain, and patient global assessment of disease compared with tender joints, swollen joints, physician global assessment of disease and HAQ-DI: pts receiving MTX showed an overall lower improvement in these PROs compared with tofacitinib 5 mg or 10 mg BID. In general, better improvements and consistency in PROs were observed in ACR50 responders compared with measures of LDA. Pts achieving ACR70, CDAI REM and SDAI REM showed similar improvements across PROs and similarly between MTX and tofacitinib. Conclusions A higher proportion of MTX-naïve pts receiving tofacitinib 5 or 10 mg BID achieved a clinical response compared with pts receiving MTX. While most pts achieve similar responses across different clinical measures, many may achieve a response in one measure but not the other. Variability of responses with clinical measures should be considered when setting treat-to-target goals in pts with RA. Acknowledgements Previously presented (Fleischmann R et al. Arthritis Rheum 2014; 66(11): S1086 abs 2488) and reproduced with permission from Arthritis and Rheumatism. This study was funded by Pfizer Inc. Editorial support, under the guidance of the authors, was provided by Amanda Pedder, of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest R. Fleischmann Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, V. Strand Consultant for: Pfizer Inc, B. Wilkinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Bananis Shareholder of: Pfizer Inc, Employee of: Pfizer Inc