Tofacitinib 5 mg Twice Daily in Patients with Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs: A Comprehensive Review of Phase 3 Efficacy and Safety.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We performed a comprehensive review of phase 3 studies of tofacitinib 5 mg twice daily (BID) (approved dose in many countries) in patients with moderate to severe RA and inadequate response to prior disease-modifying antirheumatic drugs. METHODS: A search of PubMed and ClinicalTrials.gov identified 5 studies: ORAL Solo (NCT00814307), ORAL Sync (NCT00856544), ORAL Standard (included adalimumab 40 mg once every 2 weeks; NCT00853385), ORAL Scan (NCT00847613), and ORAL Step (NCT00960440). Efficacy and safety data for tofacitinib 5 mg BID, placebo, and adalimumab were analyzed. RESULTS: Across the 5 studies, 1216 patients received tofacitinib 5 mg BID, 681 received placebo, and 204 received adalimumab. At month 3, tofacitinib demonstrated significantly higher 20%, 50%, and 70% improvement in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70, respectively) response rates, greater improvement in Health Assessment Questionnaire-Disability Index, and a higher proportion of Disease Activity Score-defined remission than placebo. Frequencies of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar for tofacitinib and placebo at month 3; serious infection events were more frequent for tofacitinib. In ORAL Standard, although not powered for formal comparisons, tofacitinib and adalimumab had numerically similar efficacy and AEs; serious AEs and serious infection events were more frequent with tofacitinib. CONCLUSIONS: Tofacitinib 5 mg BID reduced RA signs and symptoms and improved physical function versus placebo in patients with inadequate response to prior disease-modifying antirheumatic drugs. Tofacitinib 5 mg BID had a consistent, manageable safety profile across studies, with no new safety signals identified.

Efficacy and prognostic factors of treatment retention with intravenous abatacept for rheumatoid arthritis: 24-month results from an international, prospective, real-world study.

OBJECTIVES: To evaluate retention of abatacept over 24 months in patients with rheumatoid arthritis (RA) in routine clinical practice across Europe and Canada. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) was a prospective, observational, multicentre study of adult patients with moderate-to-severe RA who, at their physician's discretion, initiated treatment with intravenous abatacept. Enrolment occurred from May 2008 to December 2010, with up to 30 months of follow-up. The primary endpoint was the abatacept retention rate over 24 months. Crude abatacept retention rate was estimated using the Kaplan-Meier method. Prognostic factors of abatacept retention in patients with ≥1 prior biologic failure were derived from a Cox proportional hazards regression model, accounting for clustered data. RESULTS: A total of 1137 patients were enrolled (1573 patient-years on abatacept); most (89.2%) had experienced prior biologic failure. The overall crude abatacept retention rate at 24 months was 54.4% (95% confidence interval: 51.3, 57.4). Positivity for both rheumatoid factor and anti-cyclic citrullinated antibody, previous exposure to one or no anti-tumour necrosis factor agents, and cardiovascular comorbidity were prognostic of higher abatacept retention. Erythrocyte sedimentation rate ≥51 mm/hour and introduction of corticosteroid use at abatacept initiation were predictors of lower abatacept retention. Abatacept retention varied according to country. Abatacept was well tolerated without any unexpected safety signals. CONCLUSIONS: In a real-world setting, intravenous abatacept treatment retention was more than 50% at 24 months. The identification of prognostic factors of abatacept retention could support individualised biologic treatment strategies in patients with moderate-to-severe RA.

Prognostic factors for abatacept retention in patients who received at least one prior biologic agent: an interim analysis from the observational, prospective ACTION study.

BACKGROUND: The emergence of new therapies for the treatment of rheumatoid arthritis (RA), the paucity of head-to-head studies, and the heterogeneous nature of responses to current biologics highlight the need for the identification of prognostic factors for treatment response and retention in clinical practice. Prognostic factors for patient retention have not been explored thoroughly despite data for abatacept and other biologics being available from national registries. Real-world data from the ACTION study may supplement the findings of randomized controlled trials and show how abatacept is used in clinical practice. The aim of this interim analysis was to identify prognostic factors for abatacept retention in patients with RA who received at least one prior biologic agent. METHODS: A large, international, non-interventional cohort of patients with moderate-to-severe RA who initiated intravenous abatacept in Canada and Europe (May 2008-January 2011) enrolled in the ACTION study. Potential prognostic factors for retention in this interim analysis (data cut-off February 2012; including patients from Canada, Germany, Greece, and Italy) were baseline demographics and disease characteristics, medical history, and previous and concomitant medication. Clinically relevant variables with p ≤ 0.20 in univariate analysis and no collinearity were entered into a Cox proportional hazards regression model, adjusted for clustered data. Variables with p ≤ 0.10 were retained in the final model (backward selection). RESULTS: The multivariate model included 834 patients. Anti-cyclic citrullinated peptide (CCP) antibody positivity (hazard ratio [95% confidence interval]: 0.55 [0.40, 0.75], p < 0.001), failure of <2 prior anti-tumor necrosis factors (TNFs) (0.71 [0.56, 0.90], p = 0.005 versus ≥2 prior anti-TNFs), and cardiovascular comorbidity at abatacept initiation (0.48 [0.28, 0.83], p = 0.009) were associated with lower risk of abatacept discontinuation. Patients in Greece and Italy were less likely to discontinue abatacept than patients in Germany and Canada (Greece: 0.30 [0.16, 0.58]; Italy: 0.50 [0.33, 0.76]; Canada: 1.04 [0.78, 1.40], p < 0.001 versus Germany). CONCLUSIONS: Real-world prognostic factors for abatacept retention include anti-CCP positivity and fewer prior anti-TNF failures. Differences in retention rates between countries may reflect differences in healthcare systems. The finding that abatacept has potential advantages in patients with cardiovascular comorbidities needs to be confirmed in further research.

Real-world effectiveness of abatacept for rheumatoid arthritis treatment in European and Canadian populations: a 6-month interim analysis of the 2-year, observational, prospective ACTION study.

BACKGROUND: Discontinuation of rheumatoid arthritis (RA) treatment for lack or loss of initial response, tolerability issues, or development of antibodies against the therapeutic agent remains a challenge in clinical practice. Here we present a 6-month interim analysis of a 2-year prospective observational trial in Europe and Canada aiming to assess the real-world effectiveness, safety, and tolerability of intravenous abatacept for the treatment of moderate-to-severe RA. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) is a prospective, observational study assessing effectiveness, safety, and tolerability of abatacept in patients with RA enrolled in Europe and Canada between May 2008 and January 2011. The patient population was divided into two groups: biologic naïve ('first-line') patients and patients who had previously failed treatment with at least one biologic agent ('second-line'). Retention rates were calculated using Kaplan-Meier curve estimates. Effectiveness was measured using European League Against Rheumatism (EULAR) response criteria, the 28-item Disease Activity Score, the Clinical Disease Activity Index (CDAI), and physical function, as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Serious adverse events (SAEs) were reported for all enrolled patients. RESULTS: Of 1138 consecutively enrolled patients, 1114 and 1079 patients were evaluable for retention and effectiveness, respectively. Overall, retention rates were 88.6% (95% confidence interval [CI]: 86.4, 90.4); 67.4% of patients achieved good/moderate EULAR response; 32.8% had a CDAI Low Disease Activity State (LDAS); and 44.7% a HAQ-DI response. Retention rates among first- and second-line patients were 93.0% (95% CI: 85.9, 96.6) and 88.1% (95% CI: 85.7, 90.0), respectively. The percentage of patients achieving CDAI LDAS was 40.0% (95% CI: 26.4, 53.6) for first- and 32.2% (95% CI: 28.4, 36.0) for second-line patients and the proportion achieving a HAQ-DI response was 60.3% (95% CI: 47.8, 72.9) versus 43.1% (95% CI: 39.0, 47.2), respectively. The incidence of SAEs was 4.7%. CONCLUSIONS: Evidence from this 6-month interim analysis suggests that abatacept offers an effective and well-tolerated treatment option for patients with RA, including those who have previously failed anti-tumor necrosis factor treatment. In addition, higher retention rates and effectiveness outcomes were observed when abatacept treatment was initiated earlier in the course of the disease.

Treating rheumatoid arthritis to target: a Canadian patient survey.

BACKGROUND: Recently, many countries, including Canada, evaluated rheumatologists' acceptance and agreement with a set of 10 Treat to Target (T2T) recommendations for rheumatoid arthritis (RA), developed by an international task force. In this study, the Canadian T2T steering committee evaluated how Canadian patients with RA perceive these recommendations. OBJECTIVES: The objectives of this study were to assess the current state of RA management in Canada from a patient perspective and to assess whether and to what extent Canadians with RA agree with each of the 10 T2T recommendations and to compare the results with a previous survey completed by physicians. METHODS: Participating rheumatologists were asked to invite consecutive RA patients to complete a 20-question survey. The survey was designed to assess relevant sociodemographic variables, the current treatment, and the approach to RA management as seen from the patient's perspective, as well as their agreement with the T2T recommendations. RESULTS: A total of 959 patients (77% were female) were recruited by 22 participating rheumatologists from 6 Canadian provinces. Patients had a mean age of 59.1 years and mean disease duration of 12.9 years. Approximately 72% of patients were on methotrexate (76.1% combination therapy), and 36.7% were treated with biologics (6.4% monotherapy, 30.3% combination therapy). The agreement with T2T recommendations ranged from 8.6 for recommendation 4 (frequency of adjustment of drug therapy) to 9.5 for recommendation 8 (maintenance of treatment targets). These results are comparable to a previous physicians' survey except that there was more acceptance on the part of patients for more frequent visits (recommendation 5; patient agreement score was 9.06 vs physician agreement score of 6.92) and evaluations for adjustments of therapy (recommendation 6 patient agreement score was 9.39 vs physician agreement score of 7.49) to achieve the stated goal. CONCLUSIONS: The results of this survey showed that Canadian patients are being treated for their RA according to the published treatment recommendations with combination disease-modifying antirheumatic drugs and biologics and a small percentage with oral corticosteroids. The majority of patients seems to be satisfied with their management and is in agreement with the T2T recommendations, although they tended to place greater emphasis than did physicians on flexibility of visit frequency and detailed assessments.

Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial.

BACKGROUND: Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. METHODS: Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). RESULTS: The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo: -0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. CONCLUSIONS: Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice.

OBJECTIVE: To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis). METHODS: Patients-categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) -received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses. RESULTS: Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission. CONCLUSIONS: In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns.

Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting.

OBJECTIVE: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone. METHODS: A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded. RESULTS: A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period. CONCLUSION: This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.

A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of controlled-release (CR) tramadol and immediate-release (IR) tramadol in patients with moderate or greater intensity chronic noncancer pain. METHODS: A total of 122 patients underwent washout from all opioids 2 to 7 days before randomization to 1 of 2 groups: active CR tramadol 200 mg every morning plus placebo IR tramadol 50 mg every 4 to 6 hours PRN rescue, or placebo CR tramadol 200 mg every morning plus active IR tramadol 50 mg every 4 to 6 hours PRN rescue. After 2 weeks, the doses were increased to CR tramadol 400 mg or placebo and IR tramadol 100 mg every 4 to 6 hours PRN or placebo, as rescue. After 4 weeks in the first phase, patients crossed over to the alternative treatment for another 4 weeks. Pain intensity (100-mm visual analog scale [VAS] and 5-point ordinal scales) was assessed twice daily in diaries. Pain intensity, Pain and Disability Index (PDI; 0-10 ordinal scale), Pain and Sleep Questionnaire (100-mm VAS), and analgesic effectiveness (7-point ordinal scale) were assessed at biweekly clinic visits. RESULTS: Sixty-five patients (35 men, 30 women) completed the study. Mean (SD) age was 56.5 (12.7) years; mean (SD) weight was 82.0 (18.5) kg. Daily diary pain intensity (mean [SD]) was significantly lower in the CR tramadol group than in the IR tramadol group in the last 2 weeks of each phase (completers: VAS, 29.9 [20.5] vs 36.2 [20.4] mm, P < 0.001; ordinal scale, 1.41 [0.7] vs 1.64 [0.6], P < 0.001; intent-to-treat [ITT] population: VAS, 32.5 [22.9] vs 38.6 [21.2] mm, P < 0.003; ordinal scale, 1.50 [0.8] vs 1.72 [0.7], P < 0.002). The overall pain intensity scores from the daily diary were also significantly better with CR tramadol for both the completers and ITT. Similar results were obtained on the biweekly VAS pain intensity questionnaire. No differences were found between treatments in total PDI or overall Pain and Sleep scores in either population. For the completers, both patients and investigators rated effectiveness higher for CR tramadol than for IR tramadol (P < 0.004 and P < 0.008 for patients and investigators, respectively). CONCLUSION: This study reports significant improvement in pain intensity with CR tramadol as compared with IR tramadol.

The Effects of Noncompliance to Prolia (Denosumab) on the Changes in Bone Mineral Density: A Retrospective Review.

Although denosumab (Prolia) has been shown to be a safe and efficacious therapy for osteoporotic patients in numerous clinical trials, few studies have determined its effectiveness in real world clinical practice. A retrospective review of patients prescribed Prolia assessing the impact that noncompliance from the regular dosing regimen of six months for denosumab has on bone mineral density (BMD) was performed. 924 patient records were reviewed between August 2012 and September 2013 with 436 patients meeting the eligibility criteria. Patients were divided into three groups: subsequent injection of denosumab (1) less than five months, (2) between five and seven months, and (3) more than seven months after their initial subcutaneous injection. A multivariable regression analysis was conducted comparing the differences among the three prespecified groups in BMD change (g/cm(2)) after one year of denosumab therapy at both the lumbar spine (LS) and femoral neck (FN). The differences in LS and FN BMD have shown that the relationship between the timing of drug administration in these three groups and change in BMD over 1 year was not clinically or statistically significant (p > 0.05). A follow-up study with a larger sample size and longer follow-up duration is required to further characterize this relationship.

Decreased use of glucocorticoids in biological-experienced patients with rheumatoid arthritis who initiated intravenous abatacept: results from the 2-year ACTION study.

INTRODUCTION: Prolonged glucocorticoid use may increase the risk of adverse safety outcomes, including cardiovascular events. The European League Against Rheumatism and the Canadian Rheumatology Association advise tapering glucocorticoid dose as rapidly as clinically feasible. There is a paucity of published data on RA that adequately describe concomitant treatment patterns. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) is a non-interventional cohort study of patients from Europe and Canada that investigated the long-term retention of intravenous abatacept in clinical practice. We assessed concomitant glucocorticoids in patients with established RA who had participated in ACTION and received ≥1 biological agent prior to abatacept initiation. RESULTS: The analysis included 1009 patients. Glucocorticoids were prescribed at abatacept initiation in 734 (72.7%) patients at a median 7.5 mg/day dose (n=692). Of the patients who remained on abatacept at 24 months, 40.7% were able to decrease their dose of glucocorticoids, including 26.9% who decreased their dose from >5 mg/day to ≤5 mg/day. CONCLUSION: Reduction and/or cessation of glucocorticoid therapy is possible with intravenous abatacept in clinical practice.

Biologic Treatment Registry Across Canada (BioTRAC): a multicentre, prospective, observational study of patients treated with infliximab for ankylosing spondylitis.

OBJECTIVES: To describe the profile of patients with ankylosing spondylitis (AS) treated with infliximab in Canadian routine care and to assess the effectiveness and safety of infliximab in real world. SETTING: 46 primary care rheumatology practices across Canada. PARTICIPANTS: 303 biological-naïve patients with AS or patients previously treated with a biological for <6 months and who were eligible for infliximab treatment as per routine care within the Biologic Treatment Registry Across Canada (BioTRAC). INTERVENTION: Not applicable (non-interventional study). PRIMARY AND SECONDARY OUTCOMES: Effectiveness was assessed with changes in disease parameters (AS Disease Activity Score (ASDAS), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Health Assessment Questionnaire Disease Index (HAQ-DI), physician global assessment of disease activity (MDGA), patient global disease activity (PtGA), back pain, C-reactive protein, erythrocyte sedimentation rate (ESR), morning stiffness). Safety was assessed with the incidence of adverse events (AEs). RESULTS: Of the 303 patients included, 44.6% were enrolled in 2005-2007 and 55.4% in 2008-2013. Patients enrolled in 2005-2007 had significantly higher MDGA and ESR at baseline while all other disease parameters examined were numerically higher with the exception of PtGA. Treatment with infliximab significantly (p<0.001) improved all disease parameters over time in both groups. At 6 months, 56% and 31% of patients achieved clinically important (change≥1.1) and major (change≥2.0) improvement in ASDAS, respectively; at 48 months, these proportions increased to 75% and 50%, respectively. Among patients unemployed due to disability at baseline, 12.1% returned to work (mean Kaplan-Meier (KM)-based time=38.8 months). The estimated retention rate at 12 and 24 months was 78.3% and 60.1%, respectively. The profile and incidence of AEs were comparable to data previously reported for tumour necrosis factor-α inhibitors. CONCLUSIONS: Characteristics of patients with AS at infliximab initiation changed over time towards lower disease activity and shorter disease duration. Infliximab treatment significantly reduced disease activity independent of treatment initiation year, although patients enrolled in recent years achieved lower disease activity over 48 months. TRIAL REGISTRATION NUMBER: NCT00741793.

Upper gastrointestinal tract safety of daily oral risedronate in patients taking NSAIDs: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the frequency of upper gastrointestinal (GI) tract adverse events associated with risedronate during two (2-year) randomized, double-blind, parallel-group, placebo-controlled studies. PATIENTS AND METHODS: Male and female patients aged 40 to 80 years with mild to moderate medial-compartment knee osteoarthritis were enrolled. Data were pooled and analyzed for risedronate at 5 mg and at 15 mg once daily and compared with placebo. The results of the once-weekly dosages (35 or 50 mg) were assessed separately. RESULTS: A total of 2483 patients were randomized: 622 to placebo, 628 to risedronate at 5 mg/d, 609 to risedronate at 15 mg/d, 310 to risedronate at 35 mg once weekly, and 314 to risedronate at 50 mg once weekly. During the study, 77% of patients were regular nonsteroidal anti-inflammatory drug (NSAID) and/or analgesic users (defined as those who took medication 23 days per week), and 68% were regular NSAID users. The number of upper GI tract adverse events was similar between treatment groups, with no dose-related response: 161 for placebo, 176 for rlsedronate at 5 mg/d, and 150 for risedronate at 15 mg/d. The time to the first upper GI tract adverse event was similar between treatment groups. There was no difference in the frequency of upper GI tract adverse events In risedronate-treated patients compared with patients who were regular users of NSAIDs or NSAIDs and/or analgesics. Findings were similar for those in the once-weekly risedronate groups. CONCLUSION: The results of this study show that risedronate regimens at 5 mg/d or 15 mg/d as well as once weekly at 35 mg or 50 mg are not associated with an increased frequency of upper GI tract adverse events, even in patients who have an increased risk for such events.

Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. OBJECTIVE: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. DESIGN: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: 20 centers in the United States and Canada. PATIENTS: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. INTERVENTION: Leflunomide or matching placebo added to existing methotrexate therapy. MEASUREMENTS: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. RESULTS: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. CONCLUSIONS: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Incidence and Management of Infusion Reactions to Infliximab in a Prospective Real-world Community Registry.

OBJECTIVE: Infliximab (IFX) is a therapeutic monoclonal antibody targeting tumor necrosis factor-α indicated in the treatment of chronic inflammatory diseases. IFX is administered by intravenous infusion and may be associated with different types of infusion reactions. METHODS: RemiTRAC Infusion (NCT00723905) is a Canadian observational registry in which patients receiving IFX are followed prospectively to document premedication use, adverse events, infusion reactions, and the management of infusion reactions. The primary endpoint was to assess factors associated with infusion reactions. RESULTS: There were 1632 patients enrolled and 24,852 infusions recorded. Most patients (63.1%) were treated for rheumatologic conditions such as rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. Of the 1632 patients, 201 (12.3%) reported at least 1 infusion reaction. Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate in severity (95%). The most common infusion reactions were pruritus (19.9%), flushing (9.9%), or dyspnea (6.2%). Multivariate analysis showed that antihistamines premedication, number of previous infusion reactions, and female sex were significantly associated with an increased incidence of infusion reactions (p < 0.0011). The use of any concomitant immunosuppressant or corticosteroids did not influence the incidence of infusion reactions. Antihistamine premedication was associated with an increased incidence of infusion reactions (OR 1.58, p = 0.0007). CONCLUSION: This registry shows that in community-based infusion clinics, infusion reactions to IFX are uncommon and mild to moderate in nature. Antihistamines, intravenous steroids, and acetaminophen are widely used as preventative premedication, although this study showed an absence of benefit with their use.

Persistence with denosumab therapy among osteoporotic women in the Canadian patient-support program.

OBJECTIVE: The objective of this study was to evaluate persistence with denosumab among postmenopausal women with osteoporosis participating in the Canadian patient-support program (ProVital * ). Denosumab is an injectable therapeutic option for osteoporosis that is administered subcutaneously every 6 months. METHODS: ProVital, a support program in which patients voluntarily enroll, provides next injection reminder calls and educational material. A retrospective database analysis of patient self-reported data was conducted among osteoporotic women aged ≥50 who enrolled in the ProVital program and received their first denosumab injection between August 2010 and June 2011. To achieve 12 month persistence patients had to receive at least two denosumab injections, and to achieve 24 month persistence patients had to receive at least four denosumab injections, with consecutive injections no more than 6 months + 8 weeks apart. Logistic regression analysis was used to identify predictors of persistence. RESULTS: A total of 1676 patients (mean age 74 years) were included. The 12 month persistence with denosumab was 81.6% (1367/1676 patients), and the 24 month persistence was 59.1% (991/1676 patients). Characteristics associated with both 12 and 24 month persistence were possession of private medication insurance and residence in Quebec. Additionally, age greater than 75, previous postmenopausal osteoporosis medication use, and fracture were associated with 24 month persistence. LIMITATIONS: Patient enrollment in the program was voluntary, so there may be selection bias for the patient population included in this study. Also, this study did not have a control group of patients who were not enrolled in a patient support program. CONCLUSIONS: The persistence with denosumab among patients enrolled in the program was higher than historical persistence with oral bisphosphonates, and similar to persistence of patients in an education program taking teriparatide, patients taking bisphosphonates in a pharmaceutical care program, and two observational studies of denosumab.

Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population.

OBJECTIVE: To describe the rate of concomitant oral corticosteroid use at antitumour necrosis factor (TNF) initiation and at disease remission, and to assess its effect on incidence of infection and sustainability of remission among patients with rheumatoid arthritis (RA) treated with infliximab in Canadian routine care. METHODS: Biological naïve patients with RA followed in the Biologic Treatment Registry Across Canada (BioTRAC) were included. The time-dependent association between corticosteroid dose (no use, ≤5 mg/day, >5 mg/day) and the incidence of first infection, while considering possible confounders, remission sustainability and the incidence of subsequent infections were assessed with Cox regression. RESULTS: 838 patients were included; mean (SD) baseline age and disease duration were 55.6 (13.5) and 10.5 (9.8) years, respectively. After a mean (SD) of 51.3 (43.6) months, the total incidence of adverse events (AEs) and infections were 110.2 and 19.6 per 100 person-years (PY), respectively. In multivariate analysis, the HR (95% CI) for acquiring an infection was 2.48 (1.24 to 4.98) with >5 mg/day of corticosteroids versus no corticosteroids. Similarly, ≤5 mg/day of corticosteroids was associated with increased hazard for infection (2.12 (0.97 to 4.66)). Despite DAS28 (disease activity score 28) or Clinical Disease Activity Index (CDAI) remission, corticosteroids were continued in 16.4% and 16.7% of cases, respectively. Continued corticosteroid treatment was not associated with sustainability of remission (HRDAS28 (95% CI) 1.40 (0.95 to 2.06); HRCDAI 1.19 (0.75 to 1.88)), however, it had a significant impact on development of infection (HRDAS28 (95% CI) 1.78 (1.00 to 3.19); HRCDAI 2.38 (1.14 to 4.99)). CONCLUSIONS: Oral corticosteroid treatment was associated with increased risk of development of infection without impacting sustainability of remission. These results support the notion that corticosteroids should be used concomitantly with anti-TNF for the shortest period possible to achieve remission, and then tapered. TRIAL REGISTRATION NUMBER: NCT00741793.

Comparison of tocilizumab as monotherapy or with add-on disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and inadequate responses to previous treatments: an open-label study close to clinical practice.

This was an exploratory analysis comparing the safety and efficacy of tocilizumab monotherapy with those of tocilizumab in combination with disease-modifying anti-rheumatic drugs (DMARDs). Data were from a single-arm, nonrandomized, open-label, 24-week study in patients with rheumatoid arthritis in which patients with inadequate responses to DMARDs or tumor necrosis factor-α inhibitors received tocilizumab 8 mg/kg intravenously every 4 weeks plus methotrexate/other DMARD(s) combination therapy. If they were intolerant of methotrexate/other DMARD, patients received tocilizumab monotherapy. Effectiveness endpoints included American College of Rheumatology (ACR) responses (ACR20/50/70/90) and disease activity score using 28 joints (DAS28). Of 1,681 patients, 239 received tocilizumab monotherapy, and 1,442 received combination therapy. Methotrexate was the most common DMARD (79%) used in combination therapy. The frequency of adverse events (AEs), serious AEs, and AEs leading to withdrawal were similar between tocilizumab monotherapy (82.4, 7.9, and 5.4%, respectively) and combination therapy (76.6, 7.8, and 5.1%, respectively). No differences in ACR20/50/70/90 responses were observed between treatment groups (66.9%/43.5%/23.8%/10.0% vs 66.9%/47.2%/26.8%/8.5%, respectively; p > 0.12 for all individual comparisons, including ACR50 propensity score analyses). The decrease in DAS28 was also similar between treatment groups (mean ± standard deviation: -3.41 ± 1.49 for tocilizumab monotherapy vs -3.43 ± 1.43 for combination therapy; p > 0.33 all analyses, including propensity score analyses). Tocilizumab had a comparable safety profile, and was similarly effective, when used as monotherapy or in combination with DMARDs in a broad population of patients with rheumatoid arthritis.

Assessing the Reliability of a Semiautomated Segmentation Algorithm for Quantifying Erosions in the Metacarpophalangeal Joints of Patients with Rheumatoid Arthritis.

OBJECTIVE: Assess the reliability of early erosions in rheumatoid arthritis (EERA) software for quantifying erosive damage to the metacarpophalangeal joints of patients with rheumatoid arthritis (RA). METHODS: One hundred magnetic resonance image sets from 68 patients with early referral RA were evaluated. Reliability was assessed using 95% limits of agreement and intraclass correlation coefficient (ICC) with 95% CI. RESULTS: Limits of agreement linearly depended on erosion volume: 0.44× between readers and 0.19× within readers. Interrater ICC was 0.976 (95% CI 0.965-0.984) and intrarater ICC was 0.996 (95% CI 0.994-0.997). CONCLUSION: EERA is highly reproducible for quantifying erosions in patients with early RA.

Effectiveness and safety of infliximab in rheumatoid arthritis: analysis from a Canadian multicenter prospective observational registry.

OBJECTIVE: To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab in Canadian routine care and to assess the real-world effectiveness and safety of infliximab. METHODS: Biologics-naive RA patients from the Biologic Treatment Registry Across Canada were stratified based on their enrollment year. Effectiveness was assessed with the changes in clinical/laboratory parameters and patient-reported outcomes and the achievement of minimal disease activity and remission. Safety was assessed with the incidence of treatment-emergent adverse events (AEs). RESULTS: Among 628 patients, 45.9%, 34.6%, and 19.6% were enrolled between 2002-2005, 2005-2008, and 2008-2011, respectively. Patients recruited in more recent years had significantly lower Disease Activity Score with a 28-joint count using the C-reactive protein level (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), swollen joint count in 28 joints, tender joint count in 28 joints, physician's global assessment of disease activity, patient's global assessment of disease activity, Health Assessment Questionnaire disability index, pain, erythrocyte sedimentation rate, and CRP level (P < 0.01 for all). Patient management also changed with a trend to initiate infliximab after failure of fewer disease-modifying antirheumatic drugs (DMARDs). Six-month treatment with infliximab resulted in statistically significant and clinically important improvements in all disease parameters examined, which were sustained over 36 months. The cumulative probability of achieving remission by 36 months, as defined by the DAS28, SDAI, and CDAI, was 56.2 (95% confidence interval [95% CI] 47.8-64.8), 31.0 (95% CI 23.8-39.8), and 36.2 (95% CI 28.5-45.3), respectively, which was significantly greater in patients with lower baseline disease activity. The profile and incidence of AEs were comparable to data previously reported for tumor necrosis factor α inhibitors. CONCLUSION: RA patient characteristics at infliximab initiation changed over time toward lower disease activity. Furthermore, a trend to treat patients with fewer DMARDs before initiation of infliximab was observed. However, treatment with infliximab was effective in significantly reducing disease activity independent of the treatment initiation year.