Effectiveness and Safety of Tofacitinib in Canadian Patients With Rheumatoid Arthritis: Primary Results From a Prospective Observational Study.

OBJECTIVE: The Canadian Tofacitinib for Rheumatoid Arthritis Observational (CANTORAL) is the first Canadian prospective, observational study assessing tofacitinib. The objective was to assess effectiveness and safety for moderate to severe rheumatoid arthritis (RA). Coprimary and secondary outcomes are reported from an interim analysis. METHODS: Patients initiating tofacitinib from October 2017 to July 2020 were enrolled from 45 Canadian sites. Coprimary outcomes (month 6) included the Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission. Secondary outcomes (to month 18) included the CDAI and the 4-variable Disease Activity Score in 28 joints (DAS28) using the erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level to define LDA and remission; the proportions of patients achieving mild pain (visual analog scale <20 mm), and moderate (≥30%) and substantial (≥50%) pain improvements; and the proportions of patients achieving a Health Assessment Questionnaire disability index (HAQ DI) score greater or equal to normative values (≤0.25) and a HAQ DI score greater or equal to minimum clinically important difference (MCID) (≥0.22). Safety was assessed to month 36. RESULTS: Of 504 patients initiating tofacitinib, 44.4% received concomitant methotrexate. At month 6, 52.9% and 15.4% of patients were in CDAI-defined LDA and remission, respectively; a similar proportion of patients achieved outcomes by month 3 (first post-baseline assessment). By month 3, 27.2% and 41.7% of patients, respectively, were in DAS28-ESR-defined LDA and DAS28-CRP <3.2; 14.7% and 25.8% achieved DAS28-ESR remission and DAS28-CRP <2.6. By month 3, mild pain and moderate and substantial pain improvements occurred in 29.6%, 55.6%, and 42.9% of patients, respectively; 19.9% and 53.7% of patients achieved a HAQ DI score greater than or equal to normative values and a HAQ DI score greater than or equal to MCID, respectively. Outcomes were generally maintained to month 18. Incidence rates (events per 100 patient-years) for treatment-emergent adverse events (AEs), serious AEs, and discontinuations due to AEs were 126.8, 11.9, and 14.5, respectively, and AEs of special interest were infrequent. CONCLUSION: Tofacitinib was associated with early and sustained improvement in RA signs and symptoms in real-world patients. Effectiveness and safety were consistent with the established tofacitinib clinical profile.

Prospective observational study to evaluate the use of musculoskeletal ultrasonography in rheumatoid arthritis management: the ECHO study.

OBJECTIVES: Since the creation of the Canadian Rheumatology Ultrasonography Society, an increasing number of rheumatologists has been trained in the use of musculoskeletal US (MSUS). We compared the effectiveness of MSUS to routine care (RC) as a disease management tool in patients with moderate-to-severe RA requiring a treatment change due to lack of efficacy. The predictive value of MSUS was also assessed. METHODS: This was a prospective, two-cohort, quasi-experimental study. Patients were managed either with MSUS (within the Canadian Rheumatology Ultrasonography Society) or as per RC for up to 1 year. Main outcomes included Clinical Disease Activity Index low disease activity/remission, DAS28 low disease activity/remission, MSUS scores, patient satisfaction and perception of participation in disease management. RESULTS: A total of 383 patients were enrolled (MSUS: n = 171; RC: n = 212). At baseline, a greater proportion of MSUS patients were treated with a biologic DMARD (50.3 vs 36.8%; P = 0.008) while more patients treated per RC received a non-biologic DMARD (84.2 vs 91.5%; P = 0.027). During follow-up, a greater number of RA treatment modifications was applied in the MSUS group compared with RC [adjusted incidence rate ratio (95% CI): 1.4 (1.1, 1.8)], including steroids, non-biologic DMARDs and biologic DMARDs. Regarding clinical and patient-reported outcomes, no remarkable differences were observed between groups. However, throughout the study, 50-80% of MSUS patients in clinical remission has a MSUS synovitis score of ≥1, and 37-73% an erosion score of ≥1. Significant associations were observed between baseline synovitis and joint erosion during follow-up. CONCLUSION: MSUS assessments can be useful in detecting subclinical levels of inflammation and predicting future joint deterioration, thus allowing optimization of RA treatment and patient care.

An open-label randomized controlled trial of DMARD withdrawal in RA patients achieving therapeutic response with certolizumab pegol combined with DMARDs.

OBJECTIVES: The objective of this trial was to compare effectiveness of certolizumab pegol added to conventional synthetic DMARDs (csDMARDs) in RA patients, followed by continuing vs discontinuing background csDMARDs after treatment response. METHODS: Patients with active RA who had certolizumab pegol added to their existing csDMARD regimen due to inadequate response were eligible. At 3 or 6 months, patients who achieved a change (Δ) in DAS28 of ⩾1.2 were randomized to continue combination therapy (COMBO) or withdraw csDMARD therapy (MONO) (unblinded). The primary outcome was non-inferiority of stopping vs continuing csDMARD(s) in terms of maintaining ΔDAS28 ⩾ 1.2 or achieving DAS28 low disease activity at 18 months (non-inferiority margin: 15 percentile units). RESULTS: A total of 125 patients were enrolled, 88 randomized to COMBO (n = 43) or MONO (n = 45). No significant differences were observed between groups in baseline age, gender, race, RF status or prior biologics (16% vs 11%). Although the rate of ΔDAS28 ⩾ 1.2 and/or DAS28 low disease activity achievement at 18 months was clinically comparable between the two groups (72% vs 69%), non-inferiority assumptions were not met [absolute risk difference (upper limit of 90% CI): 2.6% (19.1%)]. Similar baseline-adjusted improvements were seen in DAS28 (COMBO vs MONO: -2.3 vs -2.1; P = 0.49) and all endpoints were not statistically different including 59% vs 56% achieved DAS28 low disease activity, 69% vs 59% ΔDAS28 ⩾ 1.2, and 41% each remission. CONCLUSION: Among RA patients achieving a therapeutic response on combination therapy with certolizumab pegol and csDMARDs, withdrawing csDMARDs was not non-inferior to maintaining csDMARDs but improvements were sustained in both groups at 18 months.

Healthcare Resource Utilization and Cost of Invasive Meningococcal Disease in Ontario, Canada.

BACKGROUND: Invasive meningococcal disease (IMD) is associated with significant morbidity and mortality, thus remaining a concern for healthcare providers and the public. Evidence of the longitudinal burden of IMD and associated costs are scarce. Here we have evaluated the healthcare utilization and cost associated with hospitalized IMD cases in Ontario, Canada. METHODS: Observational cohort study utilizing the Ontario provincial claims databases, comprising: (1) individuals hospitalized with IMD between January 1995 and June 2012 and (2) age-, gender- and area-matched non-IMD controls (1:20 ratio). IMD cases were identified through diagnostic codes from hospitalization data and medical services claims. Costs are presented in Canadian dollars. RESULTS: Nine-hundred twelve IMD cases and 18,221 non-IMD controls were included. Over 5 years of follow-up, 27% of IMD cases (excluding initial hospitalization and 30-day acute phase) versus 15% of non-IMD controls (P < 0.001) were hospitalized. Compared with controls, IMD cases were more likely to receive alternative level of care (6.7% vs. 1.1%; P < 0.001) or visit the intensive care unit (49.2% vs. 2.4%; P < 0.001), and were associated with significantly higher mean hospitalization cost per case ($40,075 vs. $2827; P < 0.001). The hospitalization cost per case remained significantly higher when excluding the initial hospitalization and acute phase ($9867 vs. $3312; P < 0.001). The mean total cost per IMD case, including medications, hospitalization and medical services, was $45,768-$52,631 ($13,520-$23,789 excluding initial hospitalization and acute phase), for an overall cost (all cases during total follow-up) of $41,740,142-$47,999,289. CONCLUSIONS: In addition to its clinical burden, IMD is associated with significant economic burden to the public health system.

The Burden of Illness Related to Chronic Obstructive Pulmonary Disease Exacerbations in Québec, Canada.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) prevalence in Canada has risen over time. COPD-related exacerbations contribute to the increased health care utilization (HCU) in this population. This study investigated the impact of exacerbations on COPD-related HCU. METHODS: This retrospective observational cohort study used patient data from the Québec provincial health insurance databases. Eligible patients with a new HCU claim with a diagnostic billing for COPD during 2001-2010 were followed until March 31, 2011. Exacerbation rates and time to first exacerbation were assessed. Unadjusted analyses and multivariable models compared the rate of HCU by exacerbation classification (any [moderate/severe], moderate, or severe). RESULTS: The exacerbation event rate in patients with an exacerbation was 34.3 events/100 patient-years (22.7 for moderate exacerbations and 11.6 for severe exacerbations). Median time to first exacerbation of any classification was 37 months. In unadjusted analyses, COPD-related HCU significantly increased with exacerbation severity. In the multivariable, HCU rates were significantly higher after exacerbation versus before exacerbation (p < 0.01) for patients with an exacerbation or moderate exacerbations. For severe exacerbations, general practitioner, respiratory specialist, emergency room, and hospital visits were significantly higher after exacerbation versus before exacerbation (p < 0.001). CONCLUSIONS: Exacerbations were associated with increased HCU, which was more pronounced for patients with severe exacerbations. Interventions to reduce the risk of exacerbations in patients with COPD may reduce disease burden.

Long-term impact of adherence to oral bisphosphonates on osteoporotic fracture incidence.

Adherence to osteoporosis treatments is a critical parameter resulting in suboptimal effectiveness in real-life practice. The long-term effect of adherence on fracture risk has not been assessed. This was a retrospective study using provincial health insurance claims databases to assess the association between adherence to oral bisphosphonates (OBP) and incidence of osteoporotic fractures in all Ontario patients with osteoporosis between April 1996 and December 2009. Multivariate logistic regression models were used to assess the association between OBP adherence and fracture risk. Treatment duration was classified into 2-year intervals. Compliance was estimated with the medication possession ratio (MPR), and persistence was defined as the length of continuous therapy without a gap in refills >30 days. The study cohort was composed of 636,114 patients, among whom 36.1% were prescribed OBPs for 0 to 2 years, 19.7% for 2 to 4 years, 15.1% for 4 to 6 years, 12% for 6 to 8 years, 9.1% for 8 to 10 years, 6.1% for 10 to 12 years, and 1.9% for 12 to 14 years. Overall, the mean (SD) compliance for the cohort was 0.72 (0.30) with 53.5% of the patients having compliance >80% and 24.6% being persistent with treatment during the 14-year follow-up period. Significant associations between high adherence and reduced fracture risk over the entire 14-year period were observed; the overall odds ratio for categorical compliance (MPR >80% or MPR ≤80%), continuous compliance, and persistence were 0.909 (95% confidence interval [CI] 0.893-0.925), 0.918 (95% CI 0.893-0.944), and 0.804 (95% CI 0.787-0.821), respectively. In conclusion, adherence to OBP in osteoporosis management is suboptimal in a real-life setting. A significant positive association exists between poor adherence and increased risk of osteoporotic fractures, which becomes augmented with longer treatment duration.

A Randomized Trial Assessing the Effectiveness of Ezetimibe in South Asian Canadians with Coronary Artery Disease or Diabetes: The INFINITY Study.

Background. There is a paucity of data regarding the effectiveness and safety of lipid-lowering treatments among South-Asian patients. Methods. Sixty-four South-Asian Canadians with coronary artery disease or diabetes and persistent hypercholesterolemia on statin therapy, were randomized to ezetimibe 10 mg/day co-administered with statin therapy (EZE + Statin) or doubling their current statin dose (STAT(2)). Primary outcome was the proportion of patients achieving target LDL-C (<2.0 mmol/L) after 6 weeks. Secondary outcomes included the change in lipid profile and the incidence of treatment-emergent adverse events through 12 weeks. Exploratory markers for vascular inflammation were assessed at baseline and 12 weeks. Results. At 6 weeks, the primary outcome was significantly higher among the EZE + Statin patients (68% versus 36%; P = 0.031) with an OR (95% CI) of 3.97 (1.19, 13.18) upon accounting for baseline LDL-C and adjusting for age. At 12 weeks, 76% of EZE + Statin patients achieved target LDL-C compared to 48% (P = 0.047) of the STAT(2) patients (adjusted OR (95% CI) = 3.31 (1.01,10.89)). No significant between-group differences in exploratory markers were observed with the exception of CRP. Conclusions. Patients receiving ezetimibe and statin were more likely to achieve target LDL-C after 6 and 12 weeks compared to patients doubling their statin dose. Ezetimibe/statin combination therapy was well tolerated among this cohort of South-Asian Canadians, without safety concerns.

Prevalence of patient-reported comorbidities in early and established psoriatic arthritis cohorts.

The aim of this study is to describe the comorbidity profile in patients with early and established psoriatic arthritis (PsA). Patients with PsA were selected from a registry of patients with psoriasis in Newfoundland. Patients with a diagnosis of psoriasis according to the CASPAR classification criteria are entered in the registry at the time of diagnosis, questioned on their medical history, and are followed indefinitely. Patients who were diagnosed with PsA within the last 2 years were included in the early PsA cohort, whereas the established cohort was comprised of patients with a diagnosis for ≥2 years. The general population of Newfoundland without psoriasis or PsA was used as external standard to conduct age- and gender-adjusted comparison of the comorbidity profile of the PsA cohorts to the general population. A total of 108 (65.5%) and 57 (34.5%) patients were included in the established and early PsA cohort, respectively. Patients with early and established PsA had significantly higher age- and gender-adjusted prevalence of hypertension, diabetes, depression, Crohn's disease, and chronic obstructive pulmonary disease. In addition, in the early PsA cohort, the age-adjusted prevalence of coronary heart disease and angina was significantly higher when compared to the general population. Distinct comorbidities are associated with PsA even at early stages of disease progression, the early detection and management of which could improve the patients' disability, morbidity, and quality of life.

Tolerability and effectiveness of preservative-free dorzolamide-timolol (preservative-free COSOPT) in patients with open-angle glaucoma or ocular hypertension.

PURPOSE: To assess the effect of preservative-free dorzolamide-timolol on nonvisual symptoms and intraocular pressure (IOP) in newly diagnosed and untreated patients with open-angle glaucoma or ocular hypertension. METHODS: This was a prospective, 8-week, open-label, Canadian multicenter study. All patients were treated with preservative-free dorzolamide-timolol formulation. The primary outcome was the change in the nonvisual symptom score of the Glaucoma Symptom Scale (GSS-SYMP-6) from baseline to 8 weeks. Secondary effectiveness outcome measures were absolute and percent changes in IOP from baseline to 4 and 8 weeks. RESULTS: One hundred and seventy-eight patients were enrolled. Mean (SD) age was 65.6 (12.1) years and 90 (50.6%) were females. There were 92 patients diagnosed with open-angle glaucoma, 62 with ocular hypertension, and 23 with both diseases (diagnosis was missing for one patient). The mean (SD) GSS-SYMP-6 score increased from 73.6 (21.8) at baseline to 76.1 (20.7) at 8 weeks (P = 0.097). Mean (SD) IOP significantly decreased by 11.7 (5.1) mmHg at 4 weeks (P < 0.001) and by 11.5 (5.3) mmHg at 8 weeks (P < 0.001), representing reductions of -38.5% (P < 0.001) and -38.0% (P < 0.001), respectively. CONCLUSION: Preservative-free dorzolamide-timolol does not increase eye discomfort while significantly reducing IOP in patients with open-angle glaucoma or ocular-hypertension.

Assessment of mortality in older trauma patients sustaining injuries from falls or motor vehicle collisions treated in regional level I trauma centers.

OBJECTIVE: To compare mortality in elderly trauma patients sustaining fall or motor vehicle collision (MVC) related injuries and who are subsequently treated at regional Level I (tertiary) trauma centers. SUMMARY BACKGROUND DATA: An increase in the mean age of the Canadian population is leading to a higher proportion of older patients injured in falls who are subsequently treated at Level 1 trauma centers in Quebec. The Level 1 centers were designed to treat younger patients injured in MVCs and violent acts. As a result, discordance may exist between the type of care supplied at these centers and the increased demand for care tailored to older trauma patients. METHODS: A retrospective cohort study comprised of 4,717 patients over the age of 65; 606 (12.8%) injured in MVCs and 4,111 (87.2%) in falls. The mean (SD) age was 79.6 (8.0) years and 67.9% were female. The mean (SD) Injury Severity Score (ISS) was 10.8 (7.4). Data were obtained from the Quebec Trauma Registry (QTR) for patients treated at 3 Level I trauma centers in the province of Quebec, Canada. The primary outcome measure in this study was mortality. RESULTS: Being injured in a fall was a strong predictor for mortality, with an odds ratio of 5.11 (95% C.I. = 1.84-14.17, P = 0.002). Additionally, the adjusted mortality rate was 25.3% among fall victims, versus 7.8% for MVC patients. Female gender, older age, higher ISS and an increasing number of injuries were all associated with heightened mortality. In contrast, the number of body regions injured, experiencing complications, sustaining a hip fracture, the Revised Trauma Score, the Prehospital Index and the Charlson (comorbidity) Index had no association with mortality in the Level I centers. CONCLUSIONS: Elderly patients sustaining fall-related injuries and treated at Level I trauma centers are at risk for excess mortality when compared with those injured in MVCs. Effective and efficient methods for treating this population must be determined.