A Canadian Retrospective Chart Review Evaluating Concomitant Methotrexate De-escalation Patterns in Patients with Rheumatoid Arthritis Treated with Biologic or Targeted Synthetic DMARDs.

INTRODUCTION: Rheumatoid arthritis (RA) guidelines recommend methotrexate (MTX)-anchored therapy with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs); however, tolerability issues often lead to non-adherence. Canadian data on MTX tapering and/or withdrawal following b/tsDMARD initiation are minimal. This chart review assessed frequency of MTX tapering or withdrawal following b/tsDMARD initiation and the impact on disease status in Canadian adults with RA. METHODS: Eligible patients had received MTX for ≥ 3 months before b/tsDMARD initiation. The b/tsDMARD was prescribed continuously for ≥ 18 months. Patients taking > 10 mg/day oral prednisone or equivalent were excluded. RESULTS: Eight hundred eighty-nine patients (mean baseline MTX dose 19.0 mg/week) prescribed b/tsDMARDs (tumor necrosis factor inhibitor 52.1%, Janus kinase inhibitor 18.3%, interleukin-6 inhibitor [IL-6i] 11.9%, other 17.7%) were evaluated at 22 Canadian centers. Within 2 years of b/tsDMARD initiation, MTX was tapered in 123 (13.8%) patients and discontinued in 147 (16.5%), most commonly due to planned tapering (36.6%) and patient decision (27.2%), respectively, and most commonly with IL-6i use (34.9%). The MTX dose was unchanged for 582 (65.5%) patients and increased for 37 (4.2%). Missing data limit interpretations of MTX dose effects on some secondary endpoints and challenge the assertion that a disease activity measure-based treat-to-target approach is routinely used in Canadian rheumatology practice. CONCLUSIONS: Methotrexate tapering or withdrawal occurred in 30.4% of Canadians with RA within 2 years following b/tsDMARD initiation. Baseline disease activity measures were missing from many medical records. However, for patients with baseline assessments, MTX tapering or discontinuation did not worsen disease activity.

Long-term effectiveness and safety of infliximab, golimumab and golimumab-IV in rheumatoid arthritis patients from a Canadian prospective observational registry.

BACKGROUND: Long-term clinical registries are essential tools to evaluate new therapies in a patient population that differs from those in randomized clinical trials. The objectives are to describe the profile of rheumatoid arthritis (RA) patients treated with anti-TNF agents in Canadian routine care. METHODS: RA patients eligible for treatment with Infliximab (IFX), golimumab (GLM) or intravenous golimumab (GLM-IV) as per their respective Canadian product monographs were enrolled into the BioTRAC registry between 2002 and 2017. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in disease activity. Safety was evaluated by the incidence of adverse events (AEs) and drug survival. RESULTS: Of the 890 IFX-, 530 GLM- and 157 GLM-IV-treated patients, the proportion of females ranged from 77.0-86.6%, the mean ages from 55.8-57.7 and the mean disease duration from 6.5-8.6 years. A significant decrease in baseline disease duration and disease activity parameters (DAS, TJC, SJC, HAQ, AM stiffness, MDGA, PtGA, CRP, ESR) was observed over time. Treatment with IFX, GLM- and GLM-IV significantly improved all disease parameters over time. The incidence of AEs was 105, 113 and 82.6 /100 PYs and the incidence of SAEs was 11.7, 11.2 and 4.68 /100 PYs for IFX, GLM- and GLM-IV-treated patients, respectively. CONCLUSION: Differences in baseline characteristics between patients treated with an anti-TNFs over time shows the evolution of treatment modalities over time. All treatments significantly reduced disease activity and improved functionality in a similar fashion. The incidence of adverse events was consistent with the safety profiles of IFX and GLM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00741793 (Retrospectively registered on August 26, 2008).

Efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis.

OBJECTIVE: To describe the efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in a post-hoc analysis of randomised controlled trials. METHODS: Data were collected from patients in seven tofacitinib studies: six phase III (four RA, two PsA) and one phase II study (AS), and grouped into five analysis populations based on rheumatic disease diagnosis and category of prior inadequate response (IR) to treatment: conventional synthetic disease-modifying antirheumatic drugs-IR (RA and PsA), tumour necrosis factor inhibitors-IR (RA and PsA), or non-steroidal anti-inflammatory drugs-IR (AS). Only patients who received tofacitinib 5 or 10 mg twice daily or placebo were included. Pain assessments included: Patient's Assessment of Arthritis Pain, Short-Form Health Survey 36v2 Question (Q)7 and Bodily Pain domain, Ankylosing Spondylitis Quality of Life Q9 and Q14, EuroQol Five Dimensions Pain/Discomfort dimension and Bath Ankylosing Spondylitis Disease Activity Index Q2 and Q3. Data were reported to month 6 (placebo to month 3) in the RA and PsA populations, and week 12 (tofacitinib and placebo) in the AS population. RESULTS: Overall, 3330 patients were included in this analysis. In the RA and PsA populations, pain improvements in tofacitinib-treated patients compared with placebo were observed at the earliest time point assessed and at month 3 (maintained to month 6). In the AS population, pain improvements compared with placebo were observed at week 12. CONCLUSION: Tofacitinib was associated with rapid and sustained improvements across multiple pain measures in patients with inflammatory rheumatic musculoskeletal diseases.

The incidence of giant cell arteritis in Ontario, Canada.

OBJECTIVE: The incidence of giant cell arteritis (GCA) is insufficiently documented for Canada, but important to ascertain for public health planning. We estimate the incidence of biopsy-proven GCA (BPGCA) in Kingston, Ontario, and for the province of Ontario. METHOD: The number of cases of BPGCA was tabulated from retrospective chart review of all temporal artery biopsies (TABx) in Kingston, Ontario from 2011-15. The relevant population denominator was determined from the Canada census federal electoral district and the patient's postal code. The province-wide estimate for the incidence of BPGCA was calculated from provincial billing data of TABx from 2015-17, the Canada census for Ontario, and the expected positive yield of TABx. RESULTS: There were 35 subjects with BPGCA in the Kingston area over the 4-year period, from a population of 179 503 individuals 50 years of age or older (≥50 years). Ontario billing data identified 2404 patients who underwent TABx for suspected GCA over a 2-year period, from a population of 5 143 610 persons ≥50 years. Meta-analysis of 5 provincial TABx series suggested a 21% positive yield from TABx procedures (95% CI 0.18-0.24). The minimum cumulative incidence of BPGCA was 4.9 per 100 000 persons ≥50 years in Kingston, and 4.9 (95% CI 4.2-5.6) per 100 000 persons ≥50 years for Ontario as a whole. CONCLUSION: The estimated incidence of BPGCA in Ontario using 2 different estimation techniques was comparable, but low compared with other countries. The actual incidence of GCA in Ontario may be higher.

Patterns and predictors of long-term retention of inflammatory bowel or rheumatoid disease patients on innovator infliximab: an analysis of a Canadian prescriptions claims database.

BACKGROUND: Long-term effectiveness is an important factor when considering treatment decisions. OBJECTIVE: To determine the long-term retention patterns of Canadian inflammatory bowel disease (IBD) and rheumatologic disease (RD) patients, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with innovator infliximab (IFX) and to assess the impact of year-over-year cumulative IFX exposure on retention in both patient populations. PATIENTS AND METHODS: This analysis used a Canadian longitudinal prescription claims database to measure retention on IFX over a period of 5 years. Twelve-month unadjusted odds ratios of retention by time on IFX were calculated for the overall cohort, and within-group comparisons evaluated differences according to age, sex, region, insurance coverage, use of concomitant immunosuppressant therapy, indication (RD cohort only), and previous biologic experience. Between-group analyses compared unadjusted 5-year retention among the same variables. Variables that were independently associated with longer retention on IFX were identified using multivariable regression. RESULTS: Seven thousand eight hundred and six IBD patients and 2,935 RD patients on stable treatment with IFX were included in the analysis. Sixty-nine percent of IBD patients and 66% of RD patients were retained on IFX after 1 year and 33% and 29%, respectively, were retained after 5 years. Moreover, the probability of being retained on IFX significantly increased with cumulative time on IFX. Independent predictors of 5-year retention included sex, region, and type of insurance coverage among IBD patients and region, type of insurance, prior biologic therapy, and specific indication among RD patients. Patients with IBD were 17% more likely to be retained on IFX over 5 years compared to patients with RD. CONCLUSION: Real-world Canadian IBD and RD patients on IFX have good overall long-term treatment retention. Previous duration of IFX treatment predicts better future retention, and this knowledge could help inform treatment decisions when patients have been stable on IFX treatment for varying periods of time.

Real-world validation of the minimal disease activity index in psoriatic arthritis: an analysis from a prospective, observational, biological treatment registry.

OBJECTIVE: To describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers. DESIGN: Biologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab. SETTING: 46 primary-care Canadian rheumatology practices. PARTICIPANTS: 223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES: MDA was defined as ≥5 of the following criteria: 28-item tender joint count (TJC28) ≤1, 28-item swollen joint count (SJC28) ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or body surface area≤3, Pain Visual Analogue Scale (VAS) ≤15 mm, patient's global assessment (PtGA) (VAS) ≤20 mm, Health Assessment Questionnaire (HAQ) ≤0.5, tender entheseal points ≤1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression. RESULTS: MDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%). CONCLUSIONS: Almost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and PASI. TRIAL REGISTRATION NUMBER: BioTRAC (NCT00741793).

Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886].

BACKGROUND: Topical NSAIDs have been proven to relieve the symptoms of osteoarthritis (OA) in short-term studies (2 weeks). To justify its chronic use, efficacy of a topical NSAID over a longer term of study should be demonstrated. The efficacy and safety of a topical diclofenac solution over a 6-week treatment course in symptomatic primary OA of the knee was investigated. METHODS: 216 men and women, age 40-85 years, with radiologically confirmed primary OA of the knee and a flare of pain at baseline following discontinuation of prior therapy were enrolled into this double-blind study. Participants applied either a topical diclofenac solution (Pennsaid) or vehicle control solution (carrier with no diclofenac); 40 drops 4 times daily directly to the painful knee(s), without massage, for 6 weeks. Pre-planned primary efficacy outcome measures included the core continuous variables pain relief and improved physical function measured by the Western Ontario and McMaster Universities (WOMAC) LK3.1 OA Index, and improved patient global assessment (PGA). Secondary efficacy measure was reduced stiffness. Safety assessments included adverse events and vital signs. RESULTS: The topical diclofenac group had a significantly greater mean change in score (final minus baseline) compared to the vehicle control group for pain (-5.2 vs. -3.3, p = 0.003), physical function (-13.4 vs. -6.9, p = 0.001), PGA (-1.3 vs. -0.7, p = 0.0001) and stiffness (-1.8 vs. -0.9, p = 0.002). The mean difference between treatment arms (95% confidence interval [CI]) was 1.9 (0.7 to 3.2), 6.5 (2.5 to 10.5), 0.6 (0.2 to 0.9), and 0.9 (0.3 to 1.4), respectively. Safety analyses showed that topical diclofenac caused skin irritation, mostly minor local skin dryness, in 42/107 (39%), leading to discontinuation of treatment in 5/107 (5%) participants. CONCLUSION: This topical diclofenac solution demonstrated relief at 6 weeks of the symptoms of primary osteoarthritis of the knee.

Regional hemodynamic effects of the N-(2-benzoylphenyl)-L-tyrosine peroxisome proliferator-activated receptor-gamma ligand, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious rats.

This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor-gamma activator, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious, male Sprague-Dawley rats. Administration of GI 262570 twice daily for 4 days caused a slowly developing, modest fall in mean arterial blood pressure, associated with a progressive, hyperemic hindquarters vasodilatation, but with no consistent changes in renal or mesenteric hemodynamics. The hindquarters vasodilator effect of GI 262570 was not inhibited by the beta2-adrenoceptor antagonist, ICI 118551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol hydrochloride), and was still apparent in the presence of the alpha-adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT1) and endothelin (ETA and ETB) receptors unmasked vasodilator responses to GI 262570 in the renal or mesenteric vascular beds. In the presence of GI 262570, vasodilator responses to acetylcholine and vasoconstrictor responses to methoxamine were normal. Furthermore, the cardiovascular responses to nonselective nitric-oxide synthase inhibition were not influenced by GI 262570. Collectively, these results indicate that the vasodilator action of GI 262570 is specific to the hindquarters vascular bed (of those studied), does not involve alpha- or beta2-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.

Effects of a PPARgamma agonist, GI262570, on renal filtration fraction and nitric oxide level in conscious rats.

PPARgamma agonists ameliorate insulin resistance and lower blood pressure. Volume expansion/edema has been observed in susceptible patients treated with these agents. Alterations of renal hemodynamics affect renal tubular reabsorption, and thus may contribute to volume expansion. This study seeks to determine whether volume expansion caused by a PPARgamma agonist, GI262570, is related to changes in glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. Chronically catheter-implanted conscious rats were studied to determine the effects on glomerular filtration rate, effective renal plasma flow, and renal filtration fraction after 1, 4, and 10 days of GI262570 treatment (8 mg/kg, p.o., B.I.D.). Elevated adipose mRNA of PPARgamma target genes confirmed PPARgamma activation in GI262570-treated rats. GI262570 treatment for 10 days decreased hematocrit, hemoglobin, and serum albumin (all P < 0.05), indicating volume expansion, but did not alter glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. However, nitrate + nitrite was significantly higher in plasma and hind limb muscle of GI262570-treated rats (both P < 0.05). This study demonstrated that treatment with PPARgamma agonist GI262570 resulted in volume expansion and increased nitric oxide, but did not affect glomerular filtration rate, effective renal plasma flow, or renal filtration fraction, indicating PPARgamma agonist-induced volume expansion is not related to changes in renal filtration fraction, and increased nitric oxide may contribute to the PPARgamma agonist-induced blood-pressure lowering.