Treating to Target(s) With Interleukin-17 Inhibitors.

BACKGROUND:: The treat-to-target (T2T) strategy has become established in several medical specialties as a key guidance to optimal therapeutic decision making. T2T may be effective in the assessment of the biologic class of agents called interleukin (IL)-17 inhibitors, which are emerging as a safe and effective treatment option for autoimmune inflammatory conditions such as plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). OBJECTIVE:: The objective of this article is to use a T2T approach for the evaluation of the effectiveness and safety of IL-17 inhibitors in the management of patients with plaque psoriasis, PsA, and AS. METHODS:: Following a comprehensive literature search, a full-day meeting was convened to discuss and identify the T2T targets for psoriasis, PsA, and AS. Clinical trial evidence was presented for the approved IL-17 inhibitors-secukinumab, ixekizumab, and brodalumab-to assess whether these data meet T2T safety and efficacy targets. RESULTS:: All 3 approved agents were significantly superior to placebo and active controls in the achievement of T2T targets for psoriasis. Secukinumab and ixekizumab were likewise associated with significantly better outcomes than controls in the PsA targets, and secukinumab resulted in significant AS target improvements vs placebo. The IL-17 inhibitors were also associated with low rates of serious adverse events and exacerbations of common comorbid conditions. CONCLUSION:: Phase III trial results support the T2T benefit and safety of IL-17 inhibitors according to their specific indications for the management of patients with plaque psoriasis, PsA, and AS.

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.

Maintenance of Patient-Reported Outcomes in Baricitinib-Treated Patients with Moderate-to-Severe Active Rheumatoid Arthritis: Post Hoc Analyses from Two Phase 3 Trials.

INTRODUCTION: Baricitinib has been shown to improve patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) who are inadequate responders (IR) to conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARDs and bDMARDs, respectively). We assessed the ability of baricitinib 2-mg to maintain minimal clinically important differences (MCIDs) in PROs until week 24 among week 4 and 12 responders. METHODS: Data were from two phase 3 trials, RA-BUILD (NCT01721057; csDMARD-IR patients) and RA-BEACON (NCT01721044; bDMARD-IR patients). PROs included Pain Visual Analogue Scale, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue, Short-Form 36 Physical Component Score, and Patient's Global Assessment of Disease Activity. Outcomes were evaluated by proportions of patients achieving MCID improvements, number needed to treat (NNT) at weeks 4, 12, and 24, proportions of patients maintaining MCID responses at week 24 among week 4 or 12 responders, and median time to achieve substantial response with baricitinib 2-mg versus placebo. RESULTS: A higher proportion of baricitinib-treated patients achieved MCID improvements, with NNTs ranging from 5 to 8 for baricitinib 2-mg versus placebo at week 24. Generally, early MCID responses in PROs at weeks 4 or 12 were better maintained through week 24 in RA patients treated with baricitinib 2-mg versus placebo. Patients treated with baricitinib 2-mg also achieved substantial PRO responses or normative values more quickly than placebo. CONCLUSIONS: These results suggest baricitinib-treated patients with RA achieving MCID improvement in PROs at weeks 4 and 12 maintained those improvements over time and that substantial PRO responses were achieved quickly.

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

OBJECTIVES: The objectives of this study were to describe the demographic profile and baseline disease characteristics of patients with psoriatic arthritis (PsA) treated with either infliximab (IFX), subcutaneous golimumab (GLM) or ustekinumab (UST) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety. METHODS: Patients with PsA were enrolled into the Biologic Treatment Registry Across Canada registry (ClinicalTrials.gov Identifier: NCT00741793) from 2005 to 2017. The study visits occurred at study enrolment (baseline) and every 6 months thereafter. Effectiveness was assessed by changes in disease parameters (joint counts, Psoriasis Area Severity Index (PASI), Health Assessment Questionnaire, patient/physician global, minimal disease activity, enthesitis, dactylitis, erythrocyte sedimentation rate, C reactive protein). Improvements from baseline were explored with the paired t-test and the McNemar's test. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates. RESULTS: A total of 111 IFX-treated, 281 GLM-treated and 70 UST-treated patients were enrolled. Most baseline disease parameters remained similar over time in all three cohorts. UST-treated patients had lower mean baseline Disease Activity Score in 28 joints CRP, swollen joint based on 28 joints and higher PASI compared with patients treated with GLM. Treatment with IFX, GLM and UST was associated with significant improvements in all disease parameters over time (p<0.001) from baseline up to 84, 84 and 40 months, respectively.AEs were reported for 74.8%, 69.8% and 52.9% (138, 114 and 115 events/100 patient-years (PYs)) covering 325, 567 and 87 years of exposure for IFX-treated, GLM-treated and UST-treated patients, respectively. Severe AEs were reported in 19.8%, 8.5% and 5.7% (8.8, 7.2 and 8.0 events/100 PYs) in IFX-treated, GLM-treated and UST-treated patients, respectively. The proportion of patients who discontinued treatment were 63.1%, 50.9% and 50.0%, respectively. CONCLUSIONS: IFX, GLM and UST treatment significantly reduced disease activity and improved functionality in patients with PsA followed by routine clinical practice and had a safety profile similar to that previously reported in the literature. TRIAL REGISTRATION NUMBER: NCT00741793.

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.

Time to disease-modifying antirheumatic drug treatment in rheumatoid arthritis and its predictors: a national, multicenter, retrospective cohort.

OBJECTIVE: To determine the proportion of patients with rheumatoid arthritis (RA) under rheumatologic care treated with disease-modifying antirheumatic drugs (DMARD) within 6 months from symptom onset and the components of time to treatment and its predictors. METHODS: A historical inception cohort of 339 patients with RA randomly selected from 18 rheumatology practices was audited. The proportion that initiated DMARD treatment within 6 months from symptom onset was estimated using Kaplan-Meier analysis. Time to each component of the care pathway was estimated. Multivariable modeling was used to determine predictors of early treatment using 12 preselected variables available in the clinical charts. Bootstrapping was used to validate the model. RESULTS: Within 6 months from symptom onset, 41% (95% CI 36%-46%) of patients were treated with DMARD. The median time to treatment was 8.4 (interquartile range 3.8-24) months. Events preceding rheumatology referral accounted for 78.1% of the time to treatment. The most prominent predictor of increased time to treatment was a concomitant musculoskeletal condition, such as osteoarthritis or fibromyalgia. The significance of other variables was less consistent across the models investigated. Included variables accounted for 0.69 ± 0.03 of the variability in the model. CONCLUSION: Fewer than 50% of patients with RA are treated with DMARD within 6 months from symptom onset. Time to referral to rheumatology represents the greatest component delay to treatment. Concomitant musculoskeletal condition was the most prominent predictor of delayed initiation of DMARD. Implications of these and other findings warrant further investigation.

Relative urgency for referral from primary care to rheumatologists: the Priority Referral Score.

OBJECTIVE: Timely access to rheumatology consultation is fundamental to appropriate and effective management of patients with musculoskeletal and autoimmune diseases. Yet, for a variety of reasons, limited and delayed access is commonplace. Moreover, information exchange for referral is often inadequate or poorly communicated. The objective of this work was to improve referral from primary care to rheumatology by formulating and testing a clinically coherent, reliable, and non-diagnosis-dependent Priority Referral Score (PRS). METHODS: Using a deliberative process, a clinical panel of 10 primary care providers (PCPs) and rheumatology specialists reviewed clinical case scenarios and engaged in a highly iterative process to develop criteria, definitions, and weights for the PRS, a linear 100-point scale to rate the relative urgency of referral. Following tool formulation, clinicians uninvolved with the process tested the PRS against their clinical judgment. RESULTS: The PRS comprises 8 criteria, with 2-4 levels for each criterion, and each having a weight generated through conjoint analysis, which forced choices around the comparative urgency of all of the criteria and levels. The PRS showed a strong correlation between clinical rankings of rheumatologists and PCPs in both the deliberative panel, and the physicians subsequently involved in the testing of the PRS. CONCLUSION: No standardized priority-setting criteria are available for the full range of primary care referrals to rheumatologists. The PRS had face value with panelists and provided acceptable interrater and intrarater reliability when tested with other rheumatologists and PCPs. Pilot testing with other clinicians and in other settings is justified and prerequisite to use in clinical practice.

Early management of newly diagnosed rheumatoid arthritis by Canadian rheumatologists: a national, multicenter, retrospective cohort.

OBJECTIVE: To describe early rheumatologic management for newly diagnosed rheumatoid arthritis (RA) in Canada. METHODS: A retrospective cohort of 339 randomly selected patients with RA diagnosed from 2001-2003 from 18 rheumatology practices was audited between 2005-2007. RESULTS: The most frequent initial disease-modifying antirheumatic drugs (DMARD) included hydroxychloroquine (55.5%) and methotrexate (40.1%). Initial therapy with multiple DMARD (15.6%) or single DMARD and corticosteroid combinations (30.7%) was infrequent. Formal assessment measures were noted infrequently, including the Health Assessment Questionnaire (34.6%) and Disease Activity Score for 28 joints (8.9%). CONCLUSION: Initial pharmacotherapy is consistent with guidelines from the period. The infrequent reporting of multiple DMARD combinations and formal assessment measures has implications for current clinical management and warrants contemporary reassessment.