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The approval and adoption of biosimilar products are essential to contain increasing healthcare costs and provide more affordable choices for patients. Despite steady progress in the number of the US Food and Drug Administration (FDA) biosimilar approvals over the years, biosimilar adoption in the United States has been slow and gradual, largely driven by payers rather than clinicians. In order to better understand the barriers to biosimilar adoption in the clinic, the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) and the FDA jointly hosted a virtual workshop on April 13, 2022, titled "Biosimilars: A Decade of Experience and Future Directions - Strategies for Improving Biosimilar Adoption and the Potential Role of Clinical Pharmacology." This summary documents the experiences of four leading academic clinicians with specialties in oncology, rheumatology, gastroenterology, and endocrinology and their perspectives on how to increase biosimilar adoption, including the role of clinical pharmacology. Besides systemic changes in pricing and reimbursement, there is a need for additional education of a broad range of providers, including advanced care practitioners, and patients themselves. Educational efforts highlighting the rigor of the studies that support the approval of biosimilars-including the clinical pharmacology studies-and the benefits of biosimilars, can play a major role in improving biosimilar acceptance.

Beyond the legal and regulatory limitations associated with biosimilar availability in the United States, the adoption of biosimilars is contingent on the willingness of health care providers (HCPs) to prescribe them and of patients to accept them. In this dynamic market, it is of paramount importance to understand the current awareness, attitudes, and preferences of a broad spectrum of stakeholders if uptake of biosimilars is to be optimized. In this article, we highlight knowledge gaps among US HCPs and patients regarding biosimilars for immune-mediated inflammatory diseases as assessed in published survey literature over the last 5 years. Although HCP familiarity and understanding of biosimilars appears to have improved over the last 5 years, survey data suggest that some physicians and pharmacists still approach use of biosimilars with caution owing to concerns regarding nonmedical switching, interchangeability, pharmacist-led substitution, and the extent of any cost savings. Patients understand the potential cost benefits of biosimilars but share many of the HCPs' concerns. A large majority of patients were also concerned that biosimilars would not treat their disease as well as the reference product and that switching may cause more adverse effects. Consequently, nonmedical switching is a major concern for patients, with the majority reporting that they would attempt to avoid a switch. Although patients trust their physicians' treatment recommendations and express confidence in biosimilars, they have mixed views on automatic substitution by pharmacists. The areas of concern identified can be used to guide further education programs for HCPs and patients, and, in doing so, improve biosimilar uptake.

Biosimilars hold the promise of substantial potential cost savings in health care with no compromise in the efficacy and safety of treatment. Despite this, their adoption in the United States has been substantially slower than might have been expected. In addition to patient and provider barriers to their widespread adoption as discussed in the second article in this supplement, additional potential barriers to their use are inherent to the current US health care system. In this article, we examine biosimilar agents from a managed care perspective and discuss some of the reasons behind their delayed adoption in the United States.

Biosimilars offer the potential to deliver substantial cost savings in biologic therapy and to contribute to increased patient access to biologic treatments, both of which are particularly relevant for immune-mediated inflammatory diseases, given the number of patients affected by and receiving treatment for these conditions. For the United States to benefit from bringing biosimilar pipeline products to the market, legal and price-related barriers to competition must be addressed. In addition, education of prescribers, patients, payers, and providers is essential to increase uptake as biosimilars reach the market. This article discusses biosimilars currently available for the treatment of immune-mediated inflammatory diseases in the United States, reviews the main concepts related to regulatory approval of biosimilars by the FDA, and considers potential barriers to the uptake of biosimilars.

Objectives We sought to evaluate perceptions of biosimilar products among US rheumatologists who prescribe TNF-α inhibitors, given that 10 TNF-α inhibitor biosimilars and two rituximab biosimilars have Food and Drug Administration (FDA) approval. Methods A 19-question self-administered online survey was conducted from 6 May to 1 June 2019, and fielded by WebMD, LLC. Rheumatologists (n = 9050) who were members of Medscape.com and its partner panels were invited to participate. Likert and other rating scales were used to collect responses, which were summarized descriptively. Results Responses were obtained from 320 board-certified US rheumatologists, 85% of whom were fellows of the ACR. Nearly all respondents were familiar with the FDA definition of a biosimilar product and were aware that an infliximab biosimilar was FDA approved; fewer realized that adalimumab, etanercept and rituximab biosimilars were also FDA approved. Most respondents (84%) were aware that an approved biosimilar was not automatically deemed interchangeable by the FDA. Rheumatologists were more likely to initiate biosimilar treatment for a biologic treatment-naïve patient with RA (73%) than they were to switch to the biosimilar for a patient with RA doing well on the reference product (35%). Conclusions The results of this survey suggest that US rheumatologists have a good understanding and acceptance of biosimilar products, particularly for the initiation of treatment in biologic-naïve individuals. They were hesitant to switch from a reference product to a biosimilar for a patient doing well on the reference product. Additional education on biosimilars is required to help inform treatment decisions by rheumatologists. A plain language summary of this article has been uploaded as supplementary material, available at Rheumatology online.

OBJECTIVE: With hydroxychloroquine (HCQ) and chloroquine (CQ) emerging as potential therapies for coronavirus disease 2019 (COVID-19), shortages have been reported. We aimed to understand how rheumatologists, one of the most common prescribers of HCQ/CQ, prescribed these medications to manage COVID-19 and to understand if their patients are affected by shortages. METHODS: Between April 8 and April 27, 2020, an online survey was distributed to a convenience sample of rheumatologists who practice medicine in a diverse range of settings globally, resulting in 506 responses. Adjusted Poisson regression models were calculated. RESULTS: Only 6% of respondents prescribed HCQ/CQ for COVID-19 prophylaxis, and only 12% for outpatient treatment of COVID-19. Compared to the United States, the likelihood of prescribing HCQ/CQ for prophylaxis was higher in India (adjusted risk ratio [aRR], 6.7; 95% confidence interval [CI], 2.7-16.8; p < 0.001). Further, compared to the United States and those with 1 to 5 years of experience, rheumatologists in Europe (aRR, 2.9; 95% CI, 1.6-5.3; p < 0.001) and those with 10+ years of experience (11-20 years: aRR, 2.5; 95% CI, 1.2-5.3; p = 0.015; 21+ years: aRR = 3.3; 95% CI, 1.4-7.4; p = 0.004) had a higher likelihood of prescribing HCQ/CQ for outpatient treatment. Of note, 71% of all rheumatologists reported that their patients were directly affected by HCQ/CQ shortages. CONCLUSION: The results suggest that only a small percentage of rheumatologists are prescribing HCQ/CQ for prophylaxis or outpatient treatment of COVID-19. Medication shortages experienced by large numbers of autoimmune disease patients are concerning and should play a role in decisions, especially given poor efficacy data for HCQ/CQ in COVID-19.

Objective.To evaluate longterm drug survival (proportion of patients still receiving treatment) and discontinuation of etanercept (ETN), infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GOL) using observational data from patients with rheumatoid arthritis (RA).Methods.Following a systematic literature review, drug survival at 12 and 12–24 months of followup was estimated by summing proportions of patients continuing treatment and dividing by number of studies. Drug survival at ≥ 36 months of followup was estimated through Metaprop.Results.There were 170 publications included. In the first-line setting, drug survival at 12 months with ETN, IFX, or ADA was 71%, 69%, and 70%, respectively, while at 12–24 months the corresponding rates were 63%, 57%, and 59%. In the second-line setting, drug survival at 12 months with ETN, IFX, or ADA was 61%, 69%, and 55%, respectively, while at 12–24 months the corresponding rates were 53%, 39%, and 43%. Drug survival at ≥ 36 months with ETN, IFX, or ADA in the first-line setting was 59% (95% CI 46–72%), 49% (95% CI 43–54%), and 51% (95% CI 41–60%), respectively, while in the second-line setting the corresponding rates were 56% (95% CI 52–61%), 48% (95% CI 40–55%), and 41% (95% CI 36–47%). Discontinuation of ETN, IFX, and ADA at 36 months of followup was 38–48%, 42–62%, and 38–59%, respectively. Data on CZP and GOL were scarce.Conclusion.After > 12 months of followup, more patients with RA receiving ETN remain on treatment compared with other tumor necrosis factor inhibitors.

Highlights • Autoimmune patients and rheumatologists face an unprecedented challenge during the COVID-19 pandemic and are changing medication practices in response. • About half of US rheumatologists believe COVID-19 risk may be heightened in rheumatic disease patients, regardless of their immunosuppressive medications. • There were significant differences in the management of biologics, steroids and NSAIDs in response to COVID-19 reported by rheumatologists in areas with a high case burden, compared to those in less affected areas., OBJECTIVE To investigate the perceptions and behaviors of rheumatologists in the United States (US) regarding the risk of COVID-19 for their autoimmune patients and the subsequent management of immunosuppressive and anti-inflammatory medications. METHODS We administered an online survey to a convenience sample of rheumatologists in the US from 4/8/20-5/4/20 via social media and group emails. Survey respondents provided demographic information such as, age, gender, state of practice, and practice type. We asked questions about COVID-19 risk in rheumatic patients, as well as their medication management during the pandemic. We conducted descriptive analysis and Multivariable regression models. RESULTS 271 respondents completed the survey nationally. 48% of respondents either agreed or strongly agreed with the statement “Patients with rheumatic diseases are at a higher risk of COVID-19 irrespective of their immunosuppressive medications”. 50% disagreed or strongly disagreed with the statement “The pandemic has led you to reduce the use/dosage/frequency of biologics”, while 56% agreed or strongly agreed with the statement “The pandemic has led you to reduce the use/dosage/frequency of steroids”. A third of respondents indicated that at least 10% of their patients had self-discontinued or reduced at least one immunosuppressive medication to mitigate their risk of COVID-19. Responses to these questions as well as to questions regarding NSAID prescription patterns were significantly different in the Northeast region of US compared to other regions. CONCLUSION In this national sample of rheumatologists, there are variations regarding perceptions of patients’ risk of COVID-19, and how to manage medications such as NSAIDs, biologics and steroids during the pandemic. These variations are more pronounced in geographical areas where COVID-19 disease burden was high.

ObjectiveLorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses.DesignSubjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2mL LOR (0.03, 0.07, 0.15, or 0.23mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling.ResultsIn total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07mg and 0.23mg LOR at Weeks 12 (-0.96, 95% CI [-1.54,-0.37], P=0.001;-0.78 [-1.39,-0.17], P=0.012) and 24 (-0.70 [-1.34,-0.06], P=0.031;-0.82 [-1.51,-0.12], P=0.022). Additionally, 0.07mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P=0.04, P=0.021), and 0.23mg LOR significantly improved both WOMAC subscores at Week 24 (P=0.031, P=0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07mg LOR as the lowest effective dose.ConclusionThis 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07mg LOR.

INTRODUCTION This survey assessed biosimilar beliefs among patients with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis (PsO) and/or psoriatic arthritis (PsA). We report here on patients with IBD. METHODS WebMD, LLC invited patients from the Dynata® consumer panel to participate in an online survey. US residents ≥18 years with a self-reported specialist diagnosis of IBD, RA, or PsO/A of ≥1 year were eligible. Patients with multiple conditions answered questions about 1 condition only; those with RA+IBD reported on IBD, whereas those with PsO/A+IBD reported on PsO/A, and those with RA+PsO/A reported on RA; neither the PsO/A or RA groups are included here. Those currently receiving an infliximab biosimilar were excluded. A quota of 500 was set and stratified based on US geographic region and condition (∼33% each); once quota was reached, no further surveys were administered for that region or condition. Responses were summarized descriptively. The survey received an IRB exemption by Advarra (Columbia, MD). RESULTS Per quota, 166 patients had IBD (ulcerative colitis, 72%; Crohn’s disease, 12%; both, 4%; IBD+RA, 11%). Mean age of IBD patients was 50 y; 67% were female. Overall, 36% (n=59/166) were currently on a biologic and 64% (n=107/166) were not currently on a biologic (ie, 46% [n=76/166)] were biologic naïve and 19% [n=31/166] had used biologics in the past). Among current biologic users, 61% (n=36/59) were on an anti-TNFα (adalimumab 50%; infliximab 19%; etanercept 17%). Overall, 68% (n=113/166) had not heard of a biosimilar, 22% (n=36/166) had, and 10% (n=17/166) were unsure. Current biologic users (42%) were more likely to have heard of biosimilars than those not currently using biologics (10%). Before answering additional questions, patients were shown the FDA biosimilar definition. Main concerns about biosimilars were side effects and long-term safety (Figure). Among current biologic users, 37% (n=22/59) would accept a switch to a biosimilar, 36% (n=21/59) were unsure, and 27% (n=16/59) would not switch. When those not currently using a biologic were asked their preference if their doctor prescribed a biologic, for 52% (n= 56/107) it depended on cost, 26% (n=28/107) had no preference, 11% (n=12/107) would take the biosimilar, and 10% (n= 11/107) preferred the original. When patients not currently using a biologic were asked if an original anti-TNFα was now prescribed but the insurance company required a biosimilar of that medicine, 54% (n=58/107) would accept the switch and 43% (n=46/107) were unsure. Overall, 76% of patients wanted additional information to help them learn more about biosimilars. DISCUSSION Most patients with IBD had not heard of biosimilars and most patient’s main concern was about the safety profile. Further education may help patients make informed choices about biosimilar switching or initiation.

Objective To assess the feasibility and efficacy of implementing a treat‐to‐target approach versus usual care in a US‐based cohort of rheumatoid arthritis patients. Methods In this behavioral intervention trial, rheumatology practices were cluster‐randomized to provide treat‐to‐target care or usual care. Eligible patients with moderate/high disease activity (Clinical Disease Activity Index [CDAI] score >10) were followed for 12 months. Both treat‐to‐target and usual care patients were seen every 3 months. Treat‐to‐target providers were to have monthly visits with treatment acceleration at a minimum of every 3 months in patients with CDAI score >10; additional visits and treatment acceleration were at the discretion of usual care providers and patients. Coprimary end points were feasibility, assessed by rate of treatment acceleration conditional on CDAI score >10, and achievement of low disease activity (LDA; CDAI score ≤10) by an intent‐to‐treat analysis. Results A total of 14 practice sites per study arm were included (246 patients receiving treat‐to‐target and 286 receiving usual care). The groups had similar baseline demographic and clinical characteristics. Rates of treatment acceleration (treat‐to‐target 47% versus usual care 50%; odds ratio [OR] 0.92 [95% confidence interval (95% CI) 0.64, 1.34]) and achievement of LDA (treat‐to‐target 57% versus usual care 55%; OR 1.05 [95% CI 0.60, 1.84]) were similar between groups. Treat‐to‐target providers reported patient reluctance and medication lag time as common barriers to treatment acceleration. Conclusion This study is the first to examine the feasibility and efficacy of a treat‐to‐target approach in typical US rheumatology practice. Treat‐to‐target care was not associated with increased likelihood of treatment acceleration or achievement of LDA, and barriers to treatment acceleration were identified.

Author(s): Yazici, Yusuf; McAlindon, Timothy E; Gibofsky, Allan; Lane, Nancy E; Clauw, Daniel; Jones, Morgan; Bergfeld, John; Swearingen, Christopher J; DiFrancesco, Anita; Simsek, Ismail; Tambiah, Jeyanesh; Hochberg, Marc C | Abstract: ObjectiveTo assess the safety and efficacy of a novel Wnt pathway modulator, lorecivivint (SM04690), for treating pain and inhibiting structural progression in moderately to severely symptomatic knee osteoarthritis (OA).MethodsSubjects in this 52-week, phase IIa, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial received a single 2-ml intraarticular injection of lorecivivint (dose of 0.03 mg, 0.07 mg, or 0.23 mg) or placebo. Efficacy was assessed based on change from baseline on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score subscales for pain and function (scale 0-100 for each) and change from baseline in the radiographic medial joint space width (JSW). Baseline-adjusted analysis of covariance with multiple imputation was performed separately to evaluate efficacy. This proof-of-concept study evaluated the intent-to-treat population as well as a prespecified group of subjects with unilateral symptoms of knee OA (designated UNI) and an additional post hoc subgroup of subjects with unilateral symptoms but without widespread pain (designated UNI WP-).ResultsIn this trial, 455 subjects were randomized to a treatment group. The primary end point, significant improvement in the WOMAC pain score compared with placebo at week 13, was not met by any lorecivivint dose group (mean ± SD change from baseline, -23.3 ± 2.2 in the 0.03 mg group, -23.5 ± 2.1 in the 0.07 mg group, -21.3 ± 2.2 in the 0.23 mg group, and -22.1 ± 2.1 in the placebo group; each P g 0.05 versus placebo). All groups (including placebo) demonstrated clinically meaningful (≥20-point) improvements from baseline in the WOMAC pain score. The durability of response was evaluated through week 52. In the prespecified UNI group and post hoc UNI WP- group at week 52, treatment with 0.07 mg lorecivivint significantly improved the WOMAC pain score (between-group difference versus placebo, -8.73, 95% confidence interval [95% CI] -17.44, -0.03 [P = 0.049] and -11.21, 95% CI -20.99, -1.43 [P = 0.025], respectively) and WOMAC function score (between-group difference versus placebo, -10.26, 95% CI -19.82, -0.69 [P = 0.036] and -13.38, 95% CI -24.33, -2.43 [P = 0.017], respectively). Relative to baseline, the mean change in the medial JSW at week 52 was -0.04 mm in the 0.03 mg cohort, -0.09 mm in the 0.07 mg cohort, -0.16 mm in the 0.23 mg cohort, and -0.14 mm in the placebo cohort; no treatment group achieved a significant change in medial JSW compared with placebo at week 52. In both unilateral symptom subgroups, the 0.07 mg lorecivivint dose significantly increased medial JSW compared with placebo at week 52 (medial JSW 0.39 mm, 95% CI 0.06, 0.72 in the UNI group [P = 0.021] and 0.42 mm, 95% CI 0.04, 0.80 in the UNI WP- group [P = 0.032]). Changes observed in the 0.03 mg and 0.23 mg dose groups were not significantly different from those in the placebo group for any of these measures. Lorecivivint appeared safe and well tolerated.ConclusionThis phase IIa, proof-of-concept trial in patients with symptomatic knee OA did not meet its primary end point. Nevertheless, the study identified a target population in whom to evaluate the potential efficacy of lorecivivint for the treatment of knee OA.

Background: A phase 2a study of SM04690, a small-molecule, intra-articular (IA) Wnt pathway inhibitor reduced knee pain and improved physical function and medial joint space width (mJSW) at 52 weeks in subgroups of subjects with unilateral symptomatic knee osteoarthritis (OA) compared to placebo (PBO).1 Objectives: A 24-week phase 2b study was conducted to refine patient-reported outcome (PRO) measures, target population, medication dose, and to evaluate safety. PRO results for Weeks 12 and 24 are presented here. Methods: Study subject inclusion criteria required ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2-3, and Pain Numeric Rating Scale (NRS) ≥4 and ≤8 in the target knee and Results: 695 subjects (mean age 59.0 [±8.5] years, BMI 29.0 [±4.0] kg/m2, female 58.4%, KL3 57.3%) were enrolled and dosed; 635 subjects (91.4%) completed the study. No meaningful differences in the incidence of adverse events were observed between treatment and control groups. In the Full Analysis Set, significant improvements from baseline compared to vehicle PBO were observed in pain NRS for 0.07 mg (Week 12 [P=0.001], Week 24 [P=0.031]) and 0.23 mg (Week 12 [P=0.012], Week 24 [P=0.022]) SM04690 dose groups (Figure). Similar improvements were observed in WOMAC Pain for 0.07 mg (Week 12 [P=0.04]) and 0.23 mg (Week 12 [P=0.003], Week 24 [P=0.031]) dose groups. For WOMAC Physical Function, improvements were observed for 0.07 mg (Week 12 [p=0.021]) and 0.23 mg (Week 12 [p=0.006], Week 24 [P=0.017]) dose groups. PtGA improvements were observed for 0.07 mg (Week 12 [P=0.031]) and 0.23 mg (Week 12 [P=0.010], Week 24 [P=0.033]) dose groups. Conclusion: SM04690, in development as a potential disease-modifying OA drug, showed in this phase 2b study statistically significant improvements from baseline in both the 0.07 mg and 0.23 mg dose groups compared to vehicle PBO for Pain NRS, WOMAC Pain, WOMAC Physical Function, and PtGA. These data support the continued development of SM04690 as a treatment for knee OA. Phase 3 studies are being planned. Reference: [1] Yazici Y, et al. Arthritis Rheumatol. 2017; 69 (suppl 10). Disclosure of Interests: Yusuf Yazici Shareholder of: Samumed, LLC, Consultant for: Celgene Corporation, BMS, Genentech, Sanofi, Employee of: Samumed, LLC, Timothy McAlindon Grant/research support from: Samumed, LLC, Consultant for: Samumed, LLC, Astellas, Flexion, Pfizer, Regeneron, Seikugaku, Allan Gibofsky Shareholder of: AbbVie, Amgen, Johnson&Johnson, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Celgene, Novartis/Sandoz, Samumed, LLC, Merck, Flexion, Lilly, Speakers bureau: AbbVie, Celgene, Pfizer, Flexion, Lilly, Merck, Nancy Lane Consultant for: Samumed, LLC, Christian Lattermann Shareholder of: Cocoon, Consultant for: Samumed, LLC, Vericel, Cariheal, Joint Restoration Foundation, Nebojsa Skrepnik Grant/research support from: Samumed, LLC, Consultant for: Orthofix, Sanofi, Regeneron, Christopher Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Anita DiFrancesco Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Jeyanesh Tambiah Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Marc Hochberg Shareholder of: BriOri Biotech, Theralogix LLC., Consultant for: Bristol Myers Squibb, Eli Lilly, EMD Serono, Novartis Pharma AG, Pfizer Inc., Samumed LLC, Symic Bio Inc., Theralogix LLC, TissueGene Inc., TLC Biopharmaceuticals, Inc., Zynerba, Galapagos, IQVIA, Hoffman LaRoche.

Background Biologic therapies have considerably improved clinical management of autoimmune diseases. Over the past few years, several biosimilars have been introduced in Europe for these conditions. Limited information is available evaluating the impact of switching stable patients from originators to their respective biosimilars in clinical practice for non-medical reasons. Objectives This real-world study reported and compared patient characteristics, clinical outcomes, and healthcare resource utilization (HRU) associated with stable patients who switched from the originator biologic etanercept to its biosimilar (switchers) vs. those who stayed on the originator (non-switchers) in adults with a rheumatic condition such as ankylosing spondylitis (AS), psoriatic arthritis (PsA), or rheumatoid arthritis (RA). Methods Medical record data were retrospectively collected anonymously from rheumatologists in the UK and Germany. Adult patients who were diagnosed with RA, AS, or PsA, treated with originator etanercept for at least 6 months with a stable dosing schedule, and had no emergency department visit or hospitalization for the disease of interest over the 6-month period were eligible for the study. The index date for a non-switcher was the prescription date closest to one year after the initiation of originator etanercept and with a stable dosing for at least 6 months. The index date for a switcher was the biosimilar initiation date. Chart data available for at least 12 months prior to and post the index date were required. Patient characteristics, disease severity, symptoms and signs, and HRU were extracted anonymously. Unadjusted and adjusted comparisons of the outcomes between non-switchers and switchers were conducted among all patients and for each individual disease. Results Data were extracted from 242 patient records (non-switchers = 123, 50.8%; switchers = 119, 49.2%; AS=26.4%; PsA=26.0%; RA=47.5%) from 162 rheumatologists. At baseline, non-switchers were significantly younger than switchers (44.5 vs. 48.4 years, p Conclusion When compared with stable patients who underwent non-medical switching, stable patients who continued therapy with the originator biologic demonstrated significantly more improvement in disease severity. Other outcomes such as HRU appeared more similar between patients who underwent non-medical switching and patients who continued therapy with the originator biologic. The value of biosimilar non-medical switching requires continued evaluation in real-world clinical practice. Acknowledgement Medical writing support provided by Cinzia Metallo of Analysis Group, and funded by AbbVie. Disclosure of Interests Allan Gibofsky Shareholder of: AbbVie, Amgen, Johnson&Johnson, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Celgene, Novartis/Sandoz, Samumed, LLC, Merck, Flexion, Lilly, Speakers bureau: AbbVie, Celgene, Pfizer, Flexion, Lilly, Merck, Martha Skup Shareholder of: Shareholder of AbbVie, Employee of: Employee of AbbVie, Min Yang Consultant for: Employee of Analysis Group, which received consultancy fees from AbbVie, Wei Gao Consultant for: Employee of Analysis Group, which received consultancy fees from AbbVie, Tahera Doctor Consultant for: Employee of Analysis Group, which received consultancy fees from AbbVie

ObjectiveThere is emerging evidence that COVID-19 disproportionately affects people from racial/ethnic minority and low socioeconomic status (SES) groups. Many physicians across the globe are changing practice patterns in response to the COVID-19 pandemic. We sought to examine the practice changes among rheumatologists and what they perceive the impact to be on their most vulnerable patients.MethodsWe administered an online survey to a convenience sample of rheumatologists worldwide during the initial height of the pandemic (between 8 April and 4 May 2020) via social media and group emails. We surveyed rheumatologists about their opinions regarding patients from low SES and racial/ethnic minority groups in the context of the COVID-19 pandemic. Mainly, what their specific concerns were, including the challenges of medication access; and about specific social factors (health literacy, poverty, food insecurity, access to telehealth video) that may be complicating the management of rheumatologic conditions during this time.Results548 rheumatologists responded from 64 countries and shared concerns of food insecurity, low health literacy, poverty and factors that preclude social distancing such as working and dense housing conditions among their patients. Although 82% of rheumatologists had switched to telehealth video, 17% of respondents estimated that about a quarter of their patients did not have access to telehealth video, especially those from below the poverty line. The majority of respondents believed these vulnerable patients, from racial/ethnic minorities and from low SES groups, would do worse, in terms of morbidity and mortality, during the pandemic.ConclusionIn this sample of rheumatologists from 64 countries, there is a clear shift in practice to telehealth video consultations and widespread concern for socially and economically vulnerable patients with rheumatic disease.

Background In order to better understand the perspectives of patients and physicians regarding the treatment and management of rheumatoid arthritis (RA), we present and compare results from a patient-based and a physician-based survey developed by the RA NarRAtive advisory panel. Methods The RA NarRAtive initiative is directed by a global advisory panel of 39 healthcare providers and patient organization leaders from 17 countries. A survey of patients self-reporting a diagnosis of RA and a physician-based survey, designed by the advisory panel, were fielded online by Harris Poll from September 2014 to April 2016, and from August 2015 to October 2015, respectively. Results We present findings from 1805 patients whose RA was primarily managed by a rheumatologist, and 1736 physicians managing patients with RA. Results confirmed that RA carries a substantial disease burden; half of the patients surveyed reported stopping participation in certain activities as a result of their disease. While 90% of physicians were satisfied with their communications with their patients regarding RA treatment, 61% of patients felt uncomfortable raising concerns or fears with their physician. Of the patients providing responses, 52% felt that improved dialogue/discussion would optimize their RA management, and 68% of physicians wished that they and their patients talked more about their RA goals and treatment. Overall, 88% of physicians agreed that patients involved in making treatment decisions tend to be more satisfied with their treatment experience. Conclusion The results of these surveys highlight the impact of RA on patients, and a discrepancy between patient and physician views on communication. Further research, focused on improving patient–physician dialogue, shared goal-setting, and treatment planning, is needed. Electronic supplementary material The online version of this article (10.1186/s12955-018-1035-3) contains supplementary material, which is available to authorized users.

Background TNFα inhibitors have profoundly altered outcomes for patients with rheumatoid arthritis (RA) since they were introduced >15 years ago, by reducing disease activity and radiographic progression and improving quality of life. As a chronic disease, RA often requires life-long treatment, understanding drug survival in real-world settings can be beneficial in optimising disease management. Objectives To compare the long-term drug survival of adalimumab (ADA), certolizumab pegol (CZP), etanercept (ETN), golimumab (GLM), and infliximab (IFX) in patients with RA based on systematic literature review (SLR). Methods In this SLR, the goal was to identify full-text articles containing registry data or systematic reviews on TNFα inhibitors, following Cochrane dual-reviewer methodology. Searches were conducted in November 2017 with no date restriction, using Embase®, MEDLINE®, the Cochrane Central Trials Register and Database of Systematic Reviews, other Cochrane Library databases, and PubMed. Outcomes extracted included drug survival data that were analysed and reported using Kaplan-Meyer or Cox regression methods. Results Of 3688 non-duplicated publications initially identified, 3299 were excluded based on titles or abstracts and 344 based on full-text screening, leaving 26 publications published between 2005 and 2017 included in the analysis. The number of studies (range of sample size) for each drug were ADA: 15 (25–2349), ETN: 17 (20–3892), IFX: 21 (26–2898), GLM: 4 (2–88) and CZP: 1 (N/A). Among the analysed studies, the mean disease duration in years (range) was ADA: 10.7 (8.2–15.1); ETN: 15.9 (5.0–18.5); IFX: 14.2 (8.5–19.3); CZP: 10.3 (N/A); GLM: 8.9 (8.1–11.5) and mean baseline DAS28 (range) was ADA: 5.0 (4.2–5.9), ETN: 5.2 (4.3–6.3), IFX: 5.3 (4.1–6.4); CZP: 4.7 (N/A) and GLM: 4.7 (4.1–5.1). Trends for survival rates of first-line ETN were slightly higher than ADA at time points≥36 months; ADA and ETN had higher survival rates than IFX at >48 months (figure 1). Conclusions Long-term survival rates for ADA, ETN, and IFX were similar and relatively high for treatment periods up to 36 months. After 36 months, there was a noticeable decline in drug survival for all three TNFα inhibitors. Heterogeneity in study size and design may contribute to the range of survival data for each agent. Disclosure of Interest P. Emery Consultant for: Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz and Lilly, B. Vlahos Shareholder of: Pfizer, Employee of: Pfizer, P. Szczypa Shareholder of: Pfizer, Employee of: Pfizer, M. Thakur Shareholder of: Pfizer, Employee of: Pfizer, H. Jones Shareholder of: Pfizer, Employee of: Pfizer, J. Woolcott Shareholder of: Pfizer, Employee of: Pfizer, P. Santos Estrella: None declared, A. Gibofsky Shareholder of: AbbVie, Angen, Celgene, Pfizer, GSK, J and J, Regeneron, Consultant for: AbbVie, Celgene, MSD, Pfizer, Iroko, Horizon, Samumed, Relburn, Sandoz, Speakers bureau: Amgen, AbbVie, Pfizer, Celgene, Iroko, Horizon, MSD, Novartis, C. Rolland Employee of: Envision Pharma Group, G. Citera Consultant for: Pfizer, AbbVie, Bristol Myers Squibb, Novartis, Roche, L. Marshall Shareholder of: Pfizer, Employee of: Pfizer

To estimate short-term costs associated with non-medical switch (NMS) from originator biologics to biosimilars among stable patients with autoimmune conditions in rheumatology, gastroenterology, and dermatology from a US provider's and third-party payer's perspective.An economic model was constructed to estimate switching costs related to physician time and healthcare resource utilisation (HRU) at the initial NMS visit and over 3 months. The proportion of patients with relevant conditions treated with originators and expected NMS rate, physician time, HRU, and payer reimbursement were derived from a physician survey. Switching costs were estimated for a practice of 1,000 patients with relevant conditions by therapeutic area and for an insurance plan with 1 million individuals by therapeutic area and all areas combined. Switching cost drivers were assessed with one-way sensitivity analyses.Physicians expected extra 6 minutes for the NMS visit and 22 minutes over 3 months; NMS rates of 14.4%, 15.5%, and 17.7%; and 11.3%, 16.2%, and 33.2% of time not reimbursed for gastroenterology, rheumatology, and dermatology, respectively. The total switching costs for payer's were $771,460 (for n = 3,609 patients with an NMS rate of 16.6%), mostly due to follow-up visits and additional laboratory tests/procedures. In sensitivity analyses, the NMS rate was the main cost driver. Increasing the NMS rate to 25% and 50% increased payer's total switching costs to $1.19 and $2.39 million, respectively.Originator-to-biosimilar NMS in stable patients with autoimmune conditions could result in considerable switching costs for both providers and payers.

Objective: To assess morning stiffness in rheumatoid arthritis (RA) patients switched from immediate-release (IR) to delayed-release (DR) prednisone. Method: Circadian Administration of Prednisone in Rheumatoid Arthritis-1 (CAPRA-1) is a 12-week, randomized, multicentre, active-controlled study of morning stiffness that consisted of a double-blind phase and a 9-month open-label extension. Patients receiving IR prednisone with no significant improvement after the double-blind study were switched to DR prednisone. Morning stiffness duration and median absolute and relative changes in pain and global assessment were evaluated (3, 6, and 9 months). Results: In patients switched from IR to DR prednisone (n = 110), statistically significant reductions in morning stiffness occurred over 3 months and were sustained for 9 months. Absolute reduction of morning stiffness was ~50 min with > 40% relative reduction at each visit. Interleukin (IL)-6 levels were reduced by the same amount. Statistically significant and clinically meaningful mean reductions in morning stiffness were maintained at > 67 min at each visit along with significant improvements in pain and patient global assessment. There was no evidence of tachyphylaxis seen over the 9-month study. Conclusions: Patients receiving disease-modifying anti-rheumatic drugs (DMARDs) and IR prednisone who had not had significant reductions in morning stiffness demonstrated statistically significant and clinically meaningful improvements when switched to DR prednisone.

Although biologic drugs have changed the face of psoriasis treatment, affording greater efficacy and enhancing quality of life, safety issues have been reported and the warning labels have expanded. A variety of issues are now linked to biologic associated tumor necrosis factor-alpha (TNF-α) blocker use. Litigation has occurred with the use of a variety of biologics. The published risks of these agents include the development of lupus and autoimmune-like syndromes, squamous cell cancer (SCC), histoplasmosis, and coccidioidomycosis. This chapter focuses on litigation related to the use of biologics in dermatology, approaches to reducing physician liability, and hypothetical lawsuits against a dermatologist using biologics.

To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins.

To evaluate health care use and outcomes among patients who experienced a non-medical switch of their prescribed anti-tumor-necrosis-factor biological agent (anti-TNF) for cost containment reasons.Retrospective evaluation of Humedica electronic health records of patients ≥18 years old with anti-TNF treatment for immune conditions. Using natural language processing, stable patients who experienced a non-medical switch (for cost reasons) of their anti-TNF between 2007 and 2013 were identified (NMS cohort, n = 158) and matched to patients who did not (control cohort, n = 4804). Rates of office visits, emergency department visits, and hospitalizations at 30, 90, and 365 days following were evaluated. Medication-related adverse events, defined as subsequent medication change due to a side effect and/or efficacy-related reason were also compared.Adjusted rates of office visits were higher among the NMS cohort than the control cohort at 30 (46.4% vs. 31.7%, p .001), 90 (71.0% vs. 57.0%, p .001), and 365 days (87.8% vs. 76.8%, p .001). Rates of emergency department use and hospitalization were comparable between cohorts. The NMS cohort had higher adjusted rates of medication-related adverse consequences (both increased side effects and diminished efficacy) than the control cohort at 30 (13.8% vs. 4.0%, p = .003), 90 (31.6% vs 9.6%, p .001), and 365 days (54.7% vs. 20.3%, p .001). Compared with controls, the NMS cohort had higher adjusted rates of subsequent medication change within 1 year (27.82% vs. 13.9%, p = .001).Non-medical switching among patients prescribed anti-TNFs was associated with increased health care use, medication-related side effects, and reports of diminished efficacy.

Background To characterize the differences between women and men with gout. Methods We analyzed a US national cohort of gout patients cared for by rheumatologists. Results Compared with the 1012 men with gout, women with gout (n = 262) were older (71 vs. 61 years, p

NSAIDs, such as diclofenac, are the most commonly used medications to treat osteoarthritis (OA), but they are associated with dose-related adverse events (AEs). Low-dose submicron diclofenac was developed using a new, proprietary dry milling process that creates submicron drug particles (SoluMatrix Fine Particle Technology * ), enabling effective treatment at lower doses than other commercially available diclofenac drug products. This phase 3 study evaluated the efficacy and safety of low-dose submicron diclofenac 35 mg three times daily (tid) and twice daily (bid) in patients with OA pain.This double-blind study enrolled patients ≥40 years of age with clinically and radiographically confirmed (Kellgren-Lawrence grade II-III) hip or knee OA. Eligible patients were chronic NSAID and/or acetaminophen (APAP) users with baseline Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain subscale scores ≥40 mm by visual analog scale and an OA flare (≥15 mm increase in WOMAC pain subscale score following discontinuation of NSAIDs/APAP at screening). Patients were randomized to submicron diclofenac 35 mg tid, submicron diclofenac 35 mg bid, or placebo for 12 weeks. ClinicalTrials.gov identifier: NCT01461369.Efficacy parameters included mean change from baseline in WOMAC pain subscale score at week 12 (primary efficacy parameter) and in average total WOMAC score over 12 weeks.Submicron diclofenac 35 mg tid significantly improved WOMAC pain subscale scores from baseline at 12 weeks (-44.1; p = 0.0024) compared with placebo (-32.5). Submicron diclofenac 35 mg bid provided numerical improvement in pain at week 12 that did not reach statistical significance (-39.0; p = 0.0795) compared with placebo. Submicron diclofenac 35 mg tid (-35.9; p = 0.0002) and 35 mg bid (-30.3; p = 0.0363) improved the average total WOMAC score in treated patients over 12 weeks compared with placebo (-23.2). The most frequent AEs in the submicron diclofenac-treated groups were diarrhea, headache, nausea, and constipation. The inclusion of patients with a documented requirement for analgesic therapy (OA 'flare') at baseline and the high rates of rescue medication usage in the placebo group may have impacted the study outcome for the submicron diclofenac treatment groups.Low-dose submicron diclofenac is an effective therapeutic option for the treatment of OA pain.

Advances in rheumatology occur at a rapid pace and staying abreast of important changes is a challenge for all. Both novel drug development and enhanced understanding of conventional or historic therapies have molded current day rheumatologic practice. Rheumatology has led the way in the use of outcome measures and imaging modalities in common disorders like rheumatoid arthritis, osteoarthritis, and gout. The expertise of the rheumatologist has widened such that knowledge of economics, legal issues, related disorders and extraarticular disease is essential. In February 2013, the 6th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2013 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c-s.com.

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice. Electronic supplementary material The online version of this article (doi:10.1007/s00296-017-3780-8) contains supplementary material, which is available to authorized users.

Low-dose SoluMatrix diclofenac was developed to provide effective pain relief for osteoarthritis pain. We evaluated the effects of SoluMatrix diclofenac on health-related quality of life (HRQoL) measures in patients with osteoarthritis, hypothesizing that SoluMatrix-treated patients would experience significant improvement compared with placebo. In this 12-week, phase 3 randomized controlled trial, 305 patients with osteoarthritis of the hip or knee received SoluMatrix diclofenac 35 mg three times (TID) or twice (BID) daily or placebo. Measures included HRQoL, assessed by Short Form 36 (SF-36, version 2), and pain, stiffness, and physical function, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline and at week 12. Descriptive statistics were calculated for mean changes from baseline; inferential statistics compared treatment groups with placebo. SoluMatrix diclofenac 35 mg BID (6.2 [0.75]; P = 0.0048) or TID (6.6 [0.80]; P = 0.0014) produced large improvements in the SF-36 physical component summary (PCS) scores at week 12 (least squares mean change from baseline [SE]) compared with placebo (3.5 [0.78]). Minimum clinically important differences were observed in six out of eight SF-36 domains among patients in SoluMatrix diclofenac groups and five out of eight domains in the placebo group; treatment with SoluMatrix diclofenac 35 mg TID produced significant improvements (P ≤ 0.03) in five out of eight domains versus placebo. SoluMatrix diclofenac 35 mg TID significantly improved responses to 23 out of 24 questions in the WOMAC versus placebo (P ≤ 0.0334). Low-dose SoluMatrix diclofenac 35 mg TID and BID significantly improved HRQoL, pain, stiffness, and physical function in patients with osteoarthritis of the hip or knee.

There is a clinical need for new nonsteroidal anti-inflammatory drugs (NSAIDs) and/or new formulations that, at minimum, retain the established efficacy of standard NSAIDs while minimizing their associated adverse events. This phase 1 clinical trial characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano-formulated, lower-dose oral diclofenac (nano-formulated diclofenac) compared with oral diclofenac in healthy subjects.A single-center, single-dose, randomized, open-label, 5-period, 5-treatment, 10-sequence crossover study was completed in 30 healthy subjects. Subjects received either nano-formulated diclofenac 18 mg or 35 mg or diclofenac 50 mg in fed and fasting states. The maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), terminal elimination half-life (T1/2), and area under the concentration time curve (AUC), along with safety and tolerability, were assessed.Mean (± standard deviation) Tmax for nano-formulated diclofenac 18 (0.62 ± 0.35 h) and 35 mg (0.59 ± 0.20 h) demonstrated faster absorption than diclofenac 50 mg (0.80 ± 0.50 h). The T1/2 was similar between nano-formulated diclofenac 35 mg and diclofenac 50 mg (1.85 ± 0.45 h vs 1.92 ± 0.38 h, respectively). The Cmax for nano-formulated diclofenac 35 mg and diclofenac 50 mg was comparable in fasted subjects (1347 ± 764 ng/mL vs 1316 ± 577 ng/mL, respectively), but lower in fed subjects (524 ± 222 ng/mL vs 951 ± 391 ng/mL, respectively). As anticipated, there was a 19% reduction in drug exposure (AUC0(-∞)) when subjects received nano-formulated diclofenac 35 mg compared with diclofenac 50 mg under fasting conditions (1225 ± 322 h*ng/mL vs 1511 ± 389 h*ng/mL, respectively). Safety and tolerability were comparable between nano-formulated diclofenac and diclofenac.The novel nano-formulated, lower-dose diclofenac demonstrated lower systemic exposure, comparable Cmax, and faster absorption compared with diclofenac. In light of the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may permit use of lower NSAID doses that improve safety and tolerability while, at minimum, relieving pain similar to standard formulations.

Individuals with osteoarthritis face an increased risk of cardiovascular (CV) disease compared with age-matched control subjects. Both conditions share some common risk factors (eg, age, obesity, and hypertension) and the consequences or treatment of osteoarthritis may increase CV risk by impairing physical activity and exacerbating CV risk factors. Nonsteroidal anti-inflammatory drugs may have prothrombotic and/or hypertensive effects and a negative impact on renal function, all of which contribute to the increased risk of CV disease associated with these agents. The magnitude of these effects differs between agents and is, in part, determined by the relative balance of cyclo-oxygenase-1 or cyclo-oxygenase-2 inhibition. To minimize risk of CV disease in patients with osteoarthritis taking nonsteroidal anti-inflammatory drugs, physicians need to 1) monitor blood pressure and the new appearance or exacerbation of edema; 2) encourage lifestyle changes/nonpharmacologic treatments for pain/risk factor management; 3) choose the lowest effective dose of appropriate drug therapy to achieve adequate pain relief while minimizing CV risk; 4) change nonsteroidal anti-inflammatory drugs as needed to one with lower propensity to aggravate CV risk; and 5) modulate antihypertensive therapy and diuretic management as needed to maintain target blood pressure and weight.

SummaryIntroductionTreatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs.ObjectiveTo assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA.Search strategyThe Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications.Data collection and analysisData collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e.

Purpose of review To review the recent efficacy and safety data comparing methotrexate (MTX) and leflunomide (LEF) monotherapy, in combination with biologic therapies and in combination with each other. Recent findings MTX is the ‘anchor drug’ in all rheumatoid arthritis treatment strategies. Patients with contraindications to or intolerance of this drug pose a challenge to the treating physician. Recent studies have re-examined LEF as an alternative to MTX and demonstrated comparable clinical and radiographic efficacy both as monotherapy and in combination with certain biologic agents (tumor necrosis factor inhibitors and rituximab). Safety data, however, are less conclusive. Though some studies have shown greater withdrawal rates with LEF, the incidence of infection and elevated transaminases have been comparable. There are few new data examining the previously demonstrated added benefit of combination MTX+LEF over either alone. The safety profile of this combination, however, has been re-examined in several studies, with conflicting results. Although two meta-analyses and two small retrospective studies have demonstrated a safety profile similar to that of MTX monotherapy, data from a large population study suggested a greater degree of hepatotoxicity with combination. Summary LEF offers an alternative with comparable efficacy to MTX as both monotherapy and, as preliminary data suggest, in combination with certain biologics agents. Addition of LEF to MTX in rheumatoid arthritis patients who have failed MTX monotherapy has added therapeutic benefit. Safety data on LEF compared to MTX are less conclusive. All patients on LEF, and particularly those on combined LEF+MTX, should be monitored closely for hepatotoxicity.

The relationship between thyroid disorders and rheumatic diseases is significant.Thyroid diseases not only emulate rheumatic disease with findings such as myopathy or arthropathy but also frequently manifest with primary rheumatologic complaints that the practitioner should be wary of, such as calcium pyrophosphate deposition disease. There is increasing recognition of the prevalence of autoimmune thyroid diseases in patients with connective tissue disorder, highlighting a common mechanism for the disease pathogenesis, which requires further inquiry.

Objective.To report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice.Methods.Adults ≥ 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively.Results.In these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy.Conclusion.The RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting.

This study compared the efficacy and tolerability of the cyclooxygenase-2-selective inhibitor valdecoxib with the nonselective NSAID naproxen and with placebo in treating severe rheumatoid arthritis (RA).This 12-week, multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and tolerability of valdecoxib 10 mg QD (n = 170) or naproxen 500 mg BID (n = 167) with placebo (n = 171) in treating the signs and symptoms of severe RA. Study patients were agedor=18 years and were diagnosed as having RA foror=6 months that was stable due to a treatment regimen. Severe RA was defined as a physician's and patient's global assessment of disease activity of fair, poor, or very poor at baseline;or=6 tender or painful joints;or=3 swollen joints;or=45 minutes of morning stiffness; a visual analog scale pain rating ofor=40 mm; or increases since baseline in these measures. Efficacy outcome measures included the percentage of patients achieving an American College of Rheumatology Responder Index 20% (ACR-20) at weeks 1, 6 and 12. Adverse events (AEs) were graded by the investigator as mild, moderate, or severe at weeks 1, 6, and 12.Of the 508 patients randomized, 340 completed the study. The study groups were comparable for age, ethnic origin, weight, height, and concomitant medications, but the naproxen group had significantly more men (29% [49/167]) than the valdecoxib (18% [31/170]) and placebo (16% [27/171]) groups. The percentage of patients achieving an ACR-20 response was significantly greater in the valdecoxib and naproxen treatment groups (58.8% [100/170] and 60.8% [101/166], respectively) than in the placebo group (39.6% [67/169]) at week 12 (both, P0.001). The percentage of patients achieving an ACR-20 response was significantly greater in the naproxen group than in the placebo group at both week 1 (53.6% [89/166] vs 37.9% [64/169]; P = 0.003) and week 6 (64.5% [107/166] vs 46.7% [79/169]; P = 0.001), and in the valdecoxib group compared with placebo at week 1 (52.9% [90/170]; P = 0.008) but not at week 6. Patients in the valdecoxib and naproxen groups had significantly improved efficacy compared with placebo in most of the other secondary assessments of inflammation, pain, and function. The incidence of AEs was similar in all groups (valdecoxib, 54.1% [92/170]; naproxen, 55.4% [92/166]; and placebo, 52.9% [90/170]).Valdecoxib 10 mg QD administered over 12 weeks was significantly better than placebo and similar to naproxen 500 mg BID in treating the signs and symptoms of severe RA in these patients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam are commonly used to treat osteoarthritis (OA) but are associated with potentially serious dose-related adverse events (AEs). SoluMatrix meloxicam has been developed with the goal of enabling effective treatment at low doses. This phase 3 study evaluated the efficacy and safety of low-dose SoluMatrix meloxicam capsules 5 mg and 10 mg administered once daily for 12 weeks in patients with OA-related pain.This randomized, double-blind study enrolled patients ≥40 years of age with confirmed hip or knee OA (Kellgren-Lawrence grade II-III) who were chronic users of NSAIDs and/or acetaminophen for OA pain and had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale mean scores ≥40 mm. Eligible patients experienced an OA pain flare (defined as a ≥15 mm increase in the WOMAC pain subscale score) following discontinuation of NSAIDs/acetaminophen. Patients were randomized to receive once-daily SoluMatrix meloxicam 5 mg or 10 mg, or placebo for 12 weeks. ClinicalTrials.gov identifier: NCT01787188.The primary outcome measure was the mean change from baseline in WOMAC pain subscale score at week 12.Low-dose SoluMatrix meloxicam 5 mg (-36.52 [2.49]; P = 0.0005) and 10 mg (-34.41 [2.68]; P = 0.0059) once-daily treatment significantly reduced the mean (standard error) WOMAC pain subscale score from baseline at week 12 compared with placebo (-25.68 [2.64]). Patients treated with SoluMatrix meloxicam 5 mg or 10 mg reported significantly greater improvements in total WOMAC score and in WOMAC stiffness and function subscale scores at 12 weeks compared with placebo. The most common AEs in the combined low-dose SoluMatrix meloxicam group were headache, diarrhea, nausea, osteoarthritis, and urinary tract infection.Low-dose SoluMatrix meloxicam may have a potential role as a new therapeutic option for the management of OA-related pain.

Early, aggressive disease management is critical for halting disease progression and joint destruction in patients with rheumatoid arthritis. Combination therapy with at least two disease-modifying antirheumatic drugs, such as methotrexate (MTX), sulfasalazine, or hydroxychloroquine, is often more effective than monotherapy in reducing disease activity. Biologic therapies represent more effective and tolerable treatment options that, when combined with MTX, have been shown to dramatically reduce inflammation, inhibit radiographic progression, and induce remission. Although several types of treatment strategies are used in clinical practice, the most aggressive approaches that target early disease have shown the most promise in reversing disease progression and reducing disease-related costs.

Rheumatoid Arthritis (RA) Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study (RADIUS) is a unique, real-world, prospective, 5-year, observational study of over 10 000 patients with RA. RADIUS provides a snapshot of use patterns, effectiveness, and safety of DMARDs, biologics, and combination therapies used to manage RA in clinical practice.Patients with RA requiring a new DMARD or biologic (addition or switch) were eligible for the RADIUS study. Two separate patient cohorts were enrolled; RADIUS 1 patients initiated any new therapy at entry, and RADIUS 2 patients initiated etanercept at entry. Patient demographics and disease activity measures were collected at study entry, and baseline characteristics were summarized for various subgroups. Effectiveness, safety, and patterns of use will be tracked for therapies utilized during the 5-year study.RADIUS 1 enrolled 4959 patients, and RADIUS 2 enrolled 5102 patients, mostly at community private practices (88%). In RADIUS 1, most patients initiated methotrexate (MTX) monotherapy, followed by MTX in combination with a biologic (e.g. infliximab plus MTX) or other DMARD. In RADIUS 2, most patients initiated etanercept in combination with MTX, followed by etanercept monotherapy. When a new therapy was required, physicians tended to add another therapy versus switching therapies. Patients initiating a biologic had a longer duration of RA and more severe disease compared with patients initiating non-biologic therapy.These real-world data provide evidence of the prescribing practices of rheumatologists in 2001-2003. Future analyses will allow evidence-based comparisons of the long-term safety and effectiveness of DMARDs, biologics, and combination therapies to assist physicians in clinical decision-making.