Assessment of Treatment Safety and Quality of Life in Patients Receiving Etanercept Biosimilar for Autoimmune Arthritis (ASQA): A Multicenter Post-marketing Surveillance Study.

INTRODUCTION: Phase IV post-marketing surveillance studies are needed to evaluate the real-world safety and effectiveness of drug products. This study aimed to evaluate the safety and effectiveness of biosimilar etanercept (Altebrel, AryoGen Co., Iran) in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). METHODS: In this open-label, multicenter, prospective, observational, post-marketing surveillance study, 583 patients received biosimilar etanercept 25 mg twice weekly or 50 mg once weekly and were followed up to 12 months. The primary objective was to evaluate the safety of biosimilar etanercept by documenting all the adverse events in the case report forms throughout the study period. The secondary objective was to evaluate the effectiveness of biosimilar etanercept in study patients, where longitudinal changes in health assessment questionnaire (HAQ), pain, and disease activity scores were assessed. RESULTS: A total of 583 patients (44.80 ± 13.09 years of age) were included and followed for an average of 8.12 ± 3.96 months. Among all patients, 172 (29.50%) experienced at least one adverse event, and injection site reaction, abdominal pain, and upper respiratory tract infection were the most common. HAQ scores decreased from 1.32 ± 0.77 at baseline to 0.81 ± 0.61 at 12 months in patients with RA/PsA (p < 0.01) and from 0.82 ± 0.58 at baseline to 0.66 ± 0.63 at 12 months in patients with AS (p = 0.18). Pain scores decreased from 6.49 ± 2.41 at baseline to 3.51 ± 2.39 at 12 months (p < 0.01). CONCLUSION: The results demonstrated the real-world safety and effectiveness of biosimilar etanercept in patients with RA, PsA, and AS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04582084.

Patient Global Assessment of Disease Activity and Radiographic Progression in Early Arthritis: Three-Year Results From the ESPOIR Cohort.

OBJECTIVE: To determine whether patient global assessment of disease activity (PtGA) over the first year of disease course, as part of a Boolean-based definition of remission and considered individually, had a significant relationship with structural progression over 3 years in patients with early arthritis. METHODS: We conducted a prospective, observational study using ESPOIR (Étude et Suivi des Polyarthrites Indifférenciées Récentes) cohort data. Remission states were defined as 1) 4-variable remission, which included a tender joint count in 28 joints, a swollen joint count in 28 joints (SJC28), a C-reactive protein (CRP; mg/dl) level, and PtGA (scored 0-10, all scores of ≤1); 2) PtGA near remission, which included the same parameters as 4-variable remission with only PtGA >1 (of a maximum possible score of 10); 3) 3-variable remission (sum of the proportion of patients in 4-variable remission and the proportion of patients in PtGA near remission); or 4) nonremission. The strictest status satisfied both at 6 and 12 months was considered. Radiographic progression was determined as a change of ≥5 points in the total Sharp/van der Heijde score (ΔSHS) from baseline to 3 years. The predictive capacities for radiographic damage of different remission definitions were assessed by odds ratio (OR). The association between each individual component of remission with ΔSHS was tested through multivariate linear regression analyses. RESULTS: Among 520 patients, 7% achieved 4-variable remission and 12% achieved PtGA near remission. Radiographic progression was observed in 29% of patients who achieved 4-variable remission (OR versus nonremission; OR 0.32 [95% confidence interval (95% CI) 0.15, 0.68]) and in 45% of patients with PtGA near remission (OR 0.65 [95% CI 0.38, 1.11]); the comparison was not statistically different (OR 0.49 [95% CI 0.20, 1.18]). In 3-variable remission, radiographic progression was observed in 39%. Of the individual components, only the SJC28 and CRP level were associated with radiographic progression. CONCLUSION: All definitions of remission led to low structural degradation in early arthritis, and 4-variable remission led to less radiographic progression than PtGA near remission, but without a statistically significant difference. Both 4-variable remission and 3-variable remission appear to be useful targets when aiming for structural nonprogression.

Trends in Office Visits During Which Opioids Were Prescribed for Adults With Arthritis in the US, 2006-2015.

OBJECTIVE: To analyze trends for visits to office-based physicians at which opioids were prescribed among adults with arthritis in the US, from 2006 to 2015. METHODS: We analyzed nationally representative data on patient visits to office-based physicians from 2006 to 2015 from the National Ambulatory Medical Care Survey (NAMCS). Visit percentages for first- and any-listed diagnosis of arthritis by age groups and sex were reported. Time points were grouped into 2-year intervals to increase the reliability of estimates. Annual percentage point change and 95% confidence intervals (95% CIs) were reported from linear regression models. RESULTS: From 2006 to 2015, the percentage of visits to office-based physicians by adults with a first-listed diagnosis of arthritis increased from 4.1% (95% CI 3.5%, 4.7%) in 2006-2007 to 5.1% (95% CI 3.9%, 6.6%) in 2014-2015 (P = 0.033). Among these visits, the percentage of visits with opioids prescribed increased from 16.5% (95% CI 13.1%, 20.5%) in 2006-2007 to 25.6% (95% CI 17.9%, 34.6%) in 2014-2015 (P = 0.017). The percentage of visits with any-listed diagnosis of arthritis increased from 6.6% (95% CI 5.9%, 7.4%) in 2006-2007 to 8.4% (95% CI 7.0%, 10.0%) in 2014-2015 (P = 0.001). Among these visits, the percentage of visits with opioids prescribed increased from 17.4% (95% CI 14.6%, 20.4%) in 2006-2007 to 25.0% (95% CI 19.7%, 30.8%) in 2014-2015 (P = 0.004). CONCLUSION: From 2006 to 2015, the percentage of visits to office-based physicians by adults with arthritis increased and the percentage of opioids prescribed at these visits also increased. NAMCS data will allow continued monitoring of these trends after the implementation of the 2016 Centers for Disease Control and Prevention Guideline for prescribing opioids for chronic pain.

Physician-patient agreement at a rheumatology consultation - construction and validation of a consultation assessment instrument.

OBJECTIVES: After consultations, the physician's perceptions differ from the patient's perceptions concerning illness level, cause, and nature of the problem and content of the consultation. Agreement on problems requiring follow-up was associated with a better outcome. The primary aim of this study was to build and validate an instrument that could assess physician-patient agreement in the rheumatology consultation. The secondary objective was to assess agreement association with patient's clinical and sociodemographic data. MATERIALS AND METHODS: A ten-item questionnaire - "Consultation Assessment Instrument" (CAI) - was developed for this study to assess the physician-patient agreement. Ten physicians and 102 patients diagnosed with an inflammatory joint disease under biological therapy were included. The items were evaluated and the index of proportional agreement for the dichotomized answers "agree" (Ppos) and "disagree" (Pneg) was calculated. RESULTS: Consultation satisfaction was the item with the highest agreement. On the opposite end, the item about the explanation of treatment importance was the item with the lowest agreement between patient and physician. Except for one item, the high level of agreement between patient and physician was due to a higher Ppos. Index of proportional agreement was high for 9 of the 10 items (0.816≤ Iv ≤0.990). Patients with lower disease activity scores had a more positive experience. A good internal consistency was obtained for both patient's and physician's questionnaire (α = 0.88 and α = 0.80, respectively). CONCLUSIONS: Both patient and physician showed a positive experience towards Rheumatology consultation. Physician-patient agreement was high in the majority of the consultation aspects (mean Iv = 0,93). A good internal consistency was obtained for both patient's and physician's questionnaire. CAI could be useful as a mental checklist in daily practice or as an educational tool for training consultation skills.

Scenario of the Treatment of Arthritis with Natural Products.

BACKGROUND: Conventional treatments of arthritis use toxic and poorly tolerated drugs. Therefore, natural products are an alternative because they are important sources of bioactive substances with therapeutic potential. OBJECTIVE: To perform synthesis of patent applications associated with the use of natural products in the technological development of the invention for use in treating arthritis. METHODS: The search for patents was conducted using the following databases of World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), United States Patents and Trademark Office (USPTO) and National Institute of Intellectual Property (INPI) using as keywords - arthritis, treatment and the International Patent Classification (IPC) A61K36 / 00. RESULTS: A total of 617 patents related to the subject were registered in the period available in patents databases during the study period from the years 2005 to 2017, of which 44 were analyzed based on the established inclusion criteria. The most important countries for protecting these inventions were China, followed by the United States of America, the Republic of Korea and Japan. As for the typology of depositors, that were identified by Educational Institutions and Public Institutes of Research (IEIPP) and Companies and Private Research Institutes (EIPP). CONCLUSION: The analysis of patents made it possible to characterize the natural products used in the treatment of arthritis, with emphasis on botanical extracts (71%), as a single component, as well as in association with other botanical extracts, isolated compounds and minerals.

Medical Use of Long-term Extended-release Opioid Analgesics in Commercially Insured Adults in the United States.

OBJECTIVES: We examined the proportion of patients initiating extended-release (ER) opioids who become long-term users and describe how pain-related diagnoses before initiation of opioid therapy vary between drugs and over time. METHODS: Using MarketScan (2006-2015), a US national commercial insurance database, we examined pain-related diagnoses in the 182-day baseline period before initiation of ER opioid therapy to characterize indications for opioid initiation. We report the proportion who became long-term users, the median length of opioid therapy, and the proportion with cancer and other noncancer chronic pain, by active ingredient. RESULTS: Among 1,077,566 adults initiating ER opioids, 31% became long-term users, with a median length of use of 209 days. The most common ER opioids prescribed were oxycodone (26%) and fentanyl (23%), and the most common noncancer pain diagnoses were back pain (65%) and arthritis (48%). Among all long-term users, 16% had a diagnosis of cancer. We found notable variation by drug. Eighteen percent of patients initiating drugs approved by the Food and Drug Administration >10 years ago had evidence of cancer during baseline compared with only 8% of patients who received newer drugs. CONCLUSIONS: In a national sample of adults with private insurance, back pain was the most common diagnosis preceding initiation of opioid therapy. Opioids that have been approved within the last 10 years were more frequently associated with musculoskeletal pains and less frequently associated with cancer. Amid increasing concerns regarding long-term opioid therapy, our findings provide context regarding the conditions for which long-term opioid therapy is prescribed.

Treatment failure in inflammatory arthritis: time to think about syndemics?

Social determinants of health play a crucial role in health and disease. In current times, it has become increasingly known that biological and non-biological factors are potentially linked and help to drive disease. For example, links between various comorbidities, both physical and mental illnesses, are known to be driven by social, environmental and economic determinants. This contributes to worse disease outcomes. This article discusses the concept of syndemics, which although well-described in some conditions, represents a novel concept in the context of rheumatic and musculoskeletal diseases. Written in the form of a viewpoint, the article focuses on a novel theoretical framework for studying inflammatory arthritis, based on a syndemic approach that takes into account the social context, biocultural disease interaction, and socio-economic characteristics of the setting. Syndemics involving inflammatory arthritis may be most likely in a social context involving limited access to health care, lack of physical activity and obesogenic diets, high rates of alcohol consumption, and high exposure to stressful life events.

Factors associated with potentially problematic opioid prescriptions among individuals with private insurance and medicaid.

If opioid analgesics are prescribed and used inappropriately, they can lead to addiction and other adverse effects. In this study, we (1) examine factors associated with potentially problematic opioid prescriptions and (2) quantify the link between potentially problematic prescriptions and the development of opioid use disorder. We found that older age; female sex; having back pain, arthritis, or migraine; hydrocodone prescription; previous pharmacotherapy for opioid use disorder; and frequent emergency department use were associated with problematic prescriptions among individuals with Medicaid and private insurance. Patients with commercial insurance and Medicaid who had potentially problematic opioid prescriptions were eight and three times more likely, respectively, to develop an opioid use disorder than patients without potentially problematic opioid prescriptions. Our findings help identify factors associated with problematic prescriptions and underscore the importance of targeted public health interventions.

Qualitative insights into the experience of pain in older Australian women with arthritis.

OBJECTIVE: To explore qualitative insights into the pain experience of older women with quantitatively derived pain profiles. METHODS: The sequential mixed methods design involved applying quantitative pain profiles, derived from an earlier latent class analysis, to qualitative comments by a sample of older Australian women with arthritis. Data from a substudy of the Australian Longitudinal Study on Women's Health, mid-aged cohort, born 1946-1951, were used. Inductive content analysis was conducted to explore qualitative insights into the experience of pain. RESULTS: The average age of women was 64.6 years (±1.4). Within each derived pain profile, themes generated from the qualitative comments of women were concordant with the profile descriptors: 'I manage my pain' for the uni-dimensional, mild pain profile (comments from 56 women); 'I live with pain every day' and 'I rely on medication regularly' for the moderate multidimensional pain profile (comments from 39 women); and 'multiple pains', 'I suffer with pain' and 'I am unable and adjust' for the severe multidimensional pain profile (comments from 31 women). CONCLUSION: Women with different pain profiles used different language and strategies in managing their pain experience, information which can guide clinicians to provide more tailored support for self-management and care of arthritis pain.

Genetic toxicological assessment and anti-arthritic effects of an ethanolic extract obtained from Salvia lachnostachys Benth leaves in mice.

In the present study, mice were subjected to prolonged treatment with ethanolic extract of Salvia lachnostachys Benth leaves (SLEE), and the inflammatory and arthritic parameters were evaluated using the Complete Freund's Adjuvant (CFA) model. The genotoxicity of SLEE were also assayed using genetic toxicological tests. For the CFA model, 28 male C57BL/6 mice were distributed randomly into four groups (control, 50 mg/kg of SLEE, 100 mg/kg of SLEE and dexamethasone) for the evaluation of hyperalgesia and paw edema for 21 days after injection of CFA into the paw. To conduct the toxicogenetic assessments (comet assay and micronuclei assay), apoptosis and splenic phagocytosis were evaluated in male Swiss mice after the administration of saline (control group), cyclophosphamide (positive control group) and SLEE (10, 100 and 1000 mg/kg). SLEE significantly reduced the mechanical hyperalgesia and edema caused by CFA injection. The results of the toxicogenetic assessment revealed no toxicogenetic potential in the mice, and the evaluation of apoptosis showed an increase in apoptotic cells in the spleen after 72 h of treatment with SLEE (1000 mg/kg). SLEE exhibited anti-arthritic activity with no toxicogenetic damage. These toxicogenic results support the safety of SLEE.

The Duality of Economic Issues With Medication Non-adherence in Patients With Inflammatory Arthritis.

PURPOSE OF REVIEW: In this review, we synthesize current data on non-adherence across inflammatory arthritides and explore (1) the effects of economic factors on non-adherence and (2) the impacts of non-adherence on economic outcomes. RECENT FINDINGS: Recent evidence demonstrates medication non-adherence rates as high as 74% in ankylosing spondylitis (AS), 90% in gout, 50% in psoriatic arthritis (PsA), 75% in systemic lupus erythematosus (SLE), and 82% in rheumatoid arthritis (RA). The effects of socioeconomic factors have been studied most in RA and SLE but with inconsistent findings. Nonetheless, the evidence points to having prescription coverage and costs of treatment as important factors in RA and education as an important factor in SLE. Limited data in AS and gout, and no studies of the effects of socioeconomic factors in PsA, show knowledge gaps for future research. Finally, there is a dearth of data with respect to the impacts of non-adherence on economic outcomes.

HLA-DRB1 Amino Acid Positions 11/13, 71, and 74 Are Associated With Inflammation Level, Disease Activity, and the Health Assessment Questionnaire Score in Patients With Inflammatory Polyarthritis.

OBJECTIVE: Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes. METHODS: We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome. RESULTS: A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10-6 ), the SJC (P = 7.51 × 10-6 ), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10-4 ). CONCLUSION: Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome.

What PASSes for good? Experience-based Swedish and hypothetical British EuroQol 5-Dimensions preference sets yield markedly different point estimates and patient acceptable symptom state cut-off values in chronic arthritis patients on TNF blockade.

OBJECTIVES: Health utilities derived from answers to generic health-related quality of life (HRQoL) questionnaires such as the EuroQol 5-Dimensions (EQ-5D) are often used in cost-utility analyses (CUAs) of new and expensive treatments. Different preference sets (tariffs) used in the computation of utility values and quality-adjusted life-years (QALYs) from questionnaire responses (health states) yield varying results, potentially affecting decisions of resource allocation. The objective of the present study was to compare British (UK), hypothetical, and Swedish (SE), experience-based, EQ-5D utilities using data from clinical practice. METHOD: UK and SE EQ-5D utilities were computed in an observational cohort of patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) treated with tumour necrosis factor (TNF) blockers, comparing point estimates and patient acceptable symptom state (PASS) cut-off levels. RESULTS: SE utilities were found to be consistently higher than UK utilities, and PASS cut-offs were essentially stable over time. CONCLUSIONS: With higher baseline utilities, there may be less room for improvement after an intervention and thus less accumulation of QALYs in CUAs applying the SE, as opposed to the UK, EQ-5D tariff.

Enhanced transdermal delivery of luteolin via non-ionic surfactant-based vesicle: quality evaluation and anti-arthritic assessment.

Luteolin (LUT) is a promising molecule with potential anti-arthritic activity. This investigation presents formulation and evaluation of niosomal transgel for enhanced transdermal delivery of LUT. Different non-ionic surfactants and vesicle compositions were employed for preparation of niosomes. The vesicle size analysis showed that all vesicles were in the range from 534.58 to 810.22 nm which favoured efficient transdermal delivery. The entrapment of LUT in vesicle was found to be higher in all surfactant. The developed formulation was proved significantly superior in terms of amount of drug permeation with an enhancement ratio of 2.66 when compared to a control formulation. The in vivo bioactivity studies revealed that the prepared niotransgel formulation of LUT was able to provide good anti-arthritic activity and the results were comparable to standard (diclofenac gel for anti-arthritic and analgesic). Finally, the results were confirmed through radiological analysis which proved that the prepared niotransgel was effectively able to treat arthritis and results were comparable with the standard formulation.

A cross-sectional assessment of the prevalence of multiple chronic conditions and medication use in a sample of community-dwelling adults with fibromyalgia in Olmsted County, Minnesota.

OBJECTIVES: The objective of this study was to evaluate the problem of multiple chronic conditions and polypharmacy in patients with fibromyalgia. DESIGN: Retrospective medical record review. SETTING: Olmsted County, Minnesota. PARTICIPANTS: 1111 adults with fibromyalgia. PRIMARY AND SECONDARY OUTCOME MEASURES: Number and type of chronic medical and psychiatric conditions, medication use. RESULTS: Medical record review demonstrated that greater than 50% of the sample had seven or more chronic conditions. Chronic joint pain/degenerative arthritis was the most frequent comorbidity (88.7%), followed by depression (75.1%), migraines/chronic headaches (62.4%) and anxiety (56.5%). Approximately, 40% of patients were taking three or more medications for symptoms of fibromyalgia. Sleep aids were the most commonly prescribed medications in our sample (33.3%) followed by selective serotonin reuptake inhibitors (28.7%), opioids (22.4%) and serotonin norepinephrine reuptake inhibitors (21.0%). CONCLUSIONS: The results of our study highlight the problem of multiple chronic conditions and high prevalence of polypharmacy in fibromyalgia. Clinicians who care for patients with fibromyalgia should take into consideration the presence of multiple chronic conditions when recommending medications.

Major cost savings associated with biologic dose reduction in patients with inflammatory arthritis.

The purpose of this study was to explore whether patients with Inflammatory Arthritis (IA) (Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) or Ankylosing Spondylitis (AS)) would remain in remission following a reduction in biologic dosing frequency and to calculate the cost savings associated with dose reduction. This prospective non-blinded non-randomised study commenced in 2010. Patients with Inflammatory Arthritis being treated with a biologic agent were screened for disease activity. A cohort of those in remission according to standardized disease activity indices (DAS28 < 2.6, BASDAI < 4) was offered a reduction in dosing frequency of two commonly used biologic therapies (etanercept 50 mg once per fortnight instead of weekly, adalimumab 40 mg once per month instead of fortnightly). Patients were assessed for disease activity at 3, 6, 12, 18 and 24 months following reduction in dosing frequency. Cost saving was calculated. 79 patients with inflammatory arthritis in remission were recruited. 57% had rheumatoid arthritis (n = 45), 13% psoriatic arthritis (n = 10) and 30% ankylosing spondylitis (n = 24). 57% (n = 45) were taking etanercept and 43% (n = 34) adalimumab. The percentage of patients in remission at 24 months was 56% (n = 44). This resulted in an actual saving to the state of approximately 600,000 euro over two years. This study demonstrates the reduction in biologic dosing frequency is feasible in Inflammatory Arthritis. There was a considerable cost saving at two years. The potential for major cost savings in biologic usage should be pursued further.

Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (coxibs) and traditional NSAIDs (tNSAIDs), have been widely used for the treatment of pain and rheumatic disease. The use of NSAIDs has been linked to increased cardiovascular toxicity in both healthy individuals and patients with established cardiovascular disease. Various recently published studies have raised concerns about the cardiovascular safety of NSAIDs; this review is focused on the cardiotoxic effects of NSAIDs. AREAS COVERED: This review focuses on arthritis trials, placebo-controlled trials, meta-analyses, preclinical and observational studies associated with the use of NSAIDs-induced cardiotoxicity. It analyses the data given in these studies and discusses the cardiotoxic risk of NSAIDs. EXPERT OPINION: Analysis of various clinical, preclinical, meta-analysis and observational studies showed that coxibs and tNSAIDs increase the risk of cardiotoxicity. Cardiotoxic risk depends on dose, duration and frequency of NSAID administration. Most studies were based on large medical databases with miscellaneous populations and pointed to an increase risk of cardiotoxicity under NSAID medication. The cardiotoxicity associated with use of NSAIDs might be due to inhibition of prostacyclin synthesis, oxidative stress, increase in blood pressure and impaired endothelial function.