Cardiovascular Disease in Rheumatoid Arthritis: Risk Factors, Autoantibodies, and the Effect of Antirheumatic Therapies

Objective: To scope the current published evidence on cardiovascular risk factors in rheumatoid arthritis (RA) focusing on the role of autoantibodies and the effect of antirheumatic agents. Methods: Two reviews were conducted in parallel: A targeted literature review (TLR) describing the risk factors associated with cardiovascular disease (CVD) in RA patients; and a systematic literature review (SLR) identifying and characterizing the association between autoantibody status and CVD risk in RA. A narrative synthesis of the evidence was carried out. Results: A total of 69 publications (49 in the TLR and 20 in the SLR) were included in the qualitative evidence synthesis. The most prevalent topic related to CVD risks in RA was inflammation as a shared mechanism behind both RA morbidity and atherosclerotic processes. Published evidence indicated that most of RA patients already had significant CV pathologies at the time of diagnosis, suggesting subclinical CVD may be developing before patients become symptomatic. Four types of autoantibodies (rheumatoid factor, anti-citrullinated peptide antibodies, anti-phospholipid autoantibodies, anti-lipoprotein autoantibodies) showed increased risk of specific cardiovascular events, such as higher risk of cardiovascular death in rheumatoid factor positive patients and higher risk of thrombosis in anti-phospholipid autoantibody positive patients. Conclusion: Autoantibodies appear to increase CVD risk; however, the magnitude of the increase and the types of CVD outcomes affected are still unclear. Prospective studies with larger populations are required to further understand and quantify the association, including the causal pathway, between specific risk factors and CVD outcomes in RA patients.

Therapeutic Effectiveness of AxioBionics Wearable Therapy Pain Management System in Patients with Chronic Lower Back Pain

Chronic lower back pain is one of the most common medical conditions leading to a significant decrease in quality of life. This study retrospectively analyzed whether the AxioBionics Wearable Therapy Pain Management (WTPM) System, a customized and wearable electrical stimulation device, alleviated chronic lower back pain, and improved muscular function. This study assessed self-reported pain levels using the visual analog scale before and during the use of the AxioBionics WTPM System when performing normal activities such as sitting, standing, and walking (n = 69). Results showed that both at-rest and activity-related pain were significantly reduced during treatment with the AxioBionics WTPM System (% reduction in pain: 64% and 60%, respectively; P < .05). Thus, this study suggests that the AxioBionics WTPM System is efficacious in treating chronic lower back pain even when other therapies have failed to sufficiently decrease reported pain levels.

Changes in Invasiveness and Latent Infection Rate Associated with Switching the Approach in Total Hip Replacement

Purpose: Muscle-sparing approaches for total hip replacement (THR) involve learning curves. This study aimed to clarify changes in invasiveness and infection rate with changes in approach. Methods: One surgeon changed the approach of THR from Dall’s approach (Dall) to anterolateral modified Watson-Jones approach (OCM). Another changed from Dall to a direct anterior approach (DAA). Another 3 surgeons changed from posterolateral approach (PL) to OCM. Subjects were 150 cases, comprising the last 25 cases with conventional approaches and the first 25 cases with new approaches (Dall to OCM: 25 + 25; Dall to DAA: 25 + 25; PL to OCM: 25 + 25 cases). Differences in operative time, bleeding volume, hospital stay, haemoglobin (Hb), white blood cell count, lymphocyte count, creatine kinase (CK) and C-reactive protein (CRP) were investigated. Results: In the change from Dall to OCM, only hospital stay decreased. In the change from Dall to DAA, hospital stay and CRP decreased, but bleeding volume increased. In the change from PL to OCM, operative time, CRP and CK decreased, but Hb also decreased. Cases with lymphocyte count <1000/μL or lymphocytes comprising <10% of total white blood cells at around day 4 after surgery were defined as latent infection cases. In these cases, operative time was longer, Hb was lower and CK was higher. Conclusion: Introducing muscle-sparing approaches improved many markers of invasiveness, but some items deteriorated. In the early stages of introducing a new approach, choosing cases without obesity and without high muscle volume may reduce the risk of infection.

Interstitial Lung Disease and its Associations in Rheumatoid Arthritis: Data from a District General Hospital in Sri Lanka

Context: Interstitial lung disease (ILD) is a frequent pulmonary manifestation of rheumatoid arthritis (RA). No Sri Lankan studies have determined the prevalence of lung disease in RA and its associations. Aims: To find the prevalence of ILD in RA and its association with rheumatoid factor (RF), erosions, Disease activity score in 28 joints (DAS 28), disease duration, Body mass index(BMI), erythrocyte sedimentation rate (ESR), smoking, and also to determine the prevalence of lung disease with demographic factors like age, sex, and income. Settings and Design: Questionnaire based retrospective study at a District General Hospital in Sri Lanka. Materials and Methods: Diagnosed RA patients included through convenient sampling as it was a simple method that could facilitate data collection in a short duration. Since all patients with a diagnosis of RA were eligible, all consecutive patients with a diagnosis of RA at the rheumatology clinics were included in the study. To reduce the bias a large sample of patients were used as well as patients attending different rheumatology clinics were included and also patients who were referred to the hospital from peripheries were included in the study. The calculated sample size was 384 and according to patient numbers attending clinics, a period of 6 months was decided to select the study sample. Statistical Analysis Used: Chi-Square calculation and logistic regression analysis using Minitab 17 software. Results: From 384 patients, the prevalence of ILD was 14.58%, been 5.4% in early RA (<2 years disease duration). Mean age of ILD group was 52.94 years (95% CI 64.66-41.22). Mean RA duration was 7.69 years (95% CI, 2.38-12.99). Male to female sex ratio of RA was 1:7, and that of ILD was 2:9. DAS 28 was 4.58 (95% CI, 3.48-5.68). Statistically significant associations were noted with ILD and DAS 28 ( P = .0006), ESR ( P = .005), RF ( P = .03), erosions ( P < .00001), and smoking ( P < .05). Mean BMI was 22.67 kg and 75.78% had low income (<50 000 rupees/month = 327 US $). Conclusions: ILD significantly associates RA severity indices like DAS 28, ESR, erosions, RF, and also with smoking. No significant association was found with BMI or gender difference. Therefore, disease severity indices could be used to predict progression to ILD in RA.

Dental Amalgams and the Incidence Rate of Arthritis among American Adults

This hypothesis-testing study evaluated the relationship between mercury (Hg)-based dental amalgams and arthritis diagnoses among adults in the United States (US). A total of 86 305 425 weighted-persons with ⩾1 dental amalgam filling surface (DAFS) (exposed group) and 32 201 088 weighted-persons with ⩾1 other dental filling surface (ODFS) (no DAFS, unexposed group) were examined in the 2015 to 2016 National Health and Nutritional Examination Survey (NHANES). All persons were 20 to 80 years-old with known demographic characteristics and arthritis status. Survey logistic regression and survey frequency modeling in SAS were employed with and without adjustment of covariates. The arthritis rate was significantly increased in the exposed group compared to the unexposed group in the unadjusted (7.68-fold) and adjusted (4.89-fold) models. Arthritis (per 10 000 weighted-person-years) was 6.0-fold significantly increased in the exposed group (6.2) compared to the unexposed group (1.06). A significant bimodal dose-dependent relationship between DAFS and arthritis rate was observed. The arthritis rate increased with increasing DAFS (peak among persons with 4-7 DAFS) and, subsequently, decreased among those with >6 DAFS. A significant decrease in arthritis rate among persons with >13 DAFS as compared to those persons with 4 to 7 DAFS was observed. A significant association between DAFS and arthritis risk and a dose-dependent DAFS associated immune-stimulation/immune-suppression with arthritis risk were observed. An estimated additional $96 835 814 US dollars (USD) are spent on annual medical costs and $184 797 680 USD are lost in annual wages from reported new onset arthritis attributably associated with DAFS (annual total cost = $281 633 494 USD).

A Randomized Placebo-Controlled Trial of Efficacy and Safety: Drug-Free Gel Containing Ultra-Deformable Phospholipid Vesicles (TDT 064) in Osteoarthritic Knees

Background: There are a number of topical agents that are used for treatment of knee osteoarthritis. Drug-free gels, containing ultra-deformable phospholipid vesicles (TDT 064) are one such topical therapy, which have been stated to act as a bio lubricant. However, the evidence of TDT 064 in treatment of knee osteoarthritis is limited. Hence, the aim of this study was to evaluate the efficacy of pain control as a primary outcome and safety of TDT 064 compared with a topical placebo. Methods: Sixty-four patients with primary osteoarthritis, with radiographic showing Kellgren and Lawrence classification grade II to III, were randomized into 2 groups. In the first group of 32 patients TDT 064 was used as topical agent, whilst in the second group of 32 patients a placebo identical in appearance was used instead. The verbal numerical rating scale (VNRS) was used for recording pain levels, Self-reported Knee Injury and Osteoarthritis Outcome Scores (KOOS) as well as amounts of rescue medication were also recorded. The data were recorded at the start of the study, and then at follow-up appointments of 14 days, 6 weeks, and 3 months. Results: The mean VNRS for pain in both groups were significantly improved, when compared to the start of treatment ( P < .0001); however, there were no differences between groups at any follow up visit. KOOS in all subscales were not significantly different between both groups at baseline and at the end of treatment. However, the average amount of NSAIDs in the TDT 064 group was 26.39 ± 22.11 tabs, which was significantly lower than the control group; which used an average 37.03 ± 19.22 tabs in 3 months ( P = .047). Conclusions: There were no differences in the VNRS for pain and KOOS scores between the active and placebo groups. Although, TDT 064 could decrease usage of rescue medication the difference with use of a placebo was minimal. Further, larger trials would also be beneficial to demonstrate any differences between TDT 064 and a placebo. Trial Registration: TCTR, TCTR 20190302001. Registered 1 March, 2019: http://www.clinicaltrials.in.th

Assessment of Adipokines, CXCL16 Chemokine Levels in Patients With Rheumatoid Arthritis Combined With Metabolic Syndrome

Objective: Rheumatoid arthritis (RA), which is a chronic systemic inflammatory disease, is associated with accelerated atherosclerosis and an increased risk of cardiovascular disease (CVD), but the causal factors have yet to be completely elucidated. The studies show that the prevalence of metabolic syndrome (MtS) was significantly higher in RA patients compared to the population. In RA and MetS inflammation and atherosclerosis are closely linked. The level of chemokines and adipokines, which may play a role in the development of atherogenesis in RA with MetS patients is currently unknown. In this study, we investigated the level of chemokine C-X-C motif chemokine ligand 16 (CXCL16) and adipokine in RA with MetS patients and assessed the association of biomarkers with clinical and biochemical activity scores of RA and components of MetS. Methods: Blood serum of 298 people (48—patients with RA and MetS, 82—with RA without MetS, 105—with MetS, 63—control group without both RA and MetS) was tested for (CXCL16), Resistin, Leptin and Fibroblast Growth Factor 21 (FGF21) levels by fluorescent antibody technique. Statistical analysis was performed using SPSS version 18.0. Results: The biomarker study showed the highest level in the RA with MetS patient group; but as compared with the RA group the differences were insignificant. CXCL16 (Me = 426.2 pg/ml (Q25-75 250.5-527.6), resistin (Me = 8685.4 pg/ml (Q25-75 6480.8-13 629.1), and FGF21 (Me = 443.6 pg/ml (Q25-75 772.9-916.3) proved to be significantly augmented in RA with MetS patients group, and in RA without MetS patients group (Me = 312.7 (Q25-75 199.4-517.7) pg/ml; Me = 8265.3 (Q25-75 5779.7-13 340.5) pg/ml; Me = 412.4 (Q25-75 300.4-497.4) pg/ml, respectively) as compared with MetS patients group (Me = 189.4 (Q25-75 130.3-280.6) pg/ml; Me = 5364.8 (Q25-75 2368.9-10 160.9) pg/ml; Me = 133.2 (Q25-75 76.2-268.6) pg/ml, respectively; P = <.001). Leptin level in all groups was higher than in the control group, but there were no differences between groups. The correlation analysis found a positive relationship between the leptin level and the waist circumference (rs = 0.39; P = .007) in the RA with MetS patients, the association of biomarkers with DAS28 score and ESR did not have any statistical significance. Conclusions: The augmented chemokine, resistin and FGF21 in the RA with MetS patients proves the systemic inflammation which is the basis of RA; the augmented leptin is linked to the abdominal obesity. These data are somewhat of an explanation of the increased risk of the CVD development in RA with MetS people. A differentiated specification can be useful to assess the cardiovascular risk of patients and justify prompt personalized treatment.

Adherence to Neuromuscular Electrical Stimulation Interventions for Muscle Impairment in Hip and Knee Osteoarthritis: A Systematic Review

Background: Neuromuscular electrical stimulation (NMES) provides a promising approach to counteract muscle impairment in hip and knee osteoarthritis, and to expedite recovery from joint replacement surgery. Nonetheless, application into clinical orthopaedic practice remains limited, partly due to concerns regarding patient tolerance. Objectives: This systematic review aimed to quantify levels of adherence to NMES interventions for muscle impairment in hip and knee osteoarthritis and identify strategies to increase compliance. Data Sources: Randomised controlled trials (RCTs) were identified in a web-based literature review, completed in December 2020. The databases sourced included the Cochrane Library, CINAHL Complete, Medline Complete and PubMed. Eligibility Criteria: Studies were included if they were: (i) conducted in cohorts of adults with hip or knee osteoarthritis; (ii) a protocol of electrical muscle stimulation prescribed to treat muscle impairment; and (iii) reported intervention adherence or attrition rate. Data were extracted on adherence rate, reasons for non-adherence and potential strategies to increase adherence. Risk of bias was assessed using the Physiotherapy Evidence Database (PEDro) scale. Results: The search yielded 120 articles, of which 15 studies were considered eligible and included in the analysis (n = 922). All NMES treatment was applied to the quadriceps, with 1 study targeting the quadriceps and calves. The mean PEDRO score of the included studies was 6.80 out of a possible 10 (range 6-8). Mean adherence did not differ between groups receiving treatment with NMES (85% ± 12%) and control groups receiving voluntary exercise or education (84% ± 9%) ( P = .97). Reasons for non-adherence or attrition included a dislike of the device, dizziness, pain and discomfort. Strategies to increase adherence included NMES education, a familiarisation period, supervision, setting thresholds based upon patient tolerance, monitoring pain levels during stimulation and using built-in adherence trackers. Conclusions: This systematic review indicates that adherence to NMES interventions for muscle impairment in hip and knee osteoarthritis in clinical trials does not differ to control groups receiving education or voluntary exercise, and hence should not be a barrier to application in clinical practice.

Can Medical Cannabis Therapies be Cost-Effective in the Non-Surgical Management of Chronic Knee Pain?

Introduction: Chronic knee pain is a common musculoskeletal condition, which usually leads to decreased quality of life and a substantial financial burden. Various non-surgical treatments have been developed to relieve pain, restore function and delay surgical intervention. Research on the benefits of medical cannabis (MC) is emerging supporting its use for chronic pain conditions. The purpose of this study was to evaluate the cost-effectiveness of MC compared to current non-surgical therapies for chronic knee pain conditions. Methods: We conducted a cost-utility analysis from a Canadian, single payer perspective and compared various MC therapies (oils, soft gels and dried flowers at different daily doses) to bracing, glucosamine, pharmaceutical-grade chondroitin oral non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. We estimated the quality-adjusted life years (QALYs) gained with each treatment over 1 year and calculated incremental cost-utility ratios (ICURs) using both the mean and median estimates for costs and utilities gained across the range of reported values. The final ICURs were compared to willingness-to-pay (WTP) thresholds of $66 714, $133 428 and $200 141 Canadian dollars (CAD) per QALY gained. Results: Regardless of the estimates used (mean or median), both MC oils and soft gels at both the minimal and maximal recommended daily doses were cost-effective compared to all current knee pain therapies at the lowest WTP threshold. Dried flowers were only cost-effective up to a certain dosage (0.75 and 1 g/day based on mean and median estimates, respectively), but all dosages were cost-effective when the WTP was increased to $133 428/QALY gained. Conclusion: Our study showed that MC may be a cost-effective strategy in the management of chronic knee pain; however, the evidence on the medical use of cannabis is limited and predominantly low-quality. Additional trials on MC are definitely needed, specifically in patients with chronic knee pain.

Intra-articular Hyaluronic Acid for Osteoarthritis of the Knee in the United States: A Systematic Review of Economic Evaluations

Background: The economic impact of intra-articular hyaluronic acid (IAHA) for the treatment of knee pain associated with osteoarthritis (OA) has been evaluated in the United States, but not systematically summarized. Objective: We reviewed the literature to determine the economic impact of IAHA for pain associated with knee OA in the United States. Methods: A literature review was performed in PubMed (including MEDLINE and MEDLINE In-Process), Embase, the Cochrane Database of Systematic Reviews, and National Health Service Economic Evaluation Database and was limited to English language human studies published from January 2000 to October 2020. Results: The literature search identified 215 unique abstracts; of these, 47 were selected for full-text review and 21 studies met the inclusion criteria. Intra-articular hyaluronic acid injections delayed progression to total knee arthroplasty (TKA), and repeated courses of treatment successfully delayed TKA by more than 5 years. Intra-articular hyaluronic acid was found to reduce the use of pain medications overall and reduce the number of patients receiving opioid prescriptions by 6% ( P < .001). Several studies showed that IAHA is more cost-effective in treating pain associated with knee OA compared with conventional care with nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids, and several authors concluded that IAHA should be the dominant treatment strategy. Conclusions: Current studies suggest that IAHA may reduce the use of pain medications, such as NSAIDs and opioids, and impact time to TKA procedures, thus potentially decreasing overall treatment costs of knee OA over time. Furthermore, IAHA was determined to be cost-effective against NSAIDs, corticosteroids, analgesics, and conservative treatment. As the safety and efficacy of IAHA for knee OA have been well established, the findings from our literature review may be used to inform future economic evaluations.