Drugs In Rheumatoid Arthritis Research Articles

PREVALENCE AND CONTROL OF THE HYPERTENSION IN PATIENTS SUFFERING FROM RHEUMATOID ARTHRITIS

Hypertension or high blood pressure (BP) is a long-term ailment in which blood pressure in the arteries raises persistently. Blood pressure can be determined using two methods, systolic pressure which is the uppermost pressure and diastolic pressure which is the lowermost blood pressure in the arterial system. It is estimated that worldwide around 1.13 billion persons are suffering from hypertension. In addition, the World Health Organization (WHO) has reported that 13% of all deaths in the world are caused by hypertension. Furthermore, they set a target to reduce its frequency by 25% from the year 2010 to 2025.1,2 Rheumatoid arthritis (RA) is a systemic autoimmune disease that leads to inflammation of the joints and pain. Approximately 1% of the global population is diagnosed with this disease. Rheumatoid arthritis can be associated with multiple comorbidities that can reduce a patient's quality of life (QoL), upturn the economic burden of the disease, and may increase the rate of mortality. Cardiovascular comorbidities are quite common in patients with rheumatoid arthritis. Cardiovascular comorbidity is estimated to be about 1.5 times more frequent in patients with rheumatoid arthritis than in healthy people. Many studies have suggested that of all cardiovascular disorders, hypertension is the most important and changeable risk factor in subjects suffering from rheumatoid arthritis. Based on a pool of 115,867 insurance claims, about 76% of rheumatoid arthritis patients in America were diagnosed with hypertension. These results are similar to studies conducted in Europe and Canada that have shown a higher incidence of hypertension in patients with rheumatoid arthritis compared to the normal group. It is unknown why patients with rheumatoid arthritis pose such a high risk for hypertension. Reduced physical activity, obesity, systemic inflammation, and medications used to treat rheumatoid arthritis can increase the risk of high blood pressure.3 Around 0.55% of the urban population in northern Pakistan suffers from rheumatoid arthritis, while the incidence rate is close to 0.14% in southern Pakistan.4 There are many reasons why people with rheumatoid arthritis have high blood pressure. Chronic inflammation in rheumatoid arthritis results in increased rigidity of arteries leading to increase systolic blood pressure. The first presumed link between low-grade systemic inflammation and hypertension has been identified in previous studies conducted on the general population. In rheumatoid arthritis, elevated levels of C-reactive protein (CRP) increase the likelihood of developing high blood pressure. Several mechanisms may be implicated in the development of hypertension with a high concentration of C-reactive protein. For example, nitric oxide synthesis may be reduced because of the increased concentration of the C-reactive protein that will cause vasoconstriction, platelet activation and thrombosis. Additionally, increased expression of the type 1 angiotensin receptor and stimulation of the plasminogen activator inhibitor-1 (PAI-1) may contribute to the progression of hypertension. Occasionally, restriction on exercise due to the fear of worsening disease condition is recommended (unwarranted) by healthcare professionals, and it could be a reason for the inactive and sedentary lifestyle of patients with rheumatoid arthritis. In turn, physical idleness can lead to obesity, which may be linked independently to high blood pressure in rheumatoid arthritis. Obesity and familial history of hypertension are significant predictors of premature death. A study has also demonstrated that an increase in sodium (Na) intake and a decrease in potassium (K) intake can play a significant role in the pathogenesis of rheumatoid arthritis and high blood pressure. The urinary Na/K quotient may be useful as an important parameter of hypertension in patients suffering from rheumatoid arthritis and in normal subjects. Optimal cardiovascular risk management continues to be a major challenge. In this regard, increased awareness and management are needed to reduce the high risk of cardiovascular disorders in patients with rheumatoid arthritis. To date, only a few studies have investigated the potential relationship between high blood pressure and these factors in patients with rheumatoid arthritis. A lifestyle shift (i.e. exercise, smoking cessation, eating a balanced diet, reducing the use of ethanol and salt) is needed in patients suffering from rheumatoid arthritis to manage their high blood pressure and improve their quality of life (QoL). To treat rheumatoid arthritis, many medications are routinely prescribed, including cyclooxygenase, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and disease-modifying anti-rheumatic drugs (DMARDs). The use of these drugs in rheumatoid arthritis should always be considered in conjunction with comorbid hypertension. Clinicians should closely monitor such patients for prior diagnosis and, where appropriate, aggressive management of hypertension. Systems for diagnosis, proper treatment, and continuous surveillance of these patients need to be in place in primary and secondary healthcare setups. Furthermore, specially designed clinical trials are required to determine the finest approaches to treat hypertension in patients of rheumatoid arthritis.5-8

Comparison of Biological Agent Monotherapy and Associations Including Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis: Literature Review and Meta-Analysis of Randomized Trials

Update the available evidence comparing biologic disease-modifying antirheumatic drugs (bDMARDs) in combination with conventional synthetic disease-modifying antirheumatic drugs (CsDMARDs) to bDMARDs in monotherapy in patients with rheumatoid arthritis. Research was limited to randomized controlled trials. Major outcome: ACR 20 response criteria at 24 weeks. clinical and radiographic criteria at week 24, 52 and 104. 23 trials (6358 patients), including seven bDMARDs and one other molecule: Anbainuo (anti-TNF-R). No study satisfied our search criteria for anakinra, certolizumab and infliximab. Compared to bDMARD monotherapy, combination therapy gives a better ACR 20 at 24 weeks (RR: 0.88 (0.84-0.94)) in fixed and random effect models, and this result is sustained at 52 and 104 weeks. The results were mostly similar for all other outcomes without increasing the risk of adverse effects. This meta-analysis confirms the superiority of combination therapy over monotherapy in rheumatoid arthritis, in accordance to the usual guidelines.

Clinicopathological findings, prognosis, and Epstein–Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders

BackgroundOther iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA).MethodsWe investigated the clinicopathological characteristics, Epstein–Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs.ResultsImmunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4− CD8− nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%).ConclusionsOIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Can hydroxychloroquine be used for COVID-19-induced arthritis? A debatable hypothesis.

Hydroxychloroquine (HCQ) is a known disease-modifying antirheumatic drug for rheumatoid arthritis. It is also being used in viral arthritis on many occasions. HCQ is also being used to treat coronavirus disease 2019, but the results are not satisfactory. HCQ has been shown to have antiviral effects. In this context, we have a hypothesis that HCQ may be used as a treatment option in post-coronavirus disease 2019 arthritis.

Inhibitory effects of Ganoderma lucidum spore oil on rheumatoid arthritis in a collagen-induced arthritis mouse model

Holistic healthcare practitioners have now started to focus on specific traditional medicinal mushrooms to treat rheumatoid arthritis (RA). Ganoderma lucidum (GL) is one of the oldest mushrooms that have been used in ancient Chinese medicine to treat inflammatory ailments, including autoimmune diseases such as RA. Spores from this mushroom have specific effects on immunomodulation, aging, and cancer. However, the effect of G. lucidum spores (GLS) on arthritis remains unclear. Therefore, we investigated the effects of GLS oil in a collagen-induced rheumatoid arthritis (CIA) model. Metabolomics analysis revealed that GLS oil contains ten acids, of which oleic acid (52.12%) and linoleic acid (16.77%) predominated. The GLS oil-treated CIA mice had a significantly lower clinical score (p = 0.0384) for RA than the control CIA mice. Moreover, GLS oil reduced CIA-induced cartilage degeneration and synovial membrane inflammation in the knee. The GLS oil group showed significantly reduced knee eosinophilia (p = 0.0056). Immunostaining of neutrophils revealed that neutrophils infiltrated the CIA group; however, infiltrated neutrophils were significantly reduced in the GLS oil group in both the knees (p = 0.0006) and ankles (p = 0.0023). GLS oil treatment substantially suppressed LPS- or TNF-α–induced IL-6 mRNA expression in primary cultured chondrocytes. IL-6 immunohistochemistry results showed that the protein levels of IL-6 were attenuated in the GLS oil group compared to the CIA group. These findings suggest that GLS oil may be useful for the development of RA drugs. Further clinical research is required to identify significant improvements.

Abstract 13560: System Gene Regulatory Network-Based Drug Repurposing Combined With Preclinical Molecular Imaging Identifies Anti-Atherosclerotic Properties of Auranofin

Introduction: The identification of new treatments for atherosclerosis (ACVD), a common complex disease, is a daunting task because sets of genes, rather than individual genes, control cell functions. Using systems genetics, our team identified gene regulatory network (GRN42) that is active in the human atherosclerotic arterial wall and is involved in the regulation of foam cell formation. Hypothesis: A network-driven drug repurposing approach combined with rigorous preclinical validation will identify new uses for existing drugs to treat ACVD. Methods: We developed a GRN42-based computational drug repurposing pipeline to infer new uses for existing drugs. Selected compounds were screened by measuring their ability to inhibit foam cell formation in vitro using THP-1-derived macrophages. The in vivo efficacy was validated in ApoE-/- mice fed a western diet by histology and in atherosclerotic rabbits using histology and non-invasive 18 F-FDG PET-MR imaging. Results: 30 candidate compounds were predicted to influence the function of GRN42 and 5 were selected for in vitro screening based on their prediction scores (Figure 1A). As expected, vitamin D reduced cholesteryl esters accumulation in foam cells. Auranofin, and FDA-approved drug for rheumatoid arthritis reduced foam cell formation. As predicted methyl-fasudil had no effect, while nicardipine and flutamide increased foam cell formation (Figure 1B). Auranofin reduced plaque burden in ApoE-/- mice (Figure 1C) and in rabbits reduced lipid accumulation (Figure 1D) and inflammation shown as reduced 18 F-FDG uptake in the arterial wall (Figure 1E). Conclusions: Our results provide robust evidence that a GRN-based computational drug repurposing approach, when combined with robust preclinical validation using translational molecular imaging, can successfully identify new uses of existing drugs for the treatment of ACVD.

Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients.

Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.

Racial Differences in Multimorbidity and Comorbidities in Rheumatoid Arthritis.

To identify differences in multimorbidity and individual comorbidities among individuals with rheumatoid arthritis (RA), separated by race and ethnicity. This case-control study within OptumLabs Data Warehouse from 2010 to 2019 matched RA cases (defined by 2 codes plus prescription of an RA drug) to non-RA controls 1:1 on age, sex, race and ethnicity, region, index date of RA, and insurance coverage duration. We defined multimorbidity as the presence of ≥2 or ≥5 validated comorbidities. Logistic regression models calculated adjusted odds of multimorbidity with 95% confidence intervals (95% CIs) within each race and ethnicity. We identified 154,391 RA cases and 154,391 controls (mean age 59.6, 76% female). Black enrollees had the most multimorbidity ≥2/≥5 (73.1%, 34.3%); Asian enrollees had the least (52.4%, 17.3%). Adjusted odds of multimorbidity ≥2 and ≥5 in RA cases versus controls was 2.19 (95% CI 2.16-2.23) and 2.06 (95% CI 2.02-2.09), respectively. This increase was similar across race and ethnicity. However, we observed elevated occurrence of certain comorbidities by race and ethnicity versus controls (P < 0.001), including renal disease in White enrollees (4.7% versus 3.2%) and valvular heart disease in Black and White enrollees (3.2% and 2.8% versus 2.6% and 2.2%). Multimorbidity is a problem for all RA patients. Targeted identification of certain comorbidities by race and ethnicity may be a helpful approach to mitigate multimorbidity.

Quality of rheumatoid arthritis recording in United Kingdom Clinical Practice Research Datalink Aurum.

While several studies have assessed quality and completeness of recording acute medical events in Clinical Practice Research Datalink (CPRD) Aurum, evaluation of additional chronic conditions is warranted. We selected patients with a first diagnosis of rheumatoid arthritis (RA) coded in their CPRD Aurum record between 2005 and 2019. We assessed quality of RA diagnosis by evaluating additional information in the patient record that would corroborate the diagnosis. We report recording of diagnoses, prescriptions, labs, and referrals expected to be present based on NICE guidelines for RA management. There were 53 083 patients with a first recorded RA diagnosis during the study period: 43606 (82%) patients had RA drug treatments in their record, 7596 (14%) had supporting codes without drug treatment, and 1881 (4%) patients had only a RA diagnoses recorded in their medical record with no supporting codes or RA treatments. Patients with RA diagnosis only were more likely to be first diagnosed in the earliest time period of study. Labs for diagnosing and monitoring RA were most common among patients with RA treatment. Analgesic and glucocorticoid prescriptions were common in all study patients but were highest among patients with RA treatment. Among patients with RA diagnosis only, the overwhelming majority had only one RA diagnosis recorded (76%). Our findings suggest that codes expected for monitoring and treatment of RA are routinely recorded in CPRD Aurum. These results support previous assessments, which found data recorded in CPRD Aurum to be of good quality for use in research.

Spectroscopic and computational approach to study the interacting mechanism of drug-adenine complex

The biomolecular complex, Adenine and Rheumatoid Arthritis drug are characterized using vibrational spectroscopy and density functional theory. The spectral characterization of the biomolecule is undertaken by using Fourier transform infrared spectroscopy, Raman and surface-enhanced Raman spectroscopy techniques. The optimization and theoretical calculation of the molecules are performed using the density functional theory method. The frontier molecular orbital, molecular electrostatic potential, natural bond orbital parameters, thermodynamic properties, and first-order hyperpolarizability of the adenine monomer, hydroxychloroquine monomer, and their interacting state are calculated by Becke–Lee–Yang–Parr method with a basis set of 6-311G + (d, p). The Quantum Theory Atoms in Molecules study is performed for investigating the topological parameters, such as the density of electrons, the Laplacian of electron density, and the energy density. The vibrational assignment of the individual and interacting molecules is accomplished through the Vibrational Energy Distribution Analysis program. The theoretical and experimental values show good agreement with one another. The drug-likeliness behavior of the biomolecular complex is also studied. The molecular docking studies of the molecules are carried out against human synovial fluid sPLA2 to determine the best binding sites.

The rheumatoid arthritis drug auranofin lowers leptin levels and exerts antidiabetic effects in obese mice

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.

Assessment of mesenchymal stem/stromal cell-based therapy in K/BxN serum transfer-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)-based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adipose-derived MSC-based therapy is unsuitable for modulating the progression of K/BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSC-based therapy.

Hydroxychloroquine Effects on THP-1 Macrophage Cholesterol Handling: Cell Culture Studies Corresponding to the TARGET Cardiovascular Trial.

Background and Objectives: Cardiovascular (CV) risk is elevated in rheumatoid arthritis (RA). RA patient plasma causes pro-atherogenic derangements in cholesterol transport leading to macrophage foam cell formation (FCF). The TARGET randomized clinical trial compares CV benefits of 2 RA drug regimens. Hydoxychloroquine (HCQ) is a key medication used in TARGET. This study examines effects of HCQ on lipid transport to elucidate mechanisms underlying TARGET outcomes and as an indicator of likely HCQ effects on atherosclerosis in RA. Materials and Methods: THP1 human macrophages were exposed to media alone, IFNγ (atherogenic cytokine), HCQ, or HCQ + IFNγ. Cholesterol efflux protein and scavenger receptor mRNA levels were quantified by qRT-PCR and corresponding protein levels were assessed by Western blot. FCF was evaluated via Oil-Red-O and fluorescent-oxidized LDL. Intracellular cholesterol and efflux were quantified with Amplex Red assay. Results: With the exception of a decrease in the efflux protein cholesterol 27-hydroxylase in the presence IFNγ at all HCQ concentrations, no significant effect on gene or protein expression was observed upon macrophage exposure to HCQ and this was reflected in the lack of change in FCF and oxidized LDL uptake. Conclusions: HCQ did not significantly affect THP1 macrophage cholesterol transport. This is consistent with TARGET, which postulates superior effects of anti-TNF agents over sulfasalazine + HCQ.

Influence of Multimorbidity on New Treatment Initiation and Achieving Target Disease Activity Thresholds in Active Rheumatoid Arthritis: A Cohort Study Using the Rheumatology Informatics System for Effectiveness Registry.

To determine whether multimorbidity is associated with treatment changes and achieving target disease activity thresholds in patients with active rheumatoid arthritis (RA). We conducted a retrospective cohort study of adults with active RA within the Rheumatology Informatics System for Effectiveness (RISE) registry. Multimorbidity was measured using RxRisk, a medication-based index of chronic disease. We used multivariable logistic regression models to assess the associations of multimorbidity with the odds of initiating a new disease-modifying antirheumatic drug (DMARD) in active RA, and among those initiating a new DMARD, the odds of achieving low disease activity or remission. We identified 15,626 patients using the Routine Assessment of Patient Index Data 3 (RAPID3) cohort and 5,733 patients using the Clinical Disease Activity Index (CDAI) cohort. All patients had active RA, of which 1,558 (RAPID3) and 834 (CDAI) initiated a new DMARD and had follow-up disease activity measures. Patients were middle aged, female, and predominantly White, and on average received medications from 6 to 7 RxRisk categories. Multimorbidity was not associated with new DMARD initiation in active RA. However, a greater burden of multimorbidity was associated with lower odds of achieving treatment targets (per 1-unit RxRisk: RAPID3 cohort odds ratio [OR] 0.95 [95% confidence interval (95% CI) 0.91, 0.98]; CDAI cohort OR 0.94 [95% CI 0.90, 0.99]). Those with the highest burden of multimorbidity had the lowest odds of achieving target RA disease activity (RAPID3 cohort OR 0.54 [95% CI 0.34, 0.85]; CDAI cohort OR 0.65 [95% CI 0.37, 1.15]). These findings from a large, real-world registry illustrate the potential impact of multimorbidity on treatment response and indicate that a more holistic management approach targeting multimorbidity may be needed to optimize RA disease control in these patients.

Dynamics of patient reported outcomes during the use various biological disease-modifying antirheumatic drugs for rheumatoid arthritis

One of the main tasks of modern complex therapy of rheumatoid arthritis (RA) is to improve the quality of life of patients. To do this, it is necessary not only to achieve remission or low activity, but also to successfully control the main, most painful, manifestations of the disease. Therefore, when evaluating the results of RA treatment, the dynamics of not only standard indices (DAS28 (Disease Activity Score 28), CDAI (Clinical Disease Activity Index), SDAI (Simplified Disease Activity Index)), but also the so-called “patient reported outcomes” (PRO) – a patient’s global assessment of disease activity (PGA), pain, functional disorders and fatigue.This review examines the effect of one of the main classes of anti–rheumatic drugs - biological disease-modifying antirheumatic drugs (bDMARDs) on the PROs. The results of a series of randomized controlled trials are presented, in which changes in PROs were studied using various tumor necrosis factor α (TNF-α) inhibitors, abatacept T-lymphocyte co-stimulation inhibitor, rituximab CD20 inhibitor and interleukin (IL) 6 inhibitors.The use of bDMARDs in combination with methotrexate (MTX) provides a reduction in PGA and pain by 50-60%, functional disorders according to HAQ (Health Assessment Questionnaire) and fatigue according to FACIT-F (Functional Assessment of Chronic Illness Therapy – Fatigue) – by 15-30%. B DMARDs monotherapy (with the exception of the effect of tocilizumab on HAQ) does not exceed MTX monotherapy in its effect on PROs. Monotherapy with tocilizumab provides more favorable dynamics of PGA and pain than monotherapy with TNF-α inhibitors. An important advantage of IL-6 inhibitors is the rapid achievement of a clinical effect, which is noted already in the first 2 weeks after the first administration of the drug.

Associations between the interleukin-6 rs1800795 G/C and interleukin-6 receptor rs12083537 A/G polymorphisms and response to disease-modifying antirheumatic drugs in rheumatoid arthritis: A meta-analysis

ObjectiveWe aimed to investigate the association between interleukin-6 (IL-6) rs1800795 G/C, IL-6 receptor (IL-6R) rs12083537 A/G, and rs4329505 T/C polymorphisms and responsiveness to disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). MethodsWe searched Medline, Embase, and Web of Science databases. We conducted a meta-analysis of studies on the association between the IL-6 rs1800795 G/C, IL-6R rs12083537 A/G and rs4329505 T/C polymorphisms and responsiveness to DMARDs in RA patients. ResultsFourteen studies from eight published articles involving 982 patients were included in this meta-analysis. The meta-analysis showed a significant association between the IL-6 rs1800795 G allele and response to DMARDs in RA (P = 0.008). Stratification by DMARD class showed that the IL-6 rs1800795 G allele was significantly associated with responsiveness to biological DMARDs (bDMARDs) (P = 0.022), but not conventional synthetic DMARDs (P = 0.145). A significant association was also found between the IL-6 rs1800795 G/C polymorphism and response to DMARDs. The meta-analysis revealed a significant association between the IL-6R rs12083537 A allele and response to tocilizumab in RA patients (P = 0.001). A significant association was also found between the IL-6R rs12083537 AA genotype and response to tocilizumab in RA patients (P = 0.001). However, no association was found between the IL-6R rs4329505 T/C polymorphism and response to tocilizumab. ConclusionsThis meta-analysis revealed associations between treatment response to bDMARDs and the IL-6 rs1800795 G/C polymorphism, and between response to tocilizumab and the IL-6R rs12083537 A/G polymorphism in RA.

Sex-related differences in health-care use in adult patients with inflammatory arthritis in Ontario, Canada: a population-based cohort study

<h2>Abstract</h2><h3>Background</h3> Timely access and appropriate use of health-care resources is crucial for the management of people with inflammatory arthritis. Sex (biological) and gender (sociocultural) are important health determinants that influence different aspects of care, such as referral to specialists, performance of diagnostic tests, continuity of care, and prescription patterns, which ultimately affect disease outcomes. We aimed to compare health-care use between males and females with inflammatory arthritis. <h3>Methods</h3> This population-based study was conducted using health administrative data of Ontario, Canada. We included Ontario residents aged 20 years or older with valid health insurance and diagnosed with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis using Ontario health administrative data (the Ontario Health Insurance Plan Claims Database). Sex (the primary predictor of this study) was coded as male or female in the database. Health-care use (the study outcome) was assessed at least once per year for 3 years before and after an inflammatory arthritis diagnosis and compared between males and females using regression models, after adjusting for demographics and comorbidities. Prescription dispensation was assessed at least once per year for 3 years after the diagnosis in individuals aged 66 years or older at the time of diagnosis. Results were expressed as female to male adjusted odds ratio (OR) with 95% CIs. <h3>Findings</h3> Between April 1, 2010, and March 31, 2017, 41 277 people with rheumatoid arthritis (28 575 [69%] females), 8150 with ankylosing spondylitis (4160 [51%] females), and 6446 with psoriatic arthritis (3483 [54%] females) were analysed. Males were significantly older (mean 60·4 years [SD 14·2]) than females (mean 57·1 years [15·2]) in the rheumatoid arthritis cohort. Across the cohorts, multimorbidity was more common in females (75–81% <i>vs</i> 58–66% in males) as was depression (8% <i>vs</i> 4%) and osteoporosis (4–5% <i>vs</i> 1%), whereas cardiovascular disease was more common in males (7–15% <i>vs</i> 4–7% in females). Females were more likely to visit family physicians (adjusted OR ranging from 1·10 [95% CI 1·05–1·15]; p<0·001 to 1·15 [1·04–1·28]; p<0·01) and rheumatologists (adjusted OR from 1·32 [1·22–1·43] to 2·28 [1·92–2·70]; p<0·001). Females also had higher odds for receiving imaging before a diagnosis in all 3 cohorts (adjusted OR from 1·15 [1·10–1·20] to 1·18 [1·12–1·23]; p<0·001 for x-rays and adjusted OR from 1·27 [1·09–1·48] to 1·44 [1·15–1·80]; p<0·01 for ultrasound examinations). Similarly, laboratory tests were more likely to be ordered for female patients before diagnosis than for males (adjusted OR from 1·10 [1·05–1·15] to 2·17 [1·89–2·50]; p<0·001) across all cohorts. These sex differences were most notable among people with rheumatoid arthritis and ankylosing spondylitis, and in the prediagnostic period. Males were more likely to visit the emergency department immediately before an inflammatory arthritis diagnosis (adjusted OR from 0·76 [95% CI 0·72–0·81]; p<0·001 to 0·87 [0·80–0·95]; p<0·01). After diagnosis, females were more likely to remain in rheumatology care (adjusted OR from 1·12 [1·01–1·25]; p=0·04 to 1·24 [1·19–1·30]; p<0·001). Prescription dispensation of non-steroidal anti-inflammatory drugs (adjusted OR 1·14 [1·04–1·25]; p<0·01) and opioids (adjusted OR 1·46 [1·27–1·68]; p<0·001) was higher in older females (aged 66 years or older) with rheumatoid arthritis and conventional disease-modifying antirheumatic drug use was higher in older females with ankylosing spondylitis (adjusted OR 1·66 [1·24–2·22]; p<0·001). <h3>Interpretation</h3> Females with inflammatory arthritis are more likely to use health care than males, which might indicate sex-related biological differences in disease course or gender-related sociocultural differences in health-care access, health-care seeking behaviour or patient–provider interactions. <h3>Funding</h3> Enid Walker Graduate Student Award for Research in Women's Health (partial).

Guar gum nanoparticles ameliorate inflammatory damage in a preclinical mouse model of collagen II-induced arthritis

Introduction: Rheumatoid arthritis (RA) is a bone disorder causing inflammation of synovial lining followed by production of proinflammatory cytokines at the same site. The synovial hyperplasia is also mediated by the infiltration of lymphocytes, macrophages and other inflammatory cells. The available drugs for RA shows temporary recovery and some are associated with side effects. Here we have used surface functionalized guar gum nanoparticles (GN) to ameliorate disease pathology using collagen II (CII) induced arthritis model in C57BL/6 mice. Methods: The systemic as well as the bone damage was assessed by the total count, differential count, clonogenic potential, flow cytometry and histological studies. The migration of inflammatory cells was assessed by flow cytometry of cells from the bone marrow, blood, spleen and the synovial tissue. The joint inflammation was assessed both by visible presentation in terms of thickness and corroborated with the H&amp;E staining of the knee joint sections. Results: Synovitis was observed in the diseased group while GN controlled the synovial inflammation. Post sacrifice, the total number of cells and the immune cells were increased significantly in the diseased group and decreased on GN treatment. The clonogenic potential of cells was also restored on GN administration. The elevated level of NO was also decreased by GN administration. The expression of proinflammatory cytokines and the signaling molecules were also restored on GN treatment. Conclusion: The results provide insights to understand the therapeutic effect of GN in CII induced arthritis for translational outcomes. Through this study we investigated the signaling mechanism involved in the pathology of disease to examine the role of GN in preventing the disease progression.

Third dose of anti-SARS-CoV-2 inactivated vaccine for patients with RA: Focusing on immunogenicity and effects of RA drugs.

ObjectivesTo evaluate the immunogenicity of the third dose of inactivated SARS-CoV-2 vaccine in rheumatoid arthritis (RA) patients and explore the effect of RA drugs on vaccine immunogenicity.MethodsWe recruited RA patients (n = 222) and healthy controls (HC, n = 177) who had been injected with a third dose of inactivated SARS-CoV-2 vaccine, and their neutralizing antibody (NAb) titer levels were assessed.ResultsRA patients and HC were age- and gender-matched, and the mean interval between 3rd vaccination and sampling was comparable. The NAb titers were significantly lower in RA patients after the third immunization compared with HC. The positive rate of NAb in HC group was 90.4%, while that in RA patients was 80.18%, and the difference was significant. Furthermore, comparison of NAb titers between RA treatment subgroups and HC showed that the patients in the conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) group exhibited no significant change in NAb titers, while in those receiving the treatment of biological DMARDs (bDMARDs), Janus Kinase (JAK) inhibitors, and prednisone, the NAb titers were significantly lower. Spearman correlation analysis revealed that NAb responses to SARS-CoV-2 in HC did differ significantly according to the interval between 3rd vaccination and sampling, but this finding was not observed in RA patients. In addition, NAb titers were not significantly correlated with RA-related laboratory indicators, including RF-IgA, RF-IgG, RF-IgM, anti-CCP antibody; C-RP; ESR; NEUT% and LYMPH%.ConclusionSerum antibody responses to the third dose of vaccine in RA patients were weaker than HC. Our study will help to evaluate the efficacy and safety of booster vaccination in RA patients and provide further guidance for adjusting vaccination strategies.

OSSEOINTEGRATED IMPLANT IN A MULTI-TREATED PATIENT FOR RHEUMATOID ARTHRITIS WITH THE USE OF TOCILIZUMABE

The present study reports a case of an osseointegrated implant in a patient using the rheumatoid arthritis drug Tocilizumab. This an alternative antirheumatic drug is not explored in the literature regarding its effect on osseointegration. <b>Case Summary:</b> Tooth 36 had extensive longitudinal fracture. Extraction was performed and bone healing awaited. Subsequently, the implant was installed without the suspension of Tocilizumab due to the risks of disease activity and painful symptoms of the patient. After 30 days, the implant prosthesis was started, and the crown was put into operation. After 1 year of follow-up, the periapical radiograph showed satisfactory osseointegration, and the patient is being followed up. With the results found in this patient, it is suggested that there are no impediments to try the oral rehabilitation with dental implants in patients using this drug.