Rheumatoid Arthritis Therapeutics Research Articles

Exploring Potential Bioactive Components of Persea americana for the Treatment of Rheumatoid Arthritis through Network Pharmacology.

Rheumatoid arthritis (RA) is a chronic autoimmune disease character-ized by inflammation and joint destruction, leading to significant disability and reduced quality of life. Current treatment options for RA have limitations, highlighting the need for novel therapeu-tic approaches. In this study, we employed network pharmacology methods to identify potential bioactive compounds from Persea Americana (avocado) for the treatment of RA. We collected information on the phytoconstituents of avocados from the IMPPAT database and used Data Warrior software to filter out 64 plant constituents based on ADMET criteria. Target genes associated with avocado compounds were identified using the Bindingdb web server, resulting in 209 genes from Persea Americana. Protein-protein interaction (PPI) network analysis was performed using Cytoscape software to identify key genes and pro-teins involved in RA. Protein-drug interactions were analyzed, and ten avocado constituents with high binding affinity were identified. Our network pharmacology analysis revealed that avocado constituents, particularly Luteolin, have the potential to be developed as novel therapeutics for RA. The PPI network analysis identified key genes and proteins associated with RA, providing insights into the molecular mechanisms of the disease. The high binding affinity observed between Luteolin and PTGS2, a protein involved in joint inflammation, suggests its potential effectiveness in mitigating RA-related inflammation. Our study highlights the potential of avocado constituents, particularly Luteolin, as promising therapeutics for the treatment of rheumatoid arthritis (RA). Through network pharma-cology analysis, we identified key target genes and proteins associated with RA, shedding light on the underlying molecular mechanisms of the disease.

Glucocorticoids promote joint microenvironment alteration of GABBR1 expression associated with mitigating rheumatoid arthritis.

GABBR1 receptors have been implicated in the progression of rheumatoid arthritis (RA), and p38 MAP kinase (MAPK) was shown to be downregulated by GABA and result in unchecked production of pro-inflammatory cytokine. GABBR1 is a member of GABA receptors, and it is known to be upregulated and plays a vital role in RA. Glucocorticoids are efficient therapeutics in rheumatoid arthritis (RA) and are known to regulate GABA actions; therefore, we intended to investigate the potential of glucocorticoids in RA concerning the potential pathway GABBR1/MAPK. Joint specimens were obtained from collagen-induced arthritis mouse model. A double-blind semi-quantitative analysis of vascularity, cell infiltration, as well as lining thickness by help of a 4-point scale setting was used to assess joint inflammation. Expression of GABBR1 and p38 was evaluated immunohistochemically. In vitro peripheral blood (PB), synovial fluid (SF), and mononuclear cells (MCs) were acquired from RA mice. Western blotting was used for detecting expression of GABBR1 and p38 proteins. The presence of high levels of GABBR1 and p38 was prevalent in RA joints relative to healthy joints and related to the inflammation level. Glucocorticoid treatment alters GABBR1 along with p38 protein expression in joints while reducing joint inflammation. Ex vivo and in vitro assays revealed glucocorticoids have a direct impact on p38, such as the decreased GABBR1 expression level after dexamethasone incubation with SFMC. GABBR1 together with p38 expression in RA joints depends on local inflammation and can be targeted by glucocorticoids.

Current Prospects in Rheumatoid Arthritis: Pathophysiology, Genetics, and Treatments.

An autoimmune inflammatory disease, rheumatoid arthritis (RA), predominantly affects the synovium joint lining, augmenting disability, early mortality, and socioeconomic difficulty. Therefore, current updates on pharmacological therapies are crucial for developing drugs to treat the disease at each stage. This review attempts to compile a thorough analysis of current developments in our knowledge of RA pathogenesis and disease-modifying drugs, with the aim of providing insights for next-generation RA therapeutics. According to the literature, the most successful drugs for treatment techniques described so far in this include (cs) DMARDs (sub-class of DMARDs), tsDMARDS (targeted synthetic DMARDS), and bDMARDs (biological DMARDs). However, current pharmacologic therapy (consisting of biological, conventional, and creative views of small molecule anti-rheumatic drugs that treat the disease or DMARD) remains the cornerstone of rheumatoid arthritis treatment with which significant progress toward disease remission has been accomplished. The pathobiology of RA involves cytokine messengers such as B and T-cells, and an intricate interplay of pro-inflammatory cytokines responsible for activating and developing effector cells, in turn, accountable for local disease and systemic symptoms. Despite the fact that the cause of rheumatoid arthritis is not known, new treatments have been created as a result of better approaches towards the biology of the disease. As they target molecules directly implicated in the genesis of rheumatoid arthritis, these drugs may be more effective, targeted, and less harmful in the short and long term than standard therapies.

Pharmacological Approaches in Rheumatoid Arthritis- An In-depth Analysis of Prescribed Medications

Inflammation, pain, swelling, and stability of the joints are some of the symptoms associated with rheumatoid arthritis (RA). A variety of treatment options are available to manage symptoms and slow the progression of RA, despite the fact that there is no cure. This cross-sectional study, which was conducted in a tertiary care hospital in Kerala, India, aimed to evaluate medication prescribing practices and therapeutic strategies in RA patients. The study included 280 RA patients and data on demographics, medications prescribed, dosage, and mode of administration were collected. The findings revealed that disease-modifying anti-rheumatic drugs (DMARDs) were the cornerstone of RA treatment, with hydroxychloroquine (HCQ), methotrexate (MTX), and sulfasalazine (SAAZ) being the most frequently prescribed DMARDs. Combination DMARD therapy, particularly the triple combination of HCQ + Folitrax + SAAZ, was prevalent among patients. Furthermore, the study highlighted the use of biologic DMARDs, such as rituximab and tofacitinib, albeit at a relatively lower rate due to the outpatient population’s milder disease severity. Supplement therapy, including vitamin D3 and folic acid, was commonly prescribed to address deficiencies and mitigate the side effects of medications like MTX. The prescription patterns also encompassed analgesics, anti-anxiety, and antidepressant medications to manage pain and psychological symptoms associated with RA. Steroids were administered initially to control inflammation, with a focus on minimizing long-term usage. The study underscores the complexity of RA management and the importance of individualized treatment approaches. It highlights the evolving landscape of RA therapeutics, emphasizing the need for clinicians to stay updated on emerging evidence and guidelines. Future research should focus on evaluating the long-term efficacy, safety, and cost-effectiveness of different treatment regimens to optimize patient outcomes in RA management.

Management and treatment outcomes of rheumatoid arthritis in the era of biologic and targeted synthetic therapies: evaluation of 10-year data from the KURAMA cohort

BackgroundAdvances in rheumatoid arthritis (RA) treatment, highlighted by biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), have altered the paradigm of RA treatment in the last decade. Therefore, real-world clinical evidence is needed to understand how treatment strategies and outcomes have changed.MethodsUsing an observational cohort of RA from 2012 to 2021, we collected cross-sectional data of RA patients annually to analyze a trend in RA management. For patients who initiated b/tsDMRDs, we evaluated treatment outcomes between b/tsDMARDs. Mixed-effect models were applied to examine the statistical implications of changes over time in treatment outcomes with a background adjustment.ResultsWe analyzed annual cross-sectional data from 5070 patients and longitudinal data from 1816 patients in whom b/tsDMARDs were initiated between 2012 and 2021. b/tsDMARD use increased, whereas glucocorticoid use decreased from 2012 to 2021. Disease activity and functional disability measures improved over time. The percentage of tsDMARD prescriptions considerably increased. All b/tsDMARDs showed clinical improvements in disease activity and functional disability. Statistically, TNFi showed better short-term improvements in b/tsDMARD-naïve patients, while IL6Ri demonstrated significant long-term benefits. IL6Ri had better retention rates in switched patients. After adjustment for patient characteristics, the annual change of RA disease activity and functional disability fared significantly better from 2012 to 2021.ConclusionsWith the development of new RA therapeutics, overall treatment outcomes advanced in the past decade.

What have we learnt from the inhibition of IL-6 in RA and what are the clinical opportunities for patient outcomes?

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients' profiles and comorbidities is essential for optimal outcomes. A 'treat-to-profile' approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars - lower-cost alternatives to biologics - further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities.

An AI Approach to Identifying Novel Therapeutics for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has a significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain; however, achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches for novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offer the ability to repurpose FDA-approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed, including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations and the ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms that have strong potential to determine novel and effective treatment regimens.

A bioinformatics system for exploring potential targets and therapies in rheumatoid arthritis

Rheumatoid arthritis (RA), one of the most common chronic inflammatory diseases, is an autoimmune disease that causes cartilage, bone damage, and disability. RA has become a concern, affecting more than 1.5% of the global population. Immunomodulatory or anti-inflammatory targets are the lead candidates in existing clinical trials to develop RA drugs. These targets were reported to be ineffective in reducing symptoms, slowing disease progression, and causing adverse side effects. Therefore, this study focuses on addressing the continuing need for safer, more selective, and more effective treatment options for RA by identifying novel targets and therapeutic approaches. The study involves six important steps: retrieving a dataset from the Gene Expression Omnibus (GEO) database, file conversion, gene differentiation (up-regulated and downregulated), Entrez gene ID retrieval for Search Tool for the Retrieval of Interacting Genes (STRING), protein–protein interaction (PPI) network delineation via STRING, drugs identification via Drug Bank, and relationship establishment between networks and drugs via The Drug–Gene​ Interaction Database (DGIdb). Nine protein hubs, three up-regulated and six down-regulated were identified as interacting with 8 and 18 drugs, respectively. Seven protein sites have never been directly associated with RA and could serve as potential therapeutic targets. Eleven drugs were shown to interact with these seven selected protein hubs as potential therapeutics for RA. These new targets and therapies will help researchers improve the RA treatment pipeline by adding these into the pipeline and bringing successful treatment options for RA patients.

Restoring Balance: Immune Tolerance in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic musculoskeletal disease where immune dysregulation and subsequent autoimmunity induce significant synovial joint inflammation and damage, causing pain and disability. RA disease onset is promoted through multifaceted interactions between genetic and environmental risk factors. However, the mechanisms of disease onset are not completely understood and disease-specific treatments are yet to be developed. Current RA treatments include nonspecific disease-modifying antirheumatic drugs (DMARDs) that suppress destructive immune responses and prevent damage. However, DMARDs are not curative, and relapses are common, necessitating lifelong therapy in most patients. Additionally, DMARD-induced systemic immunosuppression increases the risk of serious infections and malignancies. Herein, we review the current understanding of RA disease pathogenesis, with a focus on T and B cell immune tolerance breakdown, and discuss the development of antigen-specific RA therapeutics that aim to restore a state of immune tolerance, with the potential for disease prevention and reduction of treatment-associated adverse effects.

Regulation of Myeloid Dendritic Cells by Synthetic and Natural Compounds for the Treatment of Rheumatoid Arthritis

Different subsets of dendritic cells (DCs) participate in the development of rheumatoid arthritis (RA). In particular, myeloid DCs play a key role in the generation of autoreactive T and B cells. Herein, we undertook a literature review on those synthetic and natural compounds that have therapeutic efficacy/potential for RA and act through the regulation of myeloid DCs. Most of these compounds inhibit both the maturation of DCs and their secretion of inflammatory cytokines and, subsequently, alter the downstream T-cell response (suppression of Th1 and Th17 responses while expanding the Treg response). The majority of the synthetic compounds are approved for the treatment of patients with RA, which is consistent with the importance of DCs in the pathogenesis of RA. All of the natural compounds are derived from plants. Their DC-modulating effect has been demonstrated both in vitro and in vivo. In addition, these natural products ameliorate arthritis in rodents and are potential therapeutics for human RA.

Connective tissue growth factor-targeting DNA aptamer suppresses pannus formation as diagnostics and therapeutics for rheumatoid arthritis.

Connective tissue growth factor (CTGF) has been recently acknowledged as an ideal biomarker in the early disease course, participating in the pathogenesis of pannus formation in rheumatoid arthritis (RA). However, existing approaches for the detection of or antagonist targeting CTGF are either lacking or unsatisfactory in the diagnosis and treatment of RA. To address this, we synthesized and screened high-affinity single-stranded DNA aptamers targeting CTGF through a protein-based SELEX procedure. The structurally optimized variant AptW2-1-39-PEG was characterized thoroughly for its high-affinity (KD 7.86 nM), sensitivity (minimum protein binding concentration, 2 ng), specificity (negative binding to other biomarkers of RA), and stability (viability-maintaining duration in human serum, 48 h) properties using various biochemical and biophysical assays. Importantly, we showed the antiproliferative and antiangiogenic activities of the aptamers obtained using functional experiments and further verified the therapeutic effect of the aptamers on joint injury and inflammatory response in collagen-induced arthritis (CIA) mice, thus advancing this study into actual therapeutic application. Furthermore, we revealed that the binding within AptW2-1-39-PEG/CTGF was mediated by the thrombospondin 1 (TSP1) domain of CTGF using robust bioinformatics tools together with immunofluorescence. In conclusion, our results revealed a novel aptamer that holds promise as an additive or alternative approach for CTGF-targeting diagnostics and therapeutics for RA.

Umbelliferone and scopoletin target tyrosine kinases on fibroblast-like synoviocytes to block NF-κB signaling to combat rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex autoimmune condition primarily affecting synovial joints, which targeted synthetic drugs have damaging safety issues. Saussurea laniceps, a reputed anti-rheumatic medicinal herb, is an excellent place to start looking for natural products as safe, effective, targeted therapeutics for RA. Via biomimetic ultrafiltration, umbelliferone and scopoletin were screened as two anti-rheumatic candidates with the highest specific affinities towards the membrane proteomes of rheumatic fibroblast-like synoviocytes (FLS), the pivotal effector cells in RA. In vitro assays confirmed that the two compounds, to varying extents, inhibited RA-FLS proliferation, migration, invasion, and NF-κB signaling. Network pharmacology analysis and molecular docking analysis jointly revealed that umbelliferone and scopoletin act on multiple targets, mostly tyrosine kinases, in combating RA. Taken together, our present study identified umbelliferone and scopoletin as two major anti-rheumatic components from SL that may bind and inhibit tyrosine kinases and subsequently inactivate NF-κB in RA-FLSs. Our integrated drug discovery strategy could be valuable in finding other multi-target bioactive compounds from complex matrices for treating multifactorial diseases.

Rheumatoid Arthrities: Etiology Pathophysiology and Modern Treatments

Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints. Age, gender, genetics, and environmental exposure are all factors (cigarette smoking, air pollutants, and occupational). If untreated, felty syndrome, rheumatoid vasculitis, and irreversible joint damage might occur, necessitating splenectomy. Because there is no cure for RA, treatment seeks to reduce pain and prevent further damage. To develop effective RA treatments, researchers must first understand how the disease advances in people and how pathogenic pathways influence this progression. Modern pharmacologic therapy have made tremendous progress in obtaining illness remission without joint deformity (including conventional and biological treatments as well as novel potential small-molecule disease-modifying drugs). Despite this, many RA patients do not respond well to conventional treatments, necessitating the development of novel drugs. This comprehensive review of current advancements covers RA causation, disease-modifying drugs, and prospective RA therapeutics. This section summarises the various RA-related therapies available in the past and now.

Rac and Cdc42 Inhibitors in Rheumatoid Arthritis Therapy

Rheumatoid Arthritis (RA) is the most common autoimmune disorder characterized by chronic inflammation due to synovial fibroblast proliferation, neovascularization, leukocyte extravasation, and progressive joint destruction. Most RA medications focus on relieving symptoms of chronic inflammation, rather than prevent the inflammatory cells from attacking the joints and the underlying cartilage and bone. These initial processes have been shown to be under the regulation of key signaling proteins Rac and Cdc42. Therefore, the objective of this study was to demonstrate the effect of our patented Rac/Cdc42 inhibitors MBQ‐167 and EHop‐016 in inflammatory cells in vitro. Our hypothesis is that inflammatory cells in the synovium can be inhibited by Rac/Cdc42 inhibitors that have the potential as a RA therapeutics. To test this hypothesis, macrophage‐like cell lines WBC264‐9C human leukocytes or THP1 human macrophage were incubated with 0‐500 nM of MBQ‐167, lysed and subjected to Rac.GTP pulldown assays. Results showed that Rac activation was inhibited by 46‐56% at 250 nM and by 60‐77% at 500 nM MBQ‐167 for both cell lines. Total Rac levels were not significantly changed by MBQ‐167 in concentrations up to 500 nM. Moreover, preliminary results on synovial fibroblasts SW‐982 demonstrated inhibition of Rac activation in response to MBQ‐167 at 750 nM or higher. Next, macrophage‐like cells were treated with the Rac/Cdc42 inhibitors and tested for cell viability using a MTT assay. Results showed no effects on cell proliferation at high µM concentrations of Rac/Cdc42 inhibitors. Since Rac activation regulates cell migration, which is central to the inflammatory response in synovial joints, we tested the effect of MBQ‐167 in a wound healing assay. Incubation with MBQ‐167 at 250 or 500 nM inhibited macrophage migration. At 24h, 500 nM MBQ‐167 reduced macrophage cell migration by 80%. In conclusion, this data demonstrates that our Rac/Cdc42 inhibitors may be used to inhibit inflammatory cell action and their migration at sites of inflammation in RA, without affecting macrophage numbers, indicating no toxic effects in the immune system.

Activatable Near-Infrared Fluorescent Organic Nanoprobe for Hypochlorous Acid Detection in the Early Diagnosis of Rheumatoid Arthritis.

Early diagnosis of rheumatoid arthritis (RA) is crucial to prevent deterioration and improve the prognosis of disease outcome. However, current clinical diagnostic methods are unable to achieve accurate and early detection of RA. In this work, we designed an activatable organic nanoprobe (ONP-CySe) capable of specific and real-time imaging of ClO- in early RA. ONP-CySe comprises a near-infrared fluorescent selenomorpholine-caged cyanine dye as the sensing component and an amphiphilic triblock copolymer triphenyl phosphine derivative for mitochondria targeting. Our results showed that ONP-CySe successfully detected elevated levels of ClO- in the mitochondria of macrophages with high selectivity, low limit of detection (31.5 nM), excellent photostability, and good biocompatibility. Furthermore, ONP-CySe can also be used to monitor anti-inflammatory responses and efficacies of RA therapeutics, such as selenocysteine and methotrexate, in BALB/c mouse models. Therefore, our research proposes a universal molecular design strategy for the detection of ClO-, which holds potential for early diagnosis and drug screening for RA.

DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology.

Rheumatoid arthritis (RA) is an autoimmune disease that can cause joint damage and disability. Epigenetic variation, especially DNA methylation, has been shown to be involved in almost all the stages of the pathology of RA, from autoantibody production to various self-effector T cells and the defects of protective T cells that can lead to chronic inflammation and erosion of bones and joints. Given the critical role of T cells in the pathology of RA, the regulatory functions of DNA methylation in T cell biology remain unclear. In this review, we elaborate on the relationship between RA pathogenesis and DNA methylation in the context of different T cell populations. We summarize the relevant methylation events in T cell development, differentiation, and T cell-related genes in disease prediction and drug efficacy. Understanding the epigenetic regulation of T cells has the potential to profoundly translate preclinical results into clinical practice and provide a framework for the development of novel, individualized RA therapeutics.

Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.

Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited over the lifetime of the patient due to the development of antidrug antibodies that preclude proper therapeutic benefits. As a result, patients often return to more problematic therapies such as methotrexate or hydroxychloroquine, which carry long-term side effects. Thus, there is an unmet medical need to develop alternative treatments enabling patients to regain the benefits of selectively targeting TNF functions in vivo. The protein kinase TAK1 is a critical signaling node in TNF-mediated intracellular signaling, regulating downstream NF-κβ activation, leading to the transcription of inflammatory cytokines. TAK1 inhibitors have been developed but have been limited in their clinical advancement due to the lack of selectivity within the human kinome and, most importantly, lack of oral bioavailability. Using a directed medicinal chemistry approach, driven by the cocrystal structure of the TAK1 inhibitor takinib, we developed HS-276, a potent (Ki = 2.5 nM) and highly selective orally bioavailable TAK1 inhibitor. Following oral administration in normal mice, HS-276 is well tolerated (MTD >100 mg/Kg), displaying >95% bioavailability with μM plasma levels. The in vitro and in vivo efficacy of HS-276 showed significant inhibition of TNF-mediated cytokine profiles, correlating with significant attenuation of arthritic-like symptoms in the CIA mouse model of inflammatory RA. Our studies reinforce the hypothesis that TAK1 can be safely targeted pharmacologically to provide an effective alternative to frontline biologic-based RA therapeutics.

Lessons From the Success and Failure of Targeted Drugs for Rheumatoid Arthritis: Perspectives for Effective Basic and Translational Research.

Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.

Are There Any Ethnic Differences in the Response to Baricitinib for the Treatment of Rheumatoid Arthritis?

IntroductionBaricitinib is an oral synthetic Janus Kinase inhibitor that inhibits JAK1 and JAK2, and the new kid on the block in the treatment of rheumatoid arthritis (RA). To date, there are no studies comparing the clinical benefit of baricitinib in RA between different ethnicities. Ethnicity plays a role in the effectiveness of therapeutic agents. Given the large multi-ethnic population of Leicestershire in the United Kingdom and the range of new therapeutics in RA, we reviewed our cohort of patients with RA to see whether there is any difference in baricitinib Disease Activity Score 28 (DAS28) response between the Asian and White cohorts.MethodsThis was a retrospective study. The patients included were those under the care of rheumatology at University Hospitals of Leicester (UHL) with a diagnosis of RA and either receiving baricitinib or had received it in the past. Data was collected using the UHL information technology systems, clinic letters and pharmacy records. In addition to ethnicity, we reviewed patient age, gender, concurrent disease-modifying anti-rheumatic drugs (DMARDs) used, previous biologics used, baseline and post-treatment DAS28, dropout from therapy, baseline biochemical assays (anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status) and radiographic findings. An independent t-test was used to compare continuous data, and Pearson’s chi-squared test was used to compare categorical data.ResultsA total of 120 patients were included in the analysis, and data were analysed with Portable Format for Analytics (PFA). There was no statistically significant difference in the mean DAS28 at baseline (Asian: 5.17 versus White: 4.65; p-value = 0.107) and post-treatment (Asian: 2.8 versus White: 3.3; p-value = 0.404). Comparing both ethnicities, there was no statistically significant difference in previous biologics used, anti-CCP and RF titres, and radiographic findings of erosions.ConclusionThis is the first study of its kind, and it found no significant difference in baricitinib response between the Asian and White cohorts. Our study had certain limitations, and future studies will be needed to evaluate this subject further. Such data is important as it can contribute to a body of evidence that may in the future help inform clinical decision-making.

Tissue engineered skeletal muscle model of rheumatoid arthritis using human primary skeletal muscle cells.

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily targeting the joints. Autoreactive immune cells involved in RA affect other tissues, including skeletal muscle. Patients with RA experience diminished physical function, limited mobility, reduced muscle function, chronic pain, and increased mortality. To explore the impact of RA on skeletal muscle, we engineered electrically responsive, contractile human skeletal muscle constructs (myobundles) using primary skeletal muscle cells isolated from the vastus lateralis muscle of 11 RA patients (aged 57-74) and 10 aged healthy donors (aged 55-76), as well as from the hamstring muscle of six young healthy donors (less than 18years of age) as a benchmark. Since all patients were receiving treatment for the disease, RA disease activity was mild. In 2D culture, RA myoblast purity, growth rate, and senescence were not statistically different than aged controls; however, RA myoblast purity showed greater variance compared to controls. Surprisingly, in 3D culture, contractile force production by RA myobundles was greater compared to aged controls. In support of this finding, assessment of RA myofiber maturation showed increased area of sarcomeric α-actinin (SAA) expression over time compared to aged controls. Furthermore, a linear regression test indicated a positive correlation between SAA protein levels and tetanus force production in RA and controls. Our findings suggest that medications prescribed to RA patients may maintain-or even enhance-muscle function, and this effect is retained and observed in in vitro culture. Future studies regarding the effects of RA therapeutics on RA skeletal muscle, in vivo and in vitro, are warranted.