Drug Therapy For Rheumatoid Arthritis Research Articles

Synovium microenvironment-responsive injectable hydrogel inducing modulation of macrophages and elimination of synovial fibroblasts for enhanced treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.Graphic

Drug therapy of rheumatoid arthritis: where do biologics and novel synthetic disease-modifying antirheumatic drugs stand today?

Biologics and Janus kinase (JAK) inhibitors play an important role in the treatment of rheumatoid arthritis. As new therapeutic developments have emerged in recent decades, the morbidity and mortality of rheumatoid arthritis have been significantly reduced. The characterization of the structure and function of immune cell receptors has led to the development of biologics that specifically inhibit cytokines and immune cell receptors. An important therapeutic addition was the approval of JAK inhibitors, which act directly on intracellular signaling by tyrosine kinases. This article provides an overview of the current therapeutic options for rheumatoid arthritis with aspecial focus on indication, mechanism of action and the place in the treatment algorithm of biologics and JAK inhibitors.

Musculoskeletal Ultrasonography for the Assessment of Combined Drug Therapy for Rheumatoid Arthritis

Musculoskeletal Ultrasonography for the Assessment of Combined Drug Therapy for Rheumatoid Arthritis

Reasons for hip revision artroplasty in patients with rheumatoid arthritis

Hip arthroplasty (THA) is a frequently performed operation in patients with rheumatoid arthritis (RA), which can significantly improve the quality of life of this category of patients. In order to determine the main reasons and peculiarities of revision surgeries in patients with RA, this study was conducted. We analyzed 10 medical charts of the patients with RA who underwent revision surgery in Ekaterinburg Regional Clinical Hospital #1 from 2007 till 2021. We used clinical, radiological and statistical methods. Harris scale was used to assess the function of the hip joint. The leading cause of revision interventions was aseptic instability of component. The result of revisions was considered good in six cases, satisfactory in one case, and unsatisfactory in three cases. The peculiarities of the course and drug therapy of RA explain the leading role of aseptic instability among the causes of revision THA in patients with RA. A significant proportion of satisfactory and unsatisfactory outcomes of revision interventions require both the improvement in endoprosthesis designs and new materials with improved osseointegrative characteristics for bone grafting.

Missing data in randomised controlled trials of rheumatoid arthritis drug therapy are substantial and handled inappropriately

ObjectivesTo analyse the amount, reporting and handling of missing data, approach to intention-to-treat (ITT) principle application and sensitivity analysis utilisation in randomised clinical trials (RCTs) of rheumatoid arthritis (RA). To...

Comprehensive assessment of alterations in hand deformities over 11\xa0years in patients with rheumatoid arthritis using cluster analysis and analysis of covariance

BackgroundAlthough drug therapy for rheumatoid arthritis (RA) has recently improved, treating patients with established disease, whose hands have three major deformities (thumb deformity, finger deformities, and ulnar drift), remains a challenge. The underlying complex pathophysiology makes understanding these deformities difficult, and comprehensive assessment methods require accumulated skill with long learning curves. We aimed to establish a simpler composite method to understand the pathophysiology of and alterations in the hand deformities of patients with RA.MethodsWe established a rheumatoid hand cohort in 2004 and clinically evaluated 134 hands (67 patients). We repeated the evaluations in 2009 (100 hands of 52 patients) and 2015 (63 hands of 37 patients) after case exclusion. Thumb deformities, finger deformities (swan-neck and boutonnière deformity), and ulnar drift were semi-quantitated and entered as parameters into a two-step cross-sectional cluster analysis for the data in 2004. The parameters in each cluster were plotted at each evaluation point. Two-way analysis of covariance was used to examine whether differences existed between evaluation points and clusters of deformity parameters.ResultsFive clusters most appropriately described hand deformity: (i) cluster 1, minimal deformity; (ii) cluster 2, type 1 thumb deformity; (iii) cluster 3, thumb deformity and severe boutonnière deformity; (iv) cluster 4, type 2 or 3 thumb deformity and severe ulnar drift; and (v) cluster 5, thumb deformity and severe swan-neck deformity. Clusters 1 and 2 had higher function than cluster 5, and cluster 3 had moderate function. Clusters 1–4 had similar disease duration but showed different paths of deformity progression from disease onset. Clusters 1 and 2 represented conservative deformity parameters and clusters 3, 4, and 5 represented progressive deformity parameters. Over time, thumb deformity evolved into other types of deformities and swan-neck deformity worsened significantly.ConclusionsOur comprehensive analysis identified five deformity patterns and a progressive course in the rheumatoid hand. Knowledge of the characteristics of progressive deformity parameters may allow rheumatologists to more easily implement practical interventions and determine functional prognosis.

Guizhi-Shaoyao-Zhimu decoction attenuates bone erosion in rats that have collagen-induced arthritis via modulating NF‐κB signalling to suppress osteoclastogenesis

Context Guizhi-Shaoyao-Zhimu decoction (GSZD) is commonly used to treat rheumatoid arthritis (RA), but its mechanism is unclear. Objective To investigate the effect of GSZD on bone erosion in type II collagen (CII)-induced arthritis (CIA) in rats and to identify the underlying mechanism. Materials and methods The CIA model was prepared in male Wistar rats by two subcutaneous injections of CII, 1 mg/mL. Fifty CIA rats were randomized equally into the control group given saline daily, the positive group given saline daily and methotrexate 0.75 mg/kg once a week, and three GSZD-treated groups gavaged daily with 800, 1600 and 3200 mg/kg of GSZD for 21 days. GSZD effects were assessed by paw volume, arthritic severity index and histopathology. Cytokine levels were determined by ELISA. The effects of GSZD on RAW264.7 cells were evaluated by receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption assay. Expression of IκB-α and p65 was measured by Western blotting. Major components of GSZD were identified by HPLC. Results Arthritis index score, paw volume and bone destruction score showed that GSZD improved inflammatory symptoms and reduced joint tissue erosion (p < 0.01). GSZD decreased RANKL, and the number of osteoclasts (OCs) in joint tissues (p < 0.01) and increased osteoprotegerin levels (p < 0.01). GSZD inhibited RANKL-induced RAW264.7 differentiation and reduced bone resorption by OCs. GSZD upregulated IκB (p < 0.01) and p65 (p < 0.01) in the cytoplasm and downregulated p65 (p < 0.01) in the cell nucleus. Conclusions Guizhi-Shaoyao-Zhimu decoction has an anti-RA effect, suggesting its possible use as a supplement and alternative drug therapy for RA.

Changes and Recent Trends in Drug Therapy for Rheumatoid Arthritis

関節リウマチ（RA）の薬物療法は近年，劇的な変化を遂げている．かつての痛みを軽減するNSAIDsの治療から，免疫力や炎症を抑えるステロイド，抗リウマチ薬へと時代とともに変遷している．1999年に現在基本的治療薬として用いられているメトトレキサートが承認され，2003年から生物学的製剤が注射製剤で登場し劇的な変化をもたらした．さらに，2013年にはJAK阻害薬が経口製剤として登場している．現在，生物学的製剤11剤＋JAK阻害薬4剤と治療の選択肢が多様になり，多くの患者が寛解導入可能になっている．生物学的製剤やJAK阻害薬の作用メカニズムを知ることでより有効な薬物処方ができるものと思われ，その作用メカニズムと薬物投与例も提示した．

Association of Dysregulated Central Pain Processing and Response to Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis.

To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA). One hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables. A good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]). Low CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.

Medicinal plants used against various inflammatory biomarkers for the management of rheumatoid arthritis.

Rheumatoid arthritis is a chronic autoimmune disease manifested clinically by polyarthralgia associated with joint dysfunction triggering the antibodies targeting against the self-neoepitopes determined by autoimmune responses associated with chronic arthritic attacks. The activation of macrophages and other defence cells in response to self-epitopes as biomarkers in RA provides a better understanding of pathogenesis of disease and has led to the development of novel therapeutic approaches acting as potent inhibitors of these cells. The current review retrieved the various medicinal plants possessing an active phytoconstituents with anti-inflammatory and antioxidant properties, which tends to be effective alternative approach over the synthetic drugs concerned with high toxic effects. The current available literature provided an evident data concluding that the active constituents like fatty acids, flavonoids, terpenes and sesquiterpene lactones attenuate the RA symptoms by targeting the inflammatory biomarkers involved in the pathogenesis of RA. Despite the various synthetic treatment approaches targeting immune cells, cytokines improved the quality of life but still the drug management is challenging due to toxic and chronic teratogenic effects with anti-arthritic drugs. The current review has elaborated the selected traditionally used herbal medicinal plants with phytoconstituents possessing anti-inflammatory activity by suppressing the inflammatory biomarkers with lesser side effects and providing the future exploration of natural drug therapy for rheumatoid arthritis.

Successful long-term remission through tapering tocilizumab infusions: a single-center prospective study

BackgroundStrategic drug therapy for rheumatoid arthritis (RA) patients with prolonged remission is not well defined. According to recent guidelines, tapering biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) may be considered. We aimed to evaluate the effectiveness of long-term maintenance of tocilizumab (TCZ) treatment after the progressive tapering of infusions.MethodsWe conducted an exploratory, prospective, single-center, open-label study, on RA patients with sustained remission of at least 3 months and treated with TCZ infusions every 4 weeks. The initial re-treatment interval was extended to 6 weeks for the first 3 months. Thereafter, the spacing between infusions was determined by the clinician. Successful long-term maintenance following the tapering of TCZ infusions was defined by patients still treated after two years by TCZ with a minimum dosing interval of 5 weeks.ResultsThirteen patients were enrolled in the study. Eight out of thirteen were still treated by TCZ after two years. Successful long-term maintenance was possible in six patients, with four patients maintaining a re-treatment interval of 8-weeks or more. We observed 5 patients with TCZ withdrawal: one showing adverse drug reaction (neutropenia) and four with secondary failure. Patients achieving successful long-term maintenance with TCZ were significantly younger than those with secondary failure (p < 0.05). In addition, RA patients with positive rheumatoid factor and anti-citrullinated peptide antibodies, experienced a significantly greater number of flares during our 2-year follow-up (p < 0.01).ConclusionsA progressive tapering of TCZ infusions may be possible for many patients. However, larger studies, including more patients, are needed to confirm this therapeutic option.Trial registrationNCT02909998. Date of registration: October 2008.

Inhibitor of biological effects of interleukin-6 sarilumab in treatment of rheumatoid arthritis

Despite progress in pharmacotherapy, there still are urgent needs in the development of new methods of drug therapy of rheumatoid arthritis (RA). New prospects for drug therapy are currently associated with sarilumab (SAR), recently registered in the Russian Federation for the treatment of moderate to highly active RA in adult patients. SAR binds to both membrane and soluble interleukin-6 receptors (IL-6r), blocking its pro-inflammatory effect. SAR has certain differences from its predecessor, tocilizumab: it is a fully human, not humanized, antibody, it is injected subcutaneously once every 2 weeks, it has a more pronounced affinity for IL-6r. SAR is a highly effective treatment for patients with RA, it has shown higher efficacy in monotherapy compared to the representative of the class of TNF inhibitors adalimumab. Clinical studies have shown approximately equal clinical efficacy parameters and a safety profile for SAR and tocilizumab. Sarilumab should be considered as a first-line biologic drug in patients with high inflammatory activity, as well as in patients resistant to anti-TNF.

New possibilities of drug therapy for rheumatoid arthritis: focus at sarilumab

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases in humans and is a serious medical and social problem in the Russian Federation. Current synthetic and biological agents acting through specific molecular targets, play a significant role in the treatment of RA. Over the last few years, inhibitors of the biological effects of interleukin-6 (IL-6) have attracted increasing attention, being positioned as the first choice agents among the biologicals, especially if there is a need in monotherapy. IL-6 is a pleiotropic cytokine with a broad range of biological effects on immune cells, such as B and T lymphocytes, on hepatocytes, hematopoietic cells, vascular endothelial cells, and many others. In this regard, IL-6 is a good therapeutic target in RA. For several years, the group of inhibitors of IL-6 biological effects has been represented by one drug only, i.e. tocilizumab. The new drug of this group, sarilumab, is a human monoclonal antibody (IgG1 subtype) to the IL-6 receptor. Sarilumab binds specifically to both soluble and membrane IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signal transduction involving signal protein glycoprotein 130 (gp130) and signal proteins STAT-3. There is evidence that sarilumab has a higher affinity to the IL-6 receptor, and binds the receptor in a more stable manner than tocilizumab. Sarilumab has been approved for treatment of RA with moderate or high activity in adult patients with inadequate response or intolerability to one or several synthetic basic drugs, at a dose 150 mg or 200 mg subcutaneously biweekly in combination with methotrexate (MTX). It also can be prescribed as monotherapy in case of MTX intolerability or if treatment with MTX is inexpedient. Sarilumab is a highly active therapeutic agent with proven superiority in monotherapy over adalimumab. Therefore, sarilumab can be positioned as a first line biological agent in patients with high inflammatory activity, as well as in those resistant to tumor necrosis factor-α inhibitors. The safety profile of sarilumab is similar to that of tocilizumab; probably there is a slightly higher risk of neutropenia, but a lower risk of dyslipidemia, reactions at the injection site and gastrointestinal perforation for sarilumab than for tocilizumab.

Questioning a publication bias between industry-funded and non-industry-funded randomized controlled trials on biological and small molecule therapy for rheumatoid arthritis

BackgroundThere has been a significant increase in financial support of clinical research by the pharmaceutical industry. MethodsWe performed a comprehensive systematic literature review to determine whether there is publication bias for rheumatoid arthritis (RA) studies between industry-funded and non-industry funded randomized controlled trials (RCTs), and between RCTs with positive results (PRs) and those with negative results (NRs) of FDAapproved biological and small molecule drug therapy for RA. Each RCT was classified as having either a PR or a NR, and as having received commercial funding or not. ResultsMost (297/349, 85.18%) of the RCTs were commercially funded. There was no significant difference in PRs or association with publication between commercially and noncommercially funded RCTs. Sample size was significantly larger in commercially funded RCTs and in those with PRs, and it was the only significant parameter that predicted publication in higher impact factor journals in the field of RA. ConclusionThere is no significant association between commercial funding and the publication of positive results or the publication of an RCT in higher impact factor journals.

4. History and Front-line of the Drug Therapy for Rheumatoid Arthritis Based on Pathophysiological Research

4. History and Front-line of the Drug Therapy for Rheumatoid Arthritis Based on Pathophysiological Research

Cardiotropic action of combined use of celecoxib and amlodipine in rats sicked on adjuvant arthritis coupled with arterial hypertension

Drug therapy of rheumatoid arthritis combined with arterial hypertension is among actual medical objectives. The complexity of pharmacological treatment of comorbid state is due to not only pathological process severity, insufficient efficacy and side effects of disease modifying and symptomatic drugs but also property of nonsteroidal anti-inflammatory drugs (NSAIDs) to aggravate already existed arterial hypertension in patients with rheumatoid arthritis or to increase pressure. Many hypotensive drugs loose or don’t manifest their activity when used in combination with NSAIDs. High risk of cardio toxicity is registered for one of NSAIDs group – coxibs. The cardio safety of combined use of coxibs and hypotensive drugs on the ground of comorbid pathology is studied not enough.&#x0D; These aspects had predefined the aim of this study – to investigate cardiotropic effects of celecoxib when administered in combinations with amlodipine on the ground of experimental rheumatoid arthritis coupled with arterial hypertension.&#x0D; Arterial hypertension was modeled in rats by method of salt load. On the basis of arterial hypertension rheumatoid arthritis was caused by full Freund adjuvant injection. Arterial blood pressure and heart rate registered on sphygmomanometer.&#x0D; It was found that comorbid state is followed by arterial hypertension and tachyarrhythmia. Celecoxib does not facilitate hypertension enhancing but leads to increasing heart rate. Amlodipine manifests specific pharmacological activity as hypotensive drug. The results obtained predefined opportunity of combined use of celecoxib with amlodipine on the ground of rheumatoid arthritis coupled with arterial hypertension.

Clinical evaluation of shiva guggulu and simhnad guggulu in the management of amavata

Amavata is one of the dreadful disorders and included under the vata vyadhis in Ayurveda. The annual incidence rate of rheumatoid arthritis is low however the prevalence rate of the same is very high. Of all the rheumatic disorders, rheumatoid arthritis still remains a formidable disease, as it causes severe crippling deformities and functional disabilities. The disease can undergo spontaneous remission and it is difficult to forecast the outcome of the disease and it makes the evaluation of new drug is also difficult. If proper attention has not been paid the condition turns to its worse. The severe pain and crippling deformities with functional abnormalities make the patient seek doctor’s advice. Even in the modern system of medicine the drug therapy for rheumatoid arthritis is empirical and is focused on 3 issues-1. Relieving the pain along with control of inflammation,2. Improving and maintaining the function and3. Prevention of the deformity.However, none of the medicine available at present can give everlasting benefit thereby permanent remission from the symptoms. The drugs which are available as on today are only of value in achieving the symptomatic relief. But their use is restricted because of the number of adverse effects attached to their usage. It is because of this reason the people are looking towards a safe and effective drug.

Lipids and lipid changes with synthetic and biologic disease-modifying antirheumatic drug therapy in rheumatoid arthritis: implications for cardiovascular risk.

To highlight recently published studies addressing lipid changes with disease-modifying antirheumatic drug use and outline implications on cardiovascular outcomes in rheumatoid arthritis (RA). Growing evidence suggests lower lipid levels are present in patients with active RA vs. general population, and significant modifications of lipid profile with inflammation suppression. Increase in lipid levels in patients with RA on synthetic and biological disease-modifying antirheumatic drugs may be accompanied by antiatherogenic changes in lipid composition and function. The impact of lipid changes on cardiovascular outcomes in RA is a subject of active research. The role of lipids in cardiovascular risk in RA may be overpowered by the benefits of inflammation suppression with antirheumatic medication use. Recommendations on lipid management in RA are evolving but uncertainty exists regarding frequency of lipid testing and goals of treatment. Knowledge about quantitative and qualitative lipid changes in RA is expanding. The relative role of lipids in cardiovascular risk in the context of systemic inflammation and antirheumatic therapy remains uncertain, delaying development of effective strategies for cardiovascular risk management in RA. Studies are underway to address these knowledge gaps and may be expected to inform cardiovascular risk management in RA and the general population.

Outcomes of modified metatarsal shortening offset osteotomy for forefoot deformity in patients with rheumatoid arthritis: Short to mid-term follow-up

Objectives: Advances in drug therapy for rheumatoid arthritis (RA) have been encouraging us to preserve the metatarsopharangeal (MTP) joint in correction of forefoot deformities, and original metatarsal shortening offset osteotomy was recommended as one of the conventional surgical options for forefoot deformities in RA cases. The objective of this study was to evaluate short- to mid-term outcomes of modified metatarsal shortening offset osteotomy.Methods: A retrospective observational study was completed for 80 RA cases (mean follow-up period: 3.2 years) who underwent modified metatarsal shortening offset osteotomy. Both lesser toe scales and RA foot ankle scales were administered using the Japanese Society for Surgery of the Foot (JSSF) standard rating system, and a postoperative self-administered foot evaluation questionnaire (SAFE-Q) at final follow-up was also checked to evaluate clinical outcomes.Results: This procedure significantly improved clinical scores of both the JSSF [lesser toes and RA foot and ankle] scales. Of 80 feet, 24 (30%) showed recurrence of MTP joint subluxation/dislocation. Furthermore, the feet in the recurrence group showed significant varus hindfoot. On the other hand, valgus foot in the recurrence group more frequently included midfoot bony ankyloses. All of the affected feet showed the limitation of MTP joints (<70°) after surgery.Conclusions: Modified metatarsal shortening offset osteotomy was recommended for RA forefoot disorders as one of the joint preservation surgeries in short- to mid-term follow-up. However, some modifications to avoid limitation of ROM in the MTP joint are required. It must be borne in mind that varus hindfoot and/or bony ankyloses in the mid-hindfoot can cause recurrence of dorsal dislocation/subluxation of the lesser toe MTP joint.

Recent Trends in Orthopedic Surgery Aiming to Improve Quality of Life for Those with Rheumatoid Arthritis: Data from a Large Observational Cohort

To describe current trends in the numbers of rheumatoid arthritis (RA)-related surgeries. The number of operations was determined for patients with RA in a large observational cohort [Institute of Rheumatology, Rheumatoid Arthritis (IORRA)] enrolled from 2001 to 2012. The total number of operations peaked in 2002 and gradually decreased thereafter, but began to increase again in 2008. The number of total knee replacements has decreased since 2003, while the number of wrist and foot arthroplasties and the number of artificial finger prosthesis surgeries have increased gradually. Our results suggest that the number of orthopedic surgeries may change in response to changes in the drug therapy for RA.