Therapeutic Agent For Rheumatoid Arthritis Research Articles

Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA. Therapeutic efficacy and mechanisms of ectosteric (tanshinone IIA sulfonate [T06]) and active site-directed (odanacatib [ODN]) inhibitors of cathepsin K (CatK) were evaluated in RA mouse models. Pathology was assessed through biochemical analyses and histopathological examination. Flow cytometry analysis was performed to characterize immune cells. Anti-inflammatory effects of T06 on nuclear factor kappa beta (NF-κB) pathway were studied in macrophages. T06 effectively lowered the number of joint-resident immune cells, accompanied by significantly reduced production of inflammatory cytokines and collagenolytic proteases. This also included the suppression of Th17 cells and IL-17, resulting in the reduction of osteoclasts in arthritic joints and amplification of the overall anti-resorptive effect of T06, which has been attributed to its selective inhibition of the collagenolytic activity of CatK by preventing its oligomerization. The anti-inflammatory mechanism of T06 was based on blocking the phosphorylation of IκBα in the NF-κB pathway, resulting in reduced activation and expression of inflammatory cytokines. In contrast, ODN had no effect on inflammation and disease progression and was limited to the inhibition of CatK. The combined anti-resorptive and anti-inflammatory activities characterize T06 as a novel therapeutic agent for RA.

Antiarthritic and Anti-inflammatory Activity of Different Types of Milk in Complete Freund’s Adjuvant-induced Arthritis in Male Adult Rats

Background: Rheumatoid arthritis (RA) is a chronic, immune-inflammatory disease that could be managed by an attenuation in dietary habits. With the increase in research that links the effect of nutrition linked to RA. Purpose: Our study aimed to determine the possible therapeutic effect of different types of milk in rat models experimentally induced with RA using 40 ml milk (camel (CM), goat (GM), sheep (SHM), cow (CWM), almond (AM), and soy milk (SM)). Methods: Forty adult male Wistar Albino rats were divided into eight groups (five rats each) as follows: (Control group): nonarthritic, (RA): rheumatoid arthritis, (RA+CM): RA having CM, (RA+GM): RA having GM, (RA+SHM): RA having SHM, (RA+CWM): RA having CWM, (RA+AM): RA is having AM, and (RA+SM): RA has SM. Results: It has been observed that in the RA group and milk-treated groups, but not in the RA+CM group, the arthritis score changed significantly ( p ≤ 0.05) in comparison with the control group. CM and GM showed promising effects in downregulating various arthritis effector players including anticitrullinated peptide antibodies, C-reactive protein, prostaglandin E2, and other inflammatory mediators, which may be attributed to their lowest ω-6/ω-3 polyunsaturated fatty acid ratios. Conclusion: A possible benefit of this research is the potential development of new functional foods that promote health, prevent disease, and potentially enable the milk to be used as a therapeutic agent for RA.

Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models

Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.

Essential Oil of Psidium glaziovianum Kiaersk Alleviates the Effects of Complete Freund’s Adjuvant (CFA)-Induced Arthritis by Regulating Inflammation and Oxidative Stress

Rheumatoid arthritis (RA) is a chronic and debilitating condition that affects a significant number of individuals worldwide. Unfortunately, the currently available therapeutic approaches often yield unsatisfactory results and may be accompanied by harmful side effects. A medicinal plant called Psidium glaziovianum Kiaersk has potential benefits in the treatment of this condition due to its anti-inflammatory and analgesic properties. In this study, our objective was to investigate the potential therapeutic effects of P. glaziovianum essential oil (PgEO) in alleviating arthritis symptoms in mice induced by Complete Freund’s Adjuvant (CFA). The effect of P. glaziovianum essential oil was evaluated in mice with Complete Freund’s Adjuvant (CFA)-induced arthritis. Edema sizes, macroscopic and radiographic images, cytokine levels, and oxidative stress were evaluated. Administration of PgEO at dosages of 50 and 100 mg/kg effectively prevented CFA-induced osteoarticular changes in arthritic mice, resulting in a significant reduction in joint damage. Additionally, the PgEO treatment exhibited the ability to minimize edema, a common symptom associated with arthritis. Furthermore, PgEO can modulate the levels of pro-inflammatory cytokines and oxidative stress, both of which play crucial roles in the progression of the disease. In conclusion, our study suggests that PgEO holds great potential as a natural therapeutic agent for rheumatoid arthritis.

Nitazoxanide reduces inflammation and bone erosion in mice with collagen-induced arthritis via inhibiting the JAK2/STAT3 and NF-κB pathways in fibroblast-like synoviocytes

Our recent study showed that Nitazoxanide (NTZ), an FDA-approved anti-parasitic drug, prevents ovariectomy-induced bone loss by inhibiting osteoclast activity. However, there have been no investigations to determine whether NTZ has preventive potential in other bone resorbing diseases, especially rheumatoid arthritis (RA). In this study, the primary RA fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) murine model were used to evaluate the effect of NTZ. The results showed that NTZ potently inhibited proliferation, migration and invasion capacity of RA-FLS in a dose dependent manner by restraining cell entry into S phases, without induction of cell apoptosis. NTZ obviously reduced spontaneous mRNA expression of IL-1β, IL-6 and RANKL, as well as TNF-α-induced transcription of the IL-1β, IL-6, and MMP9 genes. In terms of molecular mechanism, NTZ significantly inhibited the basal or TNF-α-induced activation of JAK2/STAT3 (T705) and NF-κB pathway, but not MAPK and STAT3 (S727) phosphorylation. Moreover, NTZ ameliorated synovial inflammation and bone erosion in CIA mice through reducing the production of inflammatory mediators and osteoclast formation, respectively. Collectively, our findings indicate that NTZ exhibits anti-inflammatory and anti-erosive effects both ex vivo and in vivo, which provides promising evidence for the therapeutic application of NTZ as a novel therapeutic agent for RA.

Campesterol: A Natural Phytochemical with Anti Inflammatory Properties as Potential Therapeutic Agent for Rheumatoid Arthritis: A Systematic Review

Rheumatoid Arthritis (RA) is a persistent inflammatory and autoimmune affliction, which results in significant impairment of mobility and a decline in the overall standard of living. The present therapeutic strategies for the management of RA are frequently associated with adverse reactions of notable severity. Medicinal plants containing Phytochemicals such as Campesterol, Crocetin, Nigella Sativa, and Ginkgolic Acid have been recognized as significant alternatives for the treatment of RA. This review article provides an overview of the bioactive constituent campesterol, which exhibits the capacity to regulate interleukins and immune modulation in vitro and in vivo experimental models. The current study aimed to obtain relevant academic literature about the utilization of natural products in the treatment of arthritic conditions. A systematic search strategy was employed, involving both electronic and manual efforts, to query prominent scholarly databases including PubMed, Embase, Scopus, and Web of Science. 76 publications were identified through this review, with 30 being deemed eligible for inclusion. Four researchers have reported their discoveries on the efficacy of natural constituents in the management of RA through investigations In Vitro & In Vivo. Scholarly reports investigated the role of bioactive constituents of phytochemicals for RA treatment, while 15 studies In Vivo evaluated the effectiveness of Campesterol, in alleviating arthritis symptoms through their inflammatory responses and modulation of interleukin production. This review presents notable findings suggesting that Campesterol appears to be particularly effective in the expression of pro-inflammatory modulation of cytokines, and anti-inflammatory cytokines, hence posing therapeutic potential in RA management.

The phytochemical profiling of Aloe vera through GC-MS and compounds activity validation at NCBI for industrial value addition of the plant

The Aloe vera commonly known as Gwarpatha or Ghrit Kumari is considered as a universal panacea. It is a gifted plant for the health, beauty, medicinal and skincare industry. However, considering the multiple uses of it in other sectors also, it needed to be explored further for other than known industrial and medicinal values. The present study highlights the additional industrial and medicinal properties of the plant. It includes preliminary phytochemicals screening, GC-MS analysis of a Methanolic Extract of Aloe vera (MEAV) leaves and finding out the compounds activities at the international compounds databases of NCBI like PubChem, Drug Bank etc. Out of 200 compounds detected through GC-MS, mainly 46 compounds falling in major peak areas were further explored at the compounds databases. Accordingly, some key phytocompounds such as α-D Glucose, Lactose, Maltotriose, Citronellyl Butyrate, Phytol, Myristic Acid, Capric Acid, Heptadecanoic Acid etc. depicted the important industrial activities like sweet modulator of food stuff, diluents/sweetener for dairy, alcohol, soft drinks, health, beauty, confectionary and pharmaceutical industry; moisturizing and fragrance agent in cream, shampoo, soap, perfumed products; emulsifier, texture enhancer; agent for the lubricants, greases, dyes, plastics, detergent and biodiesel etc. Other than them, several phytocompounds showing medicinal properties like anti-cancer, anti-inflammatory, antioxidant, anti-hypertensive, anti-fungal, anti-bacterial, immunity booster, therapeutic agents for Rheumatoid Arthritis, acute respiratory distress syndrome, Asthma, Cardiovascular Disease, Cancer, Osteoporosis, Insomnia, etc. were also identified in the plant. Consequently, Aloe vera with its great industrial values can be a good source of raw material for several other industries like food, beverage, cosmetic, detergent, soaps, biodiesel pharmaceutical and may be considered for the sustainable aloe-cultivation as alternative cash crop in drought prone area like Bundelkhand region.

Nitidine chloride inhibits fibroblast like synoviocytes-mediated rheumatoid synovial inflammation and joint destruction by targeting KCNH1

ObjectiveNitidine chloride (NC), a natural small molecular compound from traditional Chinese herbal medicine zanthoxylum nitidum, has been shown to exhibit anti-tumor effect. However, its role in autoimmune diseases such as rheumatoid arthritis (RA) is unknown. Here, we investigate the effect of NC in controlling fibroblast-like synoviocytes (FLS)-mediated synovial inflammation and joint destruction in RA and further explore its underlying mechanism(s). MethodsFLSs were separated from synovial tissues obtained from patients with RA. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression was measured using quantitative RT-PCR. ELISA was used to measure the levels of cytokines and MMPs. Cell proliferation was detected using EdU incorporation. Migration and invasion were evaluated by Boyden chamber assay. RNA sequencing analysis was used to identify the target of NC. Collagen-induced arthritis (CIA) model was used to evaluate the in vivo effect of NC. ResultsNC treatment reduced the proliferation, migration, invasion, and lamellipodia formation but not apoptosis of RA FLSs. We also demonstrated the inhibitory effect of NC on TNF-α-induced expression and secretion of IL-6, IL-8, CCL-2, MMP-1 and MMP-13. Furthermore, we identified KCNH1, a gene that encodes ether-à-go-go-1 channel, as a novel targeting gene of NC in RA FLSs. KCNH1 expression was increased in FLSs and synovial tissues from patients with RA compared to healthy controls. KCNH1 knockdown or NC treatment decreased the TNF-α-induced phosphorylation of AKT. Interestingly, NC treatment ameliorated the severity of arthritis and reduced synovial KCNH1 expression in mice with CIA. ConclusionsOur data demonstrate that NC treatment inhibits aggressive and inflammatory actions of RA FLSs by targeting KCNH1 and sequential inhibition of AKT phosphorylation. Our findings suggest that NC might control FLS-mediated rheumatoid synovial inflammation and joint destruction, and be a novel therapeutic agent for RA.

Development of 186/188Re-Chitosan as an Effective Therapeutic Agent for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an inflammatory chronic disease characterized by inflammation, pain, swelling and disability, and radiosynovectomy is one of the disease treatment lines. In this study, the possibility of providing rhenium-186/rhenium-188 chitosan radiopharmaceuticals, optimization of conditions for their production and bio-distribution are reported. In order to build perrhenic acid for labeling, natural rhenium was exposed to radiation. Radionuclidic and radiochemical purities of (186/188Re)-NaReO4 were examined by gamma spectroscopy and paper chromatography methods, respectively. Labeling of chitosan with rhenium was done in different acidic situations. The radiochemical purity 186/188Re-chitosan was applied by radio thin layer chromatography (RTLC). Lastly, the bio-distribution of the radiolabeled chitosan was studied in various organs after intra articular injection of the complex to lab rats. Gamma spectrometry confirmed the high rhenium radionuclidic purity. Chromatography results showed that perrhenic acid was produced with purity greater than 97% and rhenium chitosan labeling was done over 98% in pH = 3. Dissection results showed a high bio-distribution of 186/188Re-chitosan after injection into the joint with no leakage to surrounding organs. According to the results, there is a possibility of labeling rhenium with chitosan in very high radiochemical purity. Regarding the high retention of these radiopharmaceuticals in joints with no leakage to surrounding organs, 186/188Re-chitosan can be applied as new radiosynovectomy drugs for rheumatoid arthritis treatment.

Reactive oxygen species-responsive dendritic cell-derived exosomes for rheumatoid arthritis

Although tolerogenic dendritic cell-derived exosomes (TolDex) have emerged as promising therapeutics for rheumatoid arthritis (RA), their clinical applications have been hampered by their poor in vivo disposition after systemic administration. Herein, we report the development of stimuli-responsive TolDex that induces lesion-specific immunoregulation in RA. Responsiveness to reactive oxygen species (ROS), a physiological stimulus in the RA microenvironment, was conferred on TolDex by introducing a thioketal (TK) linker-embedded poly(ethylene glycol) (PEG) on TolDex surface via hydrophobic insertion. The detachment of PEG following overproduction of ROS facilitates the cellular uptake of ROS-responsive TolDex (TKDex) into activated immune cells. Notably, TolDex and TKDex downregulated CD40 in mature dendritic cells (mDCs) and regulated secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at the cellular level. In the collagen-induced arthritis (CIA) mouse model, PEG prolonged the blood circulation of TKDex following intravenous administration and enhanced their accumulation in the joints. In addition, TKDex decreased IL-6, increased transforming growth factor-β, and induced the CD4+CD25+Foxp3+ regulatory T cells in CIA mice. Overall, ROS-responsive TolDex might have potential as therapeutic agents for RA. Statement of significanceTolerogenic dendritic cell-derived exosomes (TolDex) are emerging immunoregulators of autoimmune diseases, including rheumatoid arthritis (RA). However, their lack of long-term stability and low targetability are still challenging. To overcome these issues, we developed reactive oxygen species (ROS)-responsive TolDex (TKDex) by incorporating the ROS-sensitive functional group-embedded poly(ethylene glycol) linker into the exosomal membrane of TolDex. Surface-engineered TKDex were internalized in mature DCs because of high ROS-sensitivity and enhanced accumulation in the inflamed joint in vivo. Further, for the first time, we investigated the potential mechanism of action of TolDex relevant to CD40 downregulation and attenuation of tumor necrosis factor (TNF)-α secretion. Our strategy highlighted the promising nanotherapeutic effects of stimuli-sensitive TolDex, which induces immunoregulation.

Hyaluronic acid-green tea catechin conjugates as a potential therapeutic agent for rheumatoid arthritis.

Fibroblast-like synoviocytes are a key effector cell type involved in the pathogenesis of rheumatoid arthritis. The major green tea catechin, epigallocatechin-3-O-gallate (EGCG), has attracted significant interest for rheumatoid arthritis therapy because of its ability to suppress the proliferation and interleukin-6 secretion of synoviocytes. However, therapeutic efficacy of EGCG has been limited by a lack of target cell specificity. Herein we report hyaluronic acid–EGCG (HA–EGCG) conjugates as an anti-arthritic agent that is capable of targeting fibroblast-like synoviocytes via HA–CD44 interactions. These conjugates exhibited superior anti-proliferative and anti-inflammatory activities compared with EGCG under simulated physiological conditions. Near-infrared fluorescence imaging revealed preferential accumulation of the conjugates at inflamed joints in a collagen-induced arthritis rat model, and their anti-arthritic efficacy was investigated by measuring a change in the edema and histopathological scores. Our findings suggest the potential of HA–EGCG conjugates as an anti-arthritic agent for the treatment of rheumatoid arthritis.

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA’s pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox–Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.

Benzoylaconitine Inhibits Production of IL-6 and IL-8 via MAPK, Akt, NF-κB Signaling in IL-1β-Induced Human Synovial Cells.

Benzoylaconitine (BAC), the main hydrolysate of aconitine, is a lower toxic monoester type alkaloid considered as the pharmacodynamic constituent in Aconitum species. In this study, the effects and mechanisms of BAC on production of inflammatory cytokines interleukin (IL)-6 and IL-8 were investigated in IL-1β-stimulated human synovial SW982 cells. The SW982 cells were incubated with BAC (0, 5 and 10 µM) before stimulating with IL-1β (10 ng/mL). The results revealed that BAC suppressed gene and protein expression of IL-6 and IL-8 induced by IL-1β. BAC decreased activation of mitogen-activated protein kinase (MAPK) and phosphorylation of Akt. BAC also inhibited degradation of inhibitor of kappaB (IκB)-α, phosphorylation and nuclear transposition of p65 protein. The results demonstrate that BAC exerts an anti-inflammatory effect dependent on MAPK, Akt and nuclear factor-κB (NF-κB) pathways in human synovial cells stimulated with IL-1β, suggesting that BAC may be exploited as a potential therapeutic agent for rheumatoid arthritis (RA) treatment.

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis.

Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.

The gut microbiota modulator berberine ameliorates collagen‐induced arthritis in rats by facilitating the generation of butyrate and adjusting the intestinal hypoxia and nitrate supply

The commensal microbiota is one of the environmental triggers of rheumatoid arthritis (RA). Recent studies have identified the characteristics of the gut microbiota in patients with RA. However, it is still unclear how the microbiota can be modulated to slow down disease progression. In the present study, berberine, a modulator of gut microbiota with substantial anti-RA effect, was chosen to explore the mechanisms by which the microbiota modulators ameliorate RA. The results showed that oral administration of berberine alleviated collagen-induced arthritis (CIA) in rats in a gut microbiota-dependent manner. Berberine down-regulated the diversity and richness of the gut bacteria, reduced the abundance of Prevotella, and elevated the abundance of butyrate-producing bacteria in CIA rats as determined by the 16S rRNA gene sequence, which might function through limiting the generation of nitrate and stabilizing the physiologic hypoxia in the intestine. Moreover, berberine treatment significantly increased the intestinal butyrate level and promoted the expression and activity of butyryl-CoA:acetate-CoA transferase (BUT). The coadministration of a BUT inhibitor largely diminished the adjustment of intestinal environment and the antiarthritic effect of berberine. In conclusion, modulators of the gut microbiota might serve as therapeutic agents for RA by inducing the butyrate generation through promoting the expression and activity of BUT.-Yue, M., Tao, Y., Fang, Y., Lian, X., Zhang, Q., Xia, Y., Wei, Z., Dai, Y. The gut microbiota modulator berberine ameliorates collagen-induced arthritis in rats by facilitating the generation of butyrate and adjusting the intestinal hypoxia and nitrate supply.

Five-year incidence of common comorbidities, such as hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease, cerebrovascular disease and cancer, in older Japanese patients with rheumatoid arthritis.

To estimate the 5-year incidence of common comorbidities, including lifestyle-associated diseases, in older Japanese patients with rheumatoid arthritis (RA). We enrolled 129 consecutive patients with RA aged ≥65 years in this study. We examined all patients for the presence of hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease, cerebrovascular disease and cancer at baseline (in 2013) and 5 years later (in 2018) using clinical records, self-reported questionnaires, interviews and medication records. At baseline, hypertension was prevalent in 37.2% of the patients, dyslipidemia in 18.6%, diabetes mellitus in 9.3%, cardiovascular disease in 14.7%, cerebrovascular disease in 10.1% and cancer in 10.1%. Furthermore, the change of prevalence after 5 years from baseline of hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease, cerebrovascular disease and cancer was 4.6%, 3.9%, 0.8%, 4.7%, 2.3% and 1.5%, respectively. The factors associated at baseline and/or after 5 years of hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease and cancer included disease duration and body mass index, body mass index and anti-cyclic citrullinated peptide antibody, corticosteroid use, body mass index, and male and disease duration, respectively. The Japanese population is aging and so is the population of patients with RA. In older patients with RA, hypertension and cardiovascular disease should be particularly considered. Therefore, although the therapeutic agents for RA have improved, a better understanding of the comorbidities in older patients with RA should impact the treatment of RA. Geriatr Gerontol Int 2019; 19: 577-581.

Flemingia philippinensis Flavonoids Relieve Bone Erosion and Inflammatory Mediators in CIA Mice by Downregulating NF-κB and MAPK Pathways.

Background The dry root of Flemingia philippinensis has been widely used in the treatment of rheumatism, arthropathy, and osteoporosis in traditional Chinese medicine; the therapeutic effects of Flemingia philippinensis are associated with antiarthritis in traditional Chinese medicine theory. This study was undertaken to investigate the mechanism of bone erosion protection and anti-inflammatory effect of Flemingia philippinensis flavonoids (FPF) in collagen-induced arthritis (CIA) in mice. Methods Flavonoids were extracted from the dry root of Flemingia philippinensis. Collagen-induced arthritis in C57BL/6 mice was used as a rheumatoid arthritis model, and the mice were orally fed with FPF prior to induction to mimic clinical prophylactic therapy for a total of 39 days. After treatment, histology and immunohistochemistry staining were performed, and the levels of anti-collagen type II (CII) antibody and inflammatory mediators, as well as the key proteins of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were detected in the samples taken from ankle joints, plasma, and paws. Results FPF administration significantly suppressed the paw swelling and arthritic score in CIA mice. FPF reduced inflammatory infiltration and pannus formation, articular cartilage destruction and osteoclast infiltration, and the expression of MMP-9 and cathepsin K in the ankle joint. FPF inhibited plasma anti-CII antibody levels and the production of inflammatory cytokines and chemokines in CIA paws. FPF treatment suppressed the activation of NF-κB as indicated by downregulating the phosphorylation of NF-κB p65 and mitogen-activated protein kinases in CIA paws. Additionally, FPF significantly inhibited inflammation signaling by suppressing the activation of activator protein-1 subset and signal transducers and activators of transcription 3 (STAT3). Conclusions Our data suggest that FPF might be an active therapeutic agent for rheumatoid arthritis and the preventive effect of FPF on arthritis is attributable to an anti-inflammatory effect on CIA by preventing bone destruction, regulating inflammatory mediators, and suppressing NF-κB and MAPK signaling pathways.

Novel Drug Delivery Systems for Rheumatoid Arthritis: An Approach to Better Patient Compliance

Recent advances in science and technology radically changed the way we detect, treat and prevent different diseases in all aspects of human life. Rheumatoid arthritis (RA) is a chronic, systemic, progressive, autoimmune disease in which the body’s immune system whose major role is to protect the health by attacking foreign bacteria and viruses are mistakenly, attacking the joints resulting in thickened synovium, pannus formation, & destruction of bone, cartilage. Still now researchers are unable to know the exact cause of this disease. However, it is believed that genes and environmental factors play a role in development of RA. In this review, we discuss the Pathophysiology, predictors, & factors involved in pathogenesis of RA. We also discuss the Conventional therapeutic agents for Rheumatoid Arthritis. More importantly, we extensively discuss the emerging novel drug delivery systems (NDDS) like nanoparticles, dendrimers, micelles, microspheres, liposomes, and so on as these are the promising tools having successful applications in overcoming the limitations associated with conventional drug delivery systems. Although several NDDS have been used for various purposes, liposomes have been focused on due to its potential applications in RA diagnosis and therapy. In addition, we discuss the therapeutic effectiveness and challenges for RA by using these novel drug delivery systems. Finally, we conclude by discussing the future perspectives.

Ketoprofen and MicroRNA-124 Co-loaded poly (lactic-co-glycolic acid) microspheres inhibit progression of Adjuvant-induced arthritis in rats

Ketoprofen, a non-steroid anti-inflammatory drug, is widely used for relieving the pain and swelling caused by rheumatoid arthritis. However, ketoprofen can’t suppress disease progression effectively. In this study, in an effort to improve the therapeutic effect for rheumatoid arthritis (RA), microRNA-124 (miR-124), a promising new therapeutic agent for RA, was co-loaded with ketoprofen into poly (lactic-co-glycolic acid) (PLGA) microspheres and administrated to adjuvant-induced arthritis rats. PLGA microspheres loaded with ketoprofen and miR-124 were prepared by a modified multiple emulsion–solvent evaporation method. In vivo pharmacodynamics experimental results indicated ketoprofen in co-loaded microspheres could significantly reduce inflammation of the joints and miR-124 in the microspheres could reduce bone damage. In addition, ketoprofen and miR-124 co-loaded PLGA microspheres had a remarkable advanced activity over delivery of either miR-124 or ketoprofen in suppressing adjuvant-induced arthritis (AA) in rats. Results of western blot and immunohistochemistry revealed that miR-124 could reduce the level of receptor activator of nuclear factor kappa-B ligand (RANKL). These results suggested co-delivery of ketoprofen and miR-124 could achieve synergistic effects on preventing inflammation and bone damage caused by AA. Ketoprofen and miR-124 co-loaded PLGA microspheres could be a promising combined therapeutic strategy against RA.

Comparative study of anti-VEGF Ranibizumab and Interleukin-6 receptor antagonist Tocilizumab in Adjuvant-induced Arthritis

Although the precise etiology of Rheumatoid arthritis (RA) remains obscure, heightened immune response is thought to play a vital role in provoking joint inflammation and bone erosion. This study aims at comparatively evaluating the effects of two monoclonal antibodies Ranibizumab (RANI) as anti-VEGF antibody and Tocilizumab (TCZ) as interleukin-6 receptor (IL-6R) antagonist, against adjuvant induced arthritis in rats. CFA-induced arthritic rats were treated for three consecutive weeks with Methotrexate (MTX), TCZ and RANI monotherapy. Clinical assessment of RA, bone erosion, inflammatory, angiogenic and apoptotic markers were determined to assess the anti-arthritic effect. Liver enzymes and histopathological examination of liver and spleen were assessed to evaluate the toxicity profile of the tested therapeutic agents. MTX, TCZ and RANI monotherapy significantly enhanced the anti-arthritic parameters in comparison with the Complete Freund's Adjuvant (CFA)-induced arthritic rats through significant reduction of ankle and paw swelling. Also, they significantly reduced inflammatory, angiogenic and apoptotic markers. Importantly, Ranibizumab showed better effect than the standard anti-rheumatic drugs Methotrexate (MTX) or Tocilizumab (TCZ) in bone protection and cartilage health; hence proves to be a promising new therapeutic agent for RA.