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Pharmacology & Pharmacy
Rheumatoid arthritis refers to joint diseases of unclear etiology whose final stages can lead to unbearable pain and complete immobility of the affected joints. Modern treatment with anti-inflammatory drugs, including janus kinase (JAK) inhibitors, monoclonal antibodies, and botanicals (polyphenols, glycosides, alkaloids, etc.) has achieved some success and hope for improving the course of the disease.
- :rheumatoid arthritis
- joints
- inflammation
1. Introduction
Rheumatoid arthritis (RA) is a difficult to treat disease. This disease is characterized by synovial inflammation (synovitis), which affects bone turnover and the ability of bone to adapt to bone tissue when replacing the cartilaginous matrix with mineralized bone [9]; it also leads to degeneration of bone tissue [10]. Patients with this disease experience pain in their joints, accompanied by stiffness, which limits their mobility. In addition, over time, this disease can destroy both cartilage and bone; limited mobility becomes active disability and may lead to deformed joints. Along with deformity, extra-articular manifestations such as vasculitis and scleritis can also be observed [11,12].
Among common risk factors, cigarette smoking has the strongest association with RA [13,14,15,16]. Tobacco smoking, does not cause rheumatoid arthritis but leads to a worsening of the disease by means of citrullination of tissue proteins [17,18]. Interestingly, Jiang et al. reported that the impact of cigarette uses on the development of RA increased only when smoke was inhaled from cigarettes, but not when tobacco products containing nicotine were chewed, which suggests that nicotine is not significantly involved in the pathogenesis of RA [16,17].
As mentioned above, RA is the most common autoimmune inflammatory arthritis, with incidence of 0.5–1.0% in the northern hemisphere population [19,20]; annually, it occurs in 24–45 people per 100,000 [21]. The disability that attends rheumatoid arthritis is serious and debilitating. An extensive review showed that within 2–3 years of onset, approximately one-third of sick people with rheumatoid arthritis stopped working because of the disease; by 10–15 years after onset, almost two-thirds (50–60%) may be unable to work [22,23]. In addition to deterioration of patients’ health, this leads to adverse effects in the global economy [24,25].
There is no single cause of rheumatoid arthritis, and its prognosis remains uncertain [31]. But microbiological infections, genetic and environmental factors play a special role in the development of RA. Meta-estimates of the regional prevalence of rheumatoid arthritis in low- or middle-income countries were 0.4% (Southeast Asia), 0.37% (Eastern Mediterranean), 0.62% (Europe), 1.25% (North, Central, and South America), and 0.42% (Western Pacific). A formal meta-analysis cannot be performed for sub-Saharan Africa due to limited data. No significant difference in the prevalence of RA was found between urban and rural areas. While the prevalence of the disease in low- and middle-income men was 0.16%, it climbed to 0.75% in women, a statistically significant difference [32]. Hormones and genetic (X-linked) factors may explain the more frequent occurrence of rheumatoid arthritis among women [33]. For example, estrogens, which control the body’s immune response, can lead to autoimmune diseases [34]. To explain gender bias, scientists have shown that women with RA exhibit non-random X chromosome inactivation (XCI), which can cause autoimmunity. It is believed that this error correlates with the presence of a shared epitope and the duration of the disease. Premature immuno aging, characterized by shorter telomere length, is also associated with the presence of SE [35].
2. A Mystery That Still Needs to Be Deciphered
Although assimilation of knowledge in the study of pathogenesis of RA is still incomplete, this disease is widely accepted as an immune-mediated disorder. That immune cells play an important role in the pathogenesis of RA has been shown by studies in which treatment with anticytokine agents, for example a neutralizing Abs against TNF-α, soluble TNF receptor fusion proteins, or rIL-1β receptor antagonists resulted in the successful suppression of joint inflammation [40]. Agents that target cytokine-driven immune processes are among the most important clinical treatments used to manage disease in RA patients [41]. Disease-modifying antirheumatic drugs (DMARDs), which are divided into synthetic (sDMARDs) and biological (bDMARDs), are widely used [42].
There are three pronounced determinants that can describe the clinical picture of RA: the inflammatory process (swelling, pain, stiffness during movement); the proliferative-destructive process (destruction of joints); and the enzymatic collagenolytic process (primary necrotism) [51]. The intensity of pain is directly related to the activity of the disease as a whole [52]. The pathogenesis of RA has different etiologies of origin. Since the early 1980s, it has been assumed that the spread has a genetic link [53], including exposure to various chemicals on the respiratory tract [54]. There are a variety of ways to counteract RA, and one of the first measures is dietary nutrition, since there are already a number of scientific justifications that show an advantage in combating the disease and lead to a reduction in symptoms [55].
The pathogenesis of the studied disease involves a complex interconnection between B cells, CD4+ and CD8+ T cells, and dendritic cells [56]. Because B cells undergo isotype switching, they are more capable of supporting the inflammatory cascade. In addition, the rheumatoid factor (RF), a group of autoantibodies with the ability to respond to Fc of human IgG, behaves like heterophilic antibodies and cross-reacts with other types of antibodies [57,58]. The participation of the RF in the formation of the immune complex can lead to further fixation of the complement and the involvement of cells that cause inflammation such as macrophages, neutrophils, and lymphocytes. This leads to tissue damage and provides positive feedback for the production of even more autoantibodies. At the moment, a long list of causes for rheumatoid arthritis has been identified, including epigenetic, genetic, hormonal, reproductive, neuroendocrine and comorbid host factors [59].
It appears that macrophage-derived cytokines, for example, tumor necrosis factor alpha (TNF-α) and IL-1β, are critical to the mediation of inflammatory synovitis; however, it has also been suggested that synovial T cells participate both in triggering the disease and in contributing to the development of the disease in RA. Significant infiltration of the synovial tissue by T lymphocytes has been observed frequently in RA [60]. However, little is known about the direct action of T cells in the development of pathogenesis. While the synovial T cells observed in RA are mainly classified by type of memory type: CD4+ CD45 RO [61] with a pro-inflammatory Th1 phenotype. Compared to TNF-α and IL-1β, the classical Th1 T-cell-derived cytokine IFN-γ is also rarely seen in rheumatoid joints [62].
Scientists believe that T cells-produced cytokine IL-17 participates in the RA development. IL-17 is frequently produced by T cells clones taken from patients with RA, and it was shown that IL-17 is found in abundance in the synovial fluids of RA patients [63]. Therefore, it comes as no surprise that T cells specifically predisposed to antigen have been shown to be efficacious in the medication of rheumatoid arthritis. Generally, these data suggest that T cells are quite significant albeit their still incompletely understood role in the pathogenesis of RA.
3. Achieving Movement without Pain
In addition to adalimumab, drugs such as methotrexate [75], etanercept [76,77], prednisone [78], and leflunomide [79] quite often used in the treatment of RA. These drugs have been in use longer, and for a variety of conditions. Their side effects are also serious and must be considered.
According to EULAR (European alliance of associations for rheumatology) recommendations the biologic and targeting synthetic drugs should be used only after treatment with methotrexate [80]. Methotrexate is the first-choice treatment among most patients [81]. Treatment with methotrexate reduces inflammation but also degrades cartilage. It is unknown whether these clinical responses to methotrexate are evidence of a specific mechanism of action or merely a common final pathway. While it is possible that changes in the production of PGE2 and levels of TIMP 1 may represent the downstream effects of methotrexate on the formation of IL-1 and IL-6, respectively, no conclusive evidence exists to support this. Some of these changes are also observed following treatment with nonsteroidal anti-inflammatory drugs, and the methotrexate-specific pathways have yet to be elucidated [82]. In addition, the number of side effects—some severe—associated with methotrexate are many: nausea, headaches, fatigue, mucositis and hair loss, cytopenia, interstitial lung disease (ILD pneumonitis), and drug-related liver diseases (fibrosis and cirrhosis of the liver) [83]. Unfortunately, the exact mechanisms of methotrexate toxicity remain unclear [84].
Prednisone is another drug used to treat RA. It is a corticosteroid with anti-inflammatory properties and immunosuppressive activity [91,97]. The mechanism of action is the binding of prednisone to the glucocorticoid receptor; it promotes conformational changes in the DNA-binding domain, which leads to a displacement of the receptor into the nucleus. In the latter, various genes are activated, including anti-inflammatory genes [91]. Among these are the genes encoding annexin-1 (formerly known as lipocortin 1), IαB (NFαB inhibitor), IL-10, and the anti-inflammatory protein MAPK-phosphatase-1. This process, called transactivation, is responsible in part for the anti-inflammatory action of glucocorticoids.
The undesirable effects of corticosteroids are doses and time dependent and vary depending on the drug administered [99]. Some adverse effects follow a linear dose-response pattern, where the incidence increases together with dose increases (ecchymosis, cushingoid features, parchment-like skin and sleep disturbance).
Patients with RA are often prescribed anti-rheumatic drug leflunomide whose primary aim is to reduce swelling and inflammation in the affected joints [97]. The active metabolite of leflunomide (teriflunomidum, or A77 1726) in reversible manner inhibits dehydroorotate dehydrogenase, a step limiting the rate of de novo pyrimidine synthesis [93]. This results in a reduction in the level of circulating pyrimidines and affects their availability for DNA and RNA synthesis, which in turn has an effect on the spreading of immune cells as well as the expression of inflammatory cytokines.
4. Botanicals as a Beacon of Hope on the Horizon
Herbal preparations used in humans demonstrate their effectiveness in the treatment of rheumatoid arthritis. One of the main positive effects is anti-inflammatory and antioxidant activity [108,109,110]. For example, such an herb as Boswellia spp., which has been used in Ayurvedic medicine since ancient times. Activity of boswellic acid and other active natural compounds of Boswellia spp. includes inhibition of microsomal prostaglandin E2 synthase-1 (PGE2) and 5-lipoxygenase, reducing the production or activation of inflammatory mediators such as matrix metalloproteinase (MMP)-9, MMP-13, cyclooxygenase (COX)-2, and nitric oxide (NO) and also has analgesic and anti-arthritic effects [104,105]. It has been found to reduce the number of osteophytes by attenuating inflammatory mediators such as C-reactive protein and hyaluronic acid [111,112,113]. Research by scientists has demonstrated the safety of using Boswellia serrata R. [112]. However, knee-related activities of daily living and quality of life did not improve significantly [114].
Polyphenols constitute an alternative direction of using natural compounds against rheumatoid arthritis. Application of an extract from Curcuma spp. containing polyphenol curcumin also showed its anti-inflammatory and antioxidant actions [115,116]. Curcumin inhibits the production of inflammatory mediators, such as a variety of MMPs, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, IL-1, NO, via diminishing the activation of MAPK signaling pathways protein kinase B (Akt) and NF-κB [117,118] and leads to a decrease in prostaglandin synthesis [119]. Studies have shown that when compared with the treatment of ibuprofen, turmeric showed more effective results [120], and compared with diclofenac, a small number of side effects [121]. The dried plant Matricaria chamomilla L. has been used for many centuries in the treatment of joint pain [122,123]. The plant contains several phenolic compounds: apigenin, patuletin, luteolin, and glycosides [124] that reduce inflammation by reducing the levels of cytokines and PGE2, which play a role in the pathogenesis of arthritis. Epigallocatechin-3-gallate (EGCG), a catechin monomer that has antioxidant and anti-inflammatory effects, is isolated from tea leaves [125]. Green tea extract can inhibit the expression of IL-1β-induced chemokines This was studied in an experiment with rats having arthritis [126,127].
Date seeds of Phoenix dactylifera L. are a well-known traditional Moroccan remedy for pathological conditions involving inflammation such as RA [128]. The wild pomegranate Punica granatum L. has been used as a traditional medicine for various conditions, including pain and inflammation [129]. Pomegranate demonstrated potential inhibition of NO as well as reduction in paw edema in carrageenan-induced mice after administration of 100 mg/kg [130]. Pomegranate juice is one of the natural products that has also shown promising results in clinical trials for the treatment of RA symptoms, which may also be due to polyphenolic compounds with antioxidant and anti-inflammatory effects [131].
Glycosides from different plants show anti-inflammatory effect during rheumatoid arthritis. The root of Paeonia lactiflora P. has been used in Chinese medicine since ancient times. Inhibition of the production of leukotriene B4, PGE2, ROS, NO, and other pro-inflammatory mediators by paeoniflorin and total glucosides of paeony has been proven [132]. Combined treatment using this plant and methotrexate has shown beneficial effects in RA with fewer side effects [133]. Decoctions from Eremostachys laciniata (L.) are also used for arthritis [134,135,136]. It is assumed that the iridoid glycosides of this plant exhibited an anti-inflammatory effect. Curculigoorchioides G. contains curculiglycoside, which improves arthritis symptoms in rats [128] induced by collagen type II (CIA) and reduces levels of inflammatory factors (TNF-α, IL-1β, IL-6, IL-10, IL-12 and IL-17A). Its antiarthritic molecular mechanism may be related to the JAK/STAT/NF-Κb signaling pathway [137]. Extracts from the root of Tripterygium wilfordii Hook F. also has an immunosuppressive effect and inhibits the expression of pro-inflammatory mediators and cytokines, adhesion molecules and matrix metalloproteinases by macrophages [138,139,140].
Alkaloids of some plants show promising results against rheumatoid arthritis too. Synomenine, which is contained in the Chinese medicinal stem Sinomenium acutum Thunb., is used in the treatment of rheumatic diseases [144,145]. Synomenine can phosphorylate p62 Ser351, degrade Keap1 and increase Nrf2 expression, and play a role in protecting against bone destruction by increasing p62 expression and activating the p62-Keap1-Nrf2 axis. Research shows that sinomenine has an immunoregulatory effect on RA [146,147,148].
In recent years, scientists have agreed that a mixed herbal decoction can actively manifest itself in the fight against RA. For example, wutou decoction which consists of ephedra, peony, astragalus, licorice and Sichuan aconite [154]. In a study, wutou decoction was shown to effectively inhibit the expression of iNOS, TNF-α, and IL-6. Another example would be GuiZhiShaoYaoZhiMu Decoction (GSZD), which consists of Ramuluscinnamomi, P. lactiflora root, Radix GlycyrrhizaePreparata, Ephedra sp., Anemarrhenaasphodeloides Bunge root, Atractylodesmacrocephala and Zingiber officinale [155,156]. Combination treatment with GSZD and methotrexate was more effective and safer than RA treatment with methotrexate alone [157].
5. But How Many Joints Will We Save Tomorrow?
Today, different approaches exist that help reach successful regeneration, ranging from a gene-manipulated stem cell laden scaffold for cartilage regeneration [166] to a material-free cell therapy [167]. A promising strategy in medicine is the use of antisense techniques. Antisense technology has been widely and thoroughly explored. The perspective of antisense technology is that specific DNA or RNA can connect to target mRNA and afterward turn the ‘undesired’ gene off. According to complementarity principle, designed DNA or RNA molecules target mRNA of interest, effectively resulting in the degradation of the target mRNA or blocking initiation of translation [168,169].
Oberemok’s research group conceptualized and conducted research with the phosphorothioate antisense oligonucleotide (ASO) Cytos-11 that targets TNF-α mRNA. Cytos-11 selectively lowered levels of TNF-α in the peripheral blood and reduced swelling of joints in rats with RA with an efficacy similar to that of adalimumab. Generally, Cytos-11 was well tolerated by the rats, showing a low frequency of immunological reactions. Obtained results showed the potential of ASO to be used in combination with other drugs or as a monotherapy [170].
In an attempt to develop oligonucleotide therapy aimed at synovitis (an inflammatory disease of the synovial membrane of joints or ligaments with the accumulation of inflammatory effusion in the cavity), modulation of the phenotype of activated proliferative inflammatory synovial fibroblasts using antisense oligonucleotides was documented. For example, antisense oligonucleotides developed by Nakazawa et al. targeting the Notch-1 protein have been reported to inhibit both basal and TNF-α-caused proliferation of human synovial fibroblasts isolated from the synovial membrane of a patient with RA [171,172]. It has also been reported that antisense knockdown of the PTPN11 gene that encodes SHP-2 (a known proto-oncogene) inhibits the migration and survival of synovial fibroblasts [171,173].
In the future, better treatment for rheumatic diseases is indeed possible through the use of new methods of genetic engineering or cell therapy, such as autologous stem cell transplantation [179,180] and CAR-T-cell therapy [179,181]. Although these therapies are currently still risky and costly, the need for effective methods of therapy for autoimmune diseases is urgent, which is why other avenues should be explored as well. In the future, a new goal may be to find a cure, not just remission, for the disease [179].
Funds have already begun to appear for predicting the outcome of therapy and treatment of the disease [186]. With the help of artificial intelligence, it is possible to investigate changes in arthritis using X-rays [187] and can be used in silico trials to develop new treatments [188]. These new technologies using computerization will help to make more accurate predictions for patients for the future. The P4 (predictive, preventive, personalized and participatory) medicine approach has also appeared for early diagnosis of the disease and prevention [189].
Another innovative method is the use of gene therapy technology. An innovative method of treating rheumatoid arthritis using histone modification is a reliable alternative to traditional approaches. Histones are proteins that pack DNA inside a cell and regulate gene activity. Histone modification consists of changing the chemical structure of these proteins, which allows you to control the activity of certain genes. Found that in PDGF-induced FLS, the expression of Jumonji C family of histone demethylases (JMJD3) was increased through the Akt signaling pathway, and the proliferation and migration ability of FLS was weakened after inhibition or silence of JMJD3, and the symptoms of DBA/1 mice by collagen-induced arthritis were alleviated [191].
In recent years, a method of treating rheumatoid arthritis based on the use of phosphates has been developed. Studies have shown that phosphates can have an anti-inflammatory effect by reducing the production of inflammatory cytokines. They are also able to improve the function of the immune system. Dexamethasone sodium phosphate (DSP) is another anti-inflammatory and immunosuppressive glucocorticoid known to be used frequently in treating RA by decreasing cytokines expression and impeding functions of leukocyte, fibroblast and endothelial cells. Delivered using the beta-cyclodextrin nanocarriers (DSP-loaded H-βCD nanoparticles) was effective for RA in the AIA rat model. Thus, the use of nanocarriers has overcome the limited applications of DSP alone in chronic diseases and has been reported to be able to reduce arthritic score, paw thickness, and cytokine level [193].
6. Conclusions
Rheumatoid arthritis does not kill quickly but today it looks like a sentence to a hard-to-treat disease. This, coupled with the many different factors that can trigger RA, may explain why this disease is not treated successfully, with continued high incidence. Now the range of drugs is extensive, and nevertheless has its negative sides. Namely, side effects such as nausea, headaches, fatigue, allergic reactions, and hair loss.
A beacon of hope on the horizon is the use botanicals (polyphenols, glycosides, alkaloids, etc.) and antisense technologies, which have already proven themselves in a number of studies on the treatment of rheumatoid arthritis [194], as well as on the relief of pain in the treatment of diseases such as neurological dysfunction.
Two other useful proactive strategies are vaccination and early diagnosis of the disease, both of which can help prevent and forestall the development of any disease that has already begun. As far as treatment of ongoing disease, the ideal drug has not yet been found, and all of those in use have their side effects. But the prospects for the treatment of rheumatoid arthritis, despite its tortuous solutions, are bright, with promising areas of research fueled by people determined to help these patients. Though today’s battle is lost to rheumatoid arthritis, humanity prepares its joints for the win in the war for movement without pain.
This entry is adapted from the peer-reviewed paper 10.3390/medicina59101853
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