Kamla Nehru College of Pharmacy, Butibori, Nagpur, Maharashtra - 441108
Rheumatoid Arthritis (RA) could be a incessant immune system infection of obscure aetiology that influences 0.5% of the populace and can result in incapacity owing to joint devastation, characterized by joint synovial aggravation and dynamic cartilage and bone annihilation resulting in immobility. The most prominent drawback within the accessible strong manufactured drugs lies in their noxious quality. Alternatives to conventional drug treatments include lifestyle medicine, functional medicine, traditional and natural medicine, nutritional therapy, mind-body medicine, physical therapies, herbal medicine. With confinements of existing drug molecules herbal drugs are picking up intrigued among RA patients. Therapeutic plants are the plants containing characteristic dynamic fixings utilized to remedy malady or diminish indications of joint pain. The point of this survey is to upgrade data on RA including causes, the study of disease transmission, predominance, indications and diagnosis, medications, toxicities of allopathic anti-rheumatic drugs and significance of herbal drugs for the administration of RA. The show audit too centers on the restorative plants that connected with the mediators of inflammation and are utilized within the treatment of rheumatoid arthritis (RA). Future examinations ought to center on moving forward the definitions, conducting careful clinical trials, and investigating diverse strategies to completely utilize the inborn potential of normally inferred chemicals in treating RA.
One of the oldest recognized diseases, arthritis causes inflammation in the joints and affects almost everyone. In India, almost twenty percent of the population has arthritis. Rheumatoid arthritis (RA) is an unexplained, chronic inflammatory illness that eventually renders a person immobile due to a progressive loss of bone and cartilage as well as synovial inflammation in the joints (1). The genetics of RA can be influenced by functional aspects of disease-associated SNPs. A significant association between CCR6DNP genotype, CCR6 expression, and serum IL-17 levels in RA patients. This polymorphism is also linked to Graves' disease and Crohn's disease, suggesting its role in Th17-driven autoimmunity (Genetics). RA patients often have rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), and anti-carbmylated protein (anti-CarP) autoantibodies, which can form immune complexes in joints, attracting immune cells and secreting chemokines and cytokines, which can contribute to chronic inflammation and bone destruction (auto).
Although it may have originated in Europe after the 17th century, it was initially discovered in the early Native American population thousands of years ago (2). Tumor necrosis factor-? (TNF-?), interleukin (IL)-1?, and IL-6 are pro-inflammatory cytokines that play a key role in the persistence of the disease (3). The small joints of the hands and feet are typically where arthritis starts, then it spreads to the larger joints. The inflammation of the synovial membrane stretches and erodes the articular cartilage and bone, resulting in joint deformity and increasing physical handicap. Nodules, pericarditis, pulmonary fibrosis, peripheral neuropathy, and amyloidosis are examples of extra-articular characteristics (4).
Fig 1: Comparison of normal joint and joint affected by rheumatoid arthritis
Prevalence of RA
Strong ties exist between hereditary tissue type and RA. Family history is a significant risk factor because of the major histocompatibility complex (MHC) antigen HLA-DR4 (more especially, DR0401 and 0404). Men tend to have a slightly later risk of having the condition than women, with women between the ages of 40 and 50 appearing to have the highest risk (5). Reasons they pointed to in explaining these differences and why women were experiencing a higher disease burden were that women had lower muscular strength and lowered pain sensitivity. Sex hormones, including lowered androgen levels (hormones responsible for male traits and reproductive activity), were also contributors(women). Up until roughly age 70, the incidence and prevalence of RA often increase with advancing age (6,7). After that, they tend to decrease. There are about twice as many affected women as men. In undeveloped nations, RA is typically less common; several surveys conducted in Africa have identified either few or no instances of the disease (8).
One percent of the global population has rheumatoid arthritis, and women are affected three times more often than men (9). Arthritis is a prevalent chronic illness that significantly increases the risk of disability. Adult Americans with arthritis accounted for 43 million of the population in 2002; by 2020, that number is expected to reach 60 million (10). It is three times more common in smokers than in non-smokers, and more common in men, heavy smokers, and those with positive rheumatoid factor. In contrast to those who never drank, individuals who frequently drank modest amounts of alcohol had a four-fold lower chance of getting rheumatoid arthritis (2010 research) (11).
Citrullination, the post-translational modification of amino acid arginine into citrulline, has been linked to rheumatoid arthritis (RA) and anticitrullinated protein/peptide antibodies (ACPAs), currently measured as anticyclic citrullinated peptide (anti-CCP) auto-antibodies. The strongest genetic association of RA is with the HLA-DRB1 locus, encoding the beta chain of class II MHC molecules. HLA-DRB1 alleles that predispose to RA contain a conserved sequence within the peptide-binding groove (the shared epitope), consistent with presentation of particular auto antigenic peptides. A recent study (12) showed that shared epitope-containing HLA-DRB1 1001 can bind certain citrullinated peptides derived from putative auto-antigens, by accommodating citrulline but not arginine in several anchoring pockets. Citrullination may upgrade the immunogenicity of RA auto-antigenic peptides by expanding their partiality for shared epitope-containing course II molecules. In a case-control analysis (13), the combination of shared epitope, PTPN22, and smoking gave an chances proportion of 37 for anti-CEP-1 positive RA compared with an chances proportion of 2 for anti-CEP-1 negative RA. Immunoprecipitation of synovial fluid from anti-CCP positive RA patients identified immune complexes containing citrullinated fibrinogen? and citrullinated vimentin, with presumed pro-inflammatory potential (14). Anti-CCP antibodies, eluted from ELISA plates, recognise citrullinated antigens and therefore comprise ACPA. These may crossreact on more than one citrullinated antigen, potentially complicating attempts to link particular auto-antigens to RA pathogenesis. A few patients, be that as it may, clearly have more than one particular ACPA specificity in their serum, involving a few plasma cell clones and, conceivably, a developing B cell reaction (15).
In rheumatoid arthritis (RA), naive and memory B cells infiltrate and accumulate in synovial tissue, with continuous activation of selected B cell clones (16). Flow cytometry analysis shows that peripheral B cells from RA patients have altered expression of key molecules, such as high CD86 and low FcgRIIb levels. This may be dysregulated by inflammation, potentially contributing to tolerance breakdown and the development of humoral auto-immunity (17). FOXO3a, a transcription factor involved in cell cycle regulation and survival, was increased in RA patient blood, primarily in polymorphonuclear cells, and replicated in T cells in inflammatory aggregates in RA synovial tissue. Overexpression of FOXO3a may lead to prolonged survival of these cell types in RA, contributing to chronic inflammation (18). High levels of sH4 (soluble B7–H4) in RA patient sera have been identified, suggesting that sH4 exacerbates arthritis by competing with the cell-surface molecule. ZAP-70, an important molecule in the T cell receptor (TCR) signaling pathway, is involved in the recruitment of downstream effector molecules (19). Mutations in ZAP-70 resulted in reduced T cell development and impaired response to TCR stimulation, disrupting thymic selection and reducing regulatory T cells. The disconnection between autoreactivity and auto-immunity was postulated to be a consequence of distinct TCR repertoires in the two mouse strains (20). Regulatory T cells (Tregs) maintain immune tolerance by recruiting less protein kinase C theta (PKCu) to the immune synapse than effector Tcells, with less downstream activation of NF-kB. PKCu acts as a negative regulator of Treg function, and TNFa increases its localization to the immune synapse, affecting Treg function in RA. Inhibition of PKCu enhances Treg function and prevents inhibition by TNFa, making it a target in immune dysregulation diseases (21). Monocytes and macrophages are key players in RA pathogenesis, secreting pro-inflammatory cytokines like TNFa, IL-1, and IL-6. In RA, expression of chemokine receptor CCR9, essential for leukocyte migration and retention, was increased in peripheral monocytes and synovia macrophages. CCL25 exposure in vitro induced stronger monocyte-to-macrophage differentiation in RA monocytes (22). Osteopontin levels in RA synovial fluid significantly correlate with IL-17 production and Th17 cell frequency, and in vitro, osteopontin influences Th17 T cell differentiation (23). Th17 T cells and their cytokine product, IL-17, are increasingly implicated in RA inflammation and joint destruction. High levels of IL-17 are detected in joints of RA patients, and a recent paper (24) assessed the cytokine profile and frequency of IL-17-producing CD4þ T cells in RA synovial fluid. Synovial fluid mononuclear cells had reduced IL-22 levels and did not express IL-23R, which is important for Th17 expansion and survival. There was a modest enrichment of IL-17-producing CD4þ cells in synovial fluid, but the overall proportion was low, suggesting there may be an alternative source of intra-articular IL-17 (25). Plasticity of IL-17-producing T cells has been suggested, with most synovial fluid IL-17-secreting cells having a phenotype between Th17 and Th1. In vitro, a pro-inflammatory milieu containing low TGFb and high IL-12 promoted differentiation of Th17 cells into Th17/Th1 cells, suggesting the Th17 phenotype may be unstable and potentially convert to both Th1 and Th17/Th1 cells in response to inflammation (26).
IL-17 is not the only pro-inflammatory cytokine produced from unconventional sources. Platelet microparticles (MP) have been found in inflammatory arthritis synovial fluid, adhering to leukocyte surfaces. In the K/BxN serum transfer model, platelet depletion significantly inhibited arthritis development. Experiments suggest glycoprotein VI, a collagen receptor expressed by platelets, triggers microparticle generation from fibroblast-like synoviocytes (FLSs) and extracellular matrix, releasing pro-inflammatory IL-6 and IL-8 (27) fig 2.
Fig 2: Schematic of recent evidence suggesting a role for platelet microparticles in driving an inflammatory response.
Rheumatoid arthritis synovial fibroblasts
Synovial fibroblasts play a crucial role in regulating tissue homeostasis, modulating the inflammatory response, and mediating tissue damage in RA synovial tissue (28). Transcription factors like activator protein 1 and nuclear factor-kappa B (NF-?B) play a significant role in the activation, differentiation, and proliferation of RA synovial fibroblasts (29,30). These transcription factors regulate the expression and activation of matrix-degrading enzymes, which are key enzymes in joint destruction (31). Derl3, an endoplasmic reticulum stress-related protein, was found to be upregulated in a rat model of pristane-induced arthritis and synovial tissue of patients with RA, and intra-articular injection of si-Derl3 alleviated the disease (32). Serum amyloid A protein induces IL-6 and chemokine ligand 20 production in synovial fibroblasts from patients with RA through mitogen-activated protein kinases and NF-?B activation, contributing to chronic inflammation (33,34). Recent transcriptome studies have identified subsets of fibroblasts characteristic of RA, such as podoplanin, THY1 membrane glycoprotein, and cadherin-11, which express podoplanin, THY1 membrane glycoprotein, and cadherin-11 but lack CD34 (35). These pathogenic fibroblasts localize around blood vessels in the inflamed synovium, secrete pro-inflammatory cytokines, are proliferative, and have a phenotype characteristic of invasive cells in vitro. Hereditary investigation of synovial tissue collected by ultrasound-guided biopsy in patients with RA at the translational level appeared that the rate of patients requiring natural treatment was essentially higher when synovial tissue had solid immunoinflammatory quality expression (36).
Fig 3: Schematic highlighting the potential role of mammalian target of rapamycin in the invasive properties of fibroblasts and osteoclasts and the possibility of utilising mammalian target of rapamycin inhibitors to antagonise these processes.
B cells play a crucial role in RA pathogenesis, producing antibodies such as RF and anticyclic citrullinated peptide antibody (ACPA). Patients with RA who are persistently positive for these antibodies are more likely to experience progressive bone and joint erosions, extra-articular symptoms, and worsening of function compared to those with seronegative RA (37,38). B cells are relatively specific for RA (39,40), and their production is initiated early in the disease process. B cell exhaustion is more viable in patients who are positive for RF and/or ACPA than those who are negative for these antibodies (41,42).
Citrullinated proteins are also important in RA pathogenesis, as citrullination of arginine residues is catalyzed by peptidylarginine deiminases on ?-enolase, vimentin, fibrin, fibrinogen, and other proteins (43–45). Studies have shown that synthetic peptides containing citrullinated epitopes may have added value for RA diagnosis. B cell precursors for ACPAs are present in patients with RA and can be stimulated to produce these antibodies (46). B cells not only produce pathogenic autoantibodies but also significantly contribute to the regulation of the inflammatory response by serving as antigen-presenting cells and releasing pro- or anti-inflammatory cytokines that control T cell extension and separation and macrophage actuation (47). B cells have an antibody-independent role in RA pathogenesis and systemic auto immunity (48).
T cells play a crucial role in immune responses to rheumatoid arthritis (RA), with a majority of these being memory CD4 T cells. Th1 and Th17 T cell subsets are predominant, while Th2 and regulatory T cells are absent. A significant population of programmed cell death-1 (PD-1)hi CXCR5- CD4+ T cells has been reported in RA synovium, promoting B cell responses and antibody production (49). The effector function of T cells is mediated by cytokines, with Th1 cells secreting interferon gamma, while Th17 cells produce IL-17A, IL-17F, IL-21, and IL-22 (50). Biological therapies targeting IL-17 for RA treatment have shown modest clinical efficacy. However, several IL-17A blockers are widely available for treating psoriasis, psoriatic arthritis, and ankylosing spondylitis (51). Costimulation is an important aspect of T cell activation during the RA immune response, with CD28 and CD40 ligands providing signals. Cytotoxic T lymphocyte-associated protein 4 has been used in the treatment of RA patients, and PD-1 is a costimulatory receptor important in maintaining immune tolerance and conferring peripheral tolerance to prevent autoimmunity. SAP, a signaling lymphocyte activation molecule family receptor, has been found to have elevated levels in lymphocytes from patients with RA, positively correlated with RA disease activity (52).
Periodontits: Porphyromonas gingivalis, a bacterium found in the oral cavity, is often linked to periodontitis and has been found to be involved in the pathogenesis of rheumatoid arthritis (RA) (53). Its unique ability to citrullinate proteins using endogenously produced PAD enzymes, which modify a carboxy terminal arginine, could result in auto-immunity via molecular mimicry. P. gingivalis also causes bacteraemia and directly affects chondrocytes by increasing apoptosis and disrupting normal cell cycle progression (54). However, a recent study (55) found no correlation between late-onset RA and periodontal surgery or tooth loss. An early arthritis registry found that variations in urine and gut Escherichia coli colonisation were linked with both rheumatoid factor positivity and clinical phenotype (56), suggesting other bacterial flora may also be relevant.
Smoking: the gene–environment interaction that links smoking, the shared epitope alleles are linked to gene-environment interactions, with the combination of these alleles potentially contributing to auto-antibody negative diseases. Nicotine can modulate inflammation, but smokeless tobacco does not increase chronic inflammatory disease risk. Non-nicotinic components of cigarette smoke may play a role in disease aetiology (57). Cigarette smoke condensate (CSC) can upregulate pro-inflammatory cytokine production from human FLSs and contribute to collagen-induced arthritis, highlighting the potential role of non-nicotinic components in disease aetiology.
Alcohol: RA cases with a stored blood sample collected at least 3 months prior to the date of first symptom onset were analysed with regards to alcohol consumption over this period. There was an association between higher alcohol intake and increased markers of inflammation including IL-6 and sTNFRII during the preclinical period. However, other studies suggest that, in established RA, there is an inverse association between alcohol intake and disease development and severity, and also that radiographic joint damage is slowed in consumers of alcohol (58).
A large population study in Japan found a significant association between the CCR6DNP genotype, CCR6 expression, and serum IL-17 levels in RA patients. This study (59) also found associations between the CCR6 polymorphism, Graves' disease, and Crohn's disease, suggesting that CCR6 is involved in Th17-driven autoimmunity. The same CCR6 polymorphism has been implicated with RA in Caucasian populations. A functional polymorphism in the RANKL promoter, combined with the shared epitope, appears to promote crosstalk between activated T cells and dendritic cells, predisposing to a younger age of RA onset (60).
The current pathophysiology frameworks for RA cannot be rigorously analyzed. TNF-? or IL-6 can provide a good memorandum for therapists, but they cannot explain widely accepted data. For example, the effectiveness matrix of targeted therapies is similar, but secondary resistance is not reflected. Cytokines like TNF and IL-6 do not reflect disease severity or indications for biologics. TNF-? transgenic mice have extensive joint destruction but do not produce anti-citrullinated protein antibodies or rheumatoid factor. The modest effect of blocking cytokines, formulation problems, and incomplete pharmacological chemistry design are also unclear. Traditional players are essential but not the ultimate cause of RA. They sometimes have ambiguous roles, such as stimulating regulatory T cells and contributing to tissue inflammation. Polymorphonuclear neutrophils (PMNs) are traditionally considered proinflammatory cells in rheumatoid arthritis (RA). They are activated and recruited to inflamed joints, secrete cytokines associated with RA, and recruit proinflammatory TH17 cells. In vivo depletion of PMNs inhibits arthritis development in murine models. However, recent discoveries have revealed new functions for PMNs, such as secreting interferon-? and having non-traditional functions like RANKL expression, suggesting a role in osteoclastogenesis. PMNs and Tregs interact, contributing to Treg activity (61). Activated PMNs produce neutrophil extracellular traps (NETs), DNA filaments bound to granular proteins and released into the extracellular space. NETs may be involved in inflammatory and/or autoimmune responses. NETs are pro-inflammatory and activate PMNs and macrophages, with NET activity being highest in RA patients. Extracellular chromatin has been found in the synovial fluid of RA patients, possibly coming from NETs. chromatin acts as a danger-associated molecular pattern (DAMP), stimulating dendritic cells and neutrophils and triggering the formation of NET and release of soluble CEACAM8, potentially contributing to an amplification loop (62). PMNs are a heterogenic cell population with auxiliary, regulatory, immunosuppressive, and anti-inflammatory activities. These data suggest that PMNs are also involved in the disease's chronicity, not just its acute phases.
Regulatory T cells, particularly Tregs expressing FoxP3, play a crucial role in preventing pathological autoreactivity and are involved in autoimmune diseases like RA. Studies comparing Treg proportions in RA patients or experimental models are difficult to draw conclusions due to varying phenotypical definitions, treatments, and controls. Meta-analysis studies suggest a lower amount of Tregs in the peripheral blood of RA patients, combined with higher amounts in the synovial fluid (63). Tregs have a certain amount of plasticity and instability, especially in an inflammatory environment. These two characteristics mean that Tregs lose their ability to provide the suppression needed to control chronic inflammation due to autoimmunity. However, little is known about Treg plasticity and stability in the context of RA. The method of Treg change into Th17 cells plays a vital part in immune system aggravation (64). Recent advances in epigenetics and access to new technologies, such as high-throughput sequencing and single-cell analysis, may help characterize the various Treg phenotypes relative to different parameters, such as the treatment type of disease stability, ultimately leading to the development of new theranostics tools for RA.
Areas that may be affected include Skin, Eyes, Lungs, Heart, Kidneys Salivary glands, Nerve tissue, Bone marrow, Blood vessels (65).
RFs are autoantibodies that target the Fc portion of immunoglobulin G. They are found in up to 80% of rheumatoid arthritis (RA) patients but can occur in other inflammatory conditions, infectious diseases, malignancies, and healthy individuals (72). Smoking is associated with an increased prevalence of RF. Approximately 30% to 45% of early RA patients do not have RF, but some may develop it later. RF positivity increases the risk of developing RA, but fluctuation in titers does not correlate with disease activity (73).
Autoantibodies to citrullinated protein epitopes have been a focus of biomarker research in rheumatoid arthritis (RA). Anti-cyclic citrullinated peptide (anti-CCP2) is a widely clinically available assay with excellent diagnostic and prognostic value (13). Both RF and anti-CCP2 have similar sensitivities for RA diagnosis, but anti-CCP2 is more specific. Anti-CCP2 positivity may occur in other rheumatologic diseases and with active pulmonary tuberculosis (74). High titer anti-CCP2 antibodies may confer a higher risk of erosive joint damage (75).
ESR and CRP are two important measures in the diagnosis and management of rheumatoid arthritis (RA). ESR is an indirect measure of acute-phase reactants, such as fibrinogen, which can be affected by various factors. CRP, an acute-phase reactant, is an attractive candidate as a disease activity biomarker due to its overabundance of proinflammatory cytokines in the RA synovium. Be that as it may, CRP estimation in RA isn't secure, because it has been freely related with truncal adiposity in ladies with RA (76). The ACR/EULAR Classification Criteria for RA include elevated ESR and CRP levels, while the 2015 ACR Guideline for the Treatment of RA encourages the use of these measures. Studies have shown a correlation between ESR and CRP elevation and radiographic and functional outcomes in RA patients (77). However, ESR and CRP are normal in about 40% of patients with RA, and discordant values may no longer predict the progression of radiographic joint damage (78). Biologic treatments like tocilizumab may normalize CRP values, killing their utility as a trackable illness movement biomarker.
The MBDA test is a commercial assay that measures 12 serum protein biomarkers to determine RA inflammation. It has been found to correlate with RA disease activity measures in clinical trials and practice. However, post-hoc analysis of data from the AMPLE trial showed disagreement between the MBDA test score and these measures (79). The test may be useful in deciding whether to continue biologic therapy in clinical remission and is a strong independent predictor of radiographic progression at one year (80,81). Further study is needed to determine its cost-effectiveness and role in routine clinical practice.
Disease-modifying antirheumatic drugs (DMARDs) are crucial therapies for reducing damage progression in joint diseases. AMARDs inhibit inflammation, improving damage rate, while NSAIDs relieve pain but do not affect joint damage. Glucocorticoids can reduce symptoms severity but can cause long-term adverse events (82). DMARDs are classified into biological and synthetic groups, with synthetic DMARDs being conventional and targeted. Targeted DMARDs, like tofacitinib and baricitinib, target specific inflammation, inhibiting Janus kinase (JAK) (83).
Recent guidelines suggest starting treatment with conventional DMARDs, such as methotrexate, along with glucocorticoids in a low dose. This approach has been proven effective as an initial treatment, with no significant differences in outcomes between the two regimens. The dose of methotrexate should start low and increase by 30 mg every week, while glucocorticoids can be administered by oral, intravenous, or intramuscular routes. Low doses less than 7.5 mg are usually given in combination with methotrexate to achieve significant improvement in joint status. However, glucocorticoids should not be continued for more than six months, and they should be tapered and stopped. Methotrexate is considered one of the safest and most effective drugs, but its superior effect compared to other DMARDs is not well established.
Biological DMARDs target various mechanisms, including TNF, interleukin 6 receptors, T-cell co-stimulation, and B-cells. Five approved agents for TNF inhibition include infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol. Etanercept constructs TNF-receptors, reducing TB reactivation risk (84). Tocilizumab inhibits interleukin 6 receptors, while abatacept inhibits T-cell costimulation and myeloid cell function. Rituximab acts on CD20 B-cells (85). Proper prophylaxis is necessary for patients with positive TB tests.
Tofacitinib, a targeted DMARD for rheumatoid arthritis, has been approved for its ability to inhibit JAK receptors, reducing signal transduction and cell activation. It is used in combination with methotrexate twice daily, with monotherapy showing better efficacy than methotrexate monotherapy. Baricitinib, a JAK ½ inhibitor, is not yet approved for treatment (86).
Maintaining sufficient treatment for a sufficient period can lead to improved physical functions, quality of life, and work ability. Gradually tapering treatment, such as reducing glucocorticoids and stopping treatment, is recommended over six months. Biological agents have a high risk of exacerbating the disease when stopped, but discontinuing them over a long time reduces this risk. Patients should be re-administered when exacerbation occurs, and it is recommended to gradually reduce the dose of biological DMARDs to avoid exacerbations (87).
Over-the-counter medications for pain relief include acetaminophen (Tylenol), aspirin, naproxen, and ibuprofen. Disease-modifying antirheumatic drugs (DMARDs) consist of methotrexate, gold salts, penicillamine, sulfasalazine, and hydroxychloroquine. Common combinations of DMARDs include methotrexate-hydroxychloroquine, methotrexate-sulfasalazine, sulfasalazine-hydroxychloroquine, and methotrexate-hydroxychloroquine-sulfasalazine. Biological agents used for treatment include etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), and rituximab (Rituxan). Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a wide range of options, such as paracetamol, ibuprofen, naproxen, meloxicam, etodolac, nabumetone, sulindac, tolmetin, choline magnesium salicylate, diclofenac, indomethacin, ketoprofen, oxaprozin, and piroxicam (88). Patients who do not respond well to biopharmaceuticals may be able to manage their disease with the growing usage of these drugs, particularly inhibitors of tumor necrosis factor ? (TNF?). Even although anti-TNF? treatment is unquestionably beneficial, more than 40% of individuals do not respond to it (89). Additionally, up to 50% of primary responders lose their response within a year after starting treatment (90). Additionally, since many drugs interfere with the immune system's normal functions rather than treating the illness's root cause, they may have systemic side effects. The risk of severe infections and hospitalization can greatly reduce patients' quality of life because patients receiving biopharmaceuticals often take drugs like steroids and/or DMARDs concurrently. This is especially true for elderly patients and those with comorbidities. To alleviate symptoms and avoid long-term joint damage, RA typically requires lifelong therapy (91). Rheumatoid arthritis is a crippling illness with safety and effectiveness issues, leading many patients to seek complementary and alternative medicine (CAM) treatments. Around 60-90% use CAM, and research on herbal medicines is needed due to increasing interest. A multidisciplinary approach is used to reduce pain, inflammation, and restore joint function (88).
In the twenty-first century, there has been a growing push to find safer substitutes for pharmaceutical treatment in the treatment of RA. Worldwide, research is being done to determine the safety and effectiveness of natural remedies. Studies conducted recently have revealed new processes of herbal treatment to reduce inflammation and pain associated with arthritis. Herbal treatment has also been shown to produce favorable clinical results (92). An outline of a key role in treating RA are given below.
The biological name of the plant is Aloe barbadensis, commonly referred to as Lily of the Desert or Curacao Aloe. It belongs to the family Liliaceae.
Fig 4: Anthracene
Anthraquinone, anthracene, cinnamic corrosive and anthranilic acid are found within the Aloe vera plants that are dependable for its activity. It is known that anthraquinones, such anthracene, can be used to reduce inflammation in veterinary medicine (93). Aloe vera is utilized in assortment of skin sicknesses such as mellow cuts, creepy crawly stings, bruises, harm ivy and dermatitis. It has antibacterial and antifungal properties, utilized as anti-inflammatory, diuretic, spermatogenic, purgative, laxative and fever reliever. The hostile to joint pain property of aloe vera is due to the anthraquinone compound. Aloe vera stimulates the resistant framework and it could be a capable anti-inflammatory specialist. Aloe vera transemulgel adhered to zero order and Korsmeyer–Peppas models with case-II transport (aloe) as the transport mechanism. Topical application of aloe vera like extricate result within the diminishment of irritation and joint pain in adjuvant initiated joint pain in Sprague Dawley rats (94).
The biological name of the plant is Boswellia serrata Linn., commonly known as Boswellia or Indian Frankincense. It belongs to the family Burseraceae.
Fig 5: ?- boswellic
The mechanism of anti-inflammatory activity of the Boswellia extract is due to ? – boswellic acids (BAs), which have been identified as the main active compounds of frankincense. Shallaki comprise of monoterpenes, diterpene, triterpenes, tetracycline, triterpenes acids and four major pentacyclic triterpenic acids (95). The chemical structure of BAs closely resembles that of steroids, but their modes of action are quite different from painkillers or nonsteroidal anti-inflammatory drugs (NSAIDs). They show an anti-inflammatory effect via inhibition of the complement system and the inhibition of 5-lipoxygenase (96). The pentacyclic triterpene acids named as BAs, which are present in the gum resin are responsible for their inflammatory property (97). Ethanol is used as a suitable extracting solvent for extraction of BAs from the commercial sources that contain from 37.5% to 65?s (98). The animal study has revealed that the BSE has anti-inflammatory potential and can be used as an antiarthritic drug. BSE at the dose of 180 mg/kg is more effective as compared to other BSE doses (45, 90 mg/kg), but less than standard drug (indomethacin 3 mg/kg) in RA parameters. The results of the present study are encouraging and reveal the importance of BSE as a potential anti-arthritic agent (99).
The biological name of the plant is Calotropis procera Linn., commonly known as Mammoth Swallow Wort. It belongs to the family Asclepiadaceae.
Fig 6: Calotropin
Phytochemical studies on Calotropis procera have afforded several types of compounds such as Cardenolide, triterpinoids, alkaloids, resins, anthocyanins and proteolytic enzymes in latex, flavonoids, tannins, sterol, saponins, cardiac glycosides. Flowers contain - terpenes, multiflorenol, and cyclisadol (100). Diverse parts of this plant have been detailed to show against incendiary, pain relieving, hostile to oxidant and antifungal action. The latex of this plant has strong against incendiary property in different creature models. Both latex and its methanolic extricate have been appeared to repress the provocative cell deluge and edema arrangement initiated by different inflammagens. It too makes strides locomotor capacities in tentatively initiated mono joint pain in rats. In cotton pellet initiated granuloma and carrageenan-induced paw edema demonstrate, roots of Calotropis Procera Linn., at dosages of 180 mg/kg (methanol extricate) and 200 mg/kg (other extricates), appear anti-inflammatory activity (101). Complete Freund’s adjuvant-induced arthritis by Calotropis procera latex in rats was performed C. procera-treated rats, showed significantly lower arthritic index compared with CFA-induced arthritic rats (102).
The biological name of the plant is Justicia gendarussa Linn., commonly referred to as Gandarusa or Water Willow. It belongs to the family Acanthaceae.
Fig 7: Apigenin
The most constituents are alkaloids, flavonoids, phenolic, carbohydrates, tannins, sugar and starch. Chemical investigation of airborne parts of Justicia gendarussa Linn., appears some simple 0-distributed aromatic amine like 2-(2'-amino-benzylamino) benzyl alcohol and their respective 0-methyl ethers, 2-amino benzyl alcohol, stigmasterol, lupeol, 16-hydroxylupeol, ?-sitosterol, aromadendrin, ? -Sitosterol- ? -D-glycoside and male antifertility compound like gendarusin A and gendarusin B (104). Apigenin, flavonoid vitexin confined from the ethanolic extricate of Justicia gendarussa Linn., which is utilized within the treatment of aggravation and rheumatoid joint pain in people pharmaceutical. The ethanolic extricate of Justicia gendarussa Linn., plant takes off appeared noteworthy anti-arthritic action comparative to that of ibuprofen against Freund's adjuvant-induced and collagen-induced joint rodent models (103). The ethanolic extract of leaves of Justicia gendarussa showed potent anti arthritic activity in Freund’s complete adjuvant and bovine type II collagen methods (104).
The biological name of the plant is Tripterygium wilfordii, commonly known as Three-wing-nut. It belongs to the family Celastraceae.
Fig 8: Triptolide
Tripterygium wilfordii is a Chinese herb also called as Thunder God Vine. Triptolide could be a major component of the herb Tripterygium wilfordii, extricates of which are utilized in conventional Chinese pharmaceutical and it has been found to have immunosuppressive and anti-inflammatory properties. More than 500 compounds have been discovered in the genus Tripterygium, including sesquiterpenoids, diterpenoids, triterpenoids, flavonoids, lignans, etc (105). Triptolide, a diterpene triepoxide, is the primary active ingredient extracted from Tripterygium wilfordii Hook F to treat rheumatic diseases, including RA, nephritis and systemic lupus erythematosus. Extricates from the root of Tripterygium wilfordii restrain the expression of proinflammatory cytokines, proinflammatory arbiters, and network metalloproteinases by macrophages, lymphocytes, synovial fibroblasts, and chondrocytes. The extricate of root of Tripterygium wilfordii is utilized for the treatment of rheumatoid joint pain. Extricate of Tripterygium wilfordii cause diminish in Joint tallies, joint seriousness scores, and anticollagen counter acting agent titers in sort II collagen initiated joint pain (CIA) in DBA/1LacJ mice (106).
The biological name of the plant is Cleome gynandra Linn., commonly known as the Creepy Crawly Plant, Cat's Bristles, or Insect Blossom. It belongs to the family Capparaceae.
Fig 9: Luteolin
Cleome gynandra Linn., happens all through the tropic and subtropic districts. It is utilized within the treatment of rheumatoid joint pain. It contains chemical constituents such as triterpenes, tannins, anthroquinones, flavonoids, saponins, steroids, tars, lectins, glycosides, sugars phenolic compounds and alkaloids and these compounds could be capable for anti-arthritic properties. Studies show that different flavonoids, for example, luteolin, rutin, hesperidin, quercetin, and bioflavonoids produced substantial antinociceptive and anti-inflammatory activities (107). Ethanolic extricate of Cleome gynandra Linn., have against incendiary activity on both intense and inveterate aggravation. The ethanolic extricate of Cleome gynandra Linn., managed at the dosage of 150 mg/kg body weight for 30 days to the Freund's complete adjuvant actuated joint rats appears against joint impact (108).
The biological name of the plant is Terminalia chebula Retz., commonly known as Haritaki. It belongs to the family Combretaceae.
Fig 10: Chebulagic acid
Terminalia chebula Retz., is a deciduous tree. It is local to southern Asia from India and Nepal east to southwestern China and south to Sri Lanka, Malaysia and Vietnam. It contains phytochemical constituents such as tannic corrosive, chebulinic corrosive, gallic corrosive, gums, anthraquinone and sinnosides. Chebulagic acid, chebulinic acid, corilagin, hydrolysable tannins collected from aqueous extract from fruit of terminalia chebula used as anti inflammatory and anti arthritic (109). Hydro-alcoholic extricate of Terminalia chebula Retz., appears the anti-arthritic action in formaldehyde or Complete Freund's adjuvant actuated joint pain. The anti-arthritic action of Terminalia chebula Retz., is due to its modulatory impact on master fiery cytokine expression within the synovium (110).
The biological name of the plant is Premna corymbosa Rottl., commonly known as Buas Buas. It belongs to the family Verbenaceae.
Fig 11: ?- sitosterol
All the parts of the plant are medically usefull. Leaves are reported to have anti-inflammatory activity (111). Preparatory phytochemical screening of clears out of Premna corymbosa Rottl., illustrated the nearness of alkaloids, glycosides, flavanoids, steroids and triterpenoids. The roots are astringent, biting, bitter, sweet, thermogenic, hostile to fiery, alexeteric, cardiotonic, alterant, expectorant, deputative stomach related, carminative, stomachic, purgative, febrifuge, antibacterial and tonic. The takes off are stomachic, carminative, galactagogue, are valuable in dyspepsia, colic tooting, agalactia, hack, fever, rheumatalgia, neuralgia, heamorrhoids and tumors. Upon long term treatment with Premna corymbosa Rottl., it essentially stifled the improvement of persistent joint pain actuated by Complete Freund's Adjuvant (112). The present study results show that PCEE significantly (p<01>(113).
RA, an autoimmune disorder characterized by joint inflammation and degeneration, has led to a growing interest in plant-derived natural compounds for treatment. These compounds have potential anti-inflammatory, immunomodulatory, and analgesic properties. However, challenges such as limited bioavailability and the need for improved absorption, stability, and pharmacokinetic characteristics must be addressed. Innovative drug delivery systems like nanocarriers and liposomes could help address these issues. Integrating naturally derived compounds with conventional therapies could enhance disease management. These compounds may enhance the effectiveness of current therapies while mitigating adverse reactions. Synergistic effects can be achieved through precise formulation or combination strategies and optimal dosing regimens. Despite these challenges, the potential of these compounds in treating RA is promising. RA therapy's effectiveness is influenced by factors like gender, comorbidities, drug pharmacokinetics, and interactions. Current therapeutic methods lack routine monitoring, but evidence suggests the predictive value of individual biomarkers for personalized therapy. Combining conventional drugs with natural substances requires extensive knowledge of their properties and possible interactions, as well as detailed monitoring of the patient's condition throughout the treatment period. Natural compounds may affect the pharmacokinetics and pharmacodynamics of drugs, and their toxic properties can increase the risk of side effects or toxicity profiles when combined with conventional drugs. There are distinctive medications accessible for joint pain like NSAIDs, Steroids, etc. these medicines can calm torment, and the illness can be controlled to a certain degree, with extreme side impacts. Traditionally, different restorative plants are utilized to remedy patients with arthritis. Hence, this audit article makes a difference to collect restorative plants having potential anti-arthritic action. Plant parts like roots, rhizomes, takes off, gum tar, and entire plants are moreover utilized which have anti-arthritic action. The show audit centered on the improvement and thinks about on traditional medicines as hostile to- joint specialists. This audit concluded that home grown medications have numerous focal points and they are exceptionally promising area of hostile to joint pain medicate improvement
REFERENCES
Shruti Nagrale*, Reshma Lohkare, Shilpa Borkar, Jagdish Baheti, Rheumatoid Arthritis: An Overview and Herbal Approaches for Management, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 3096-3117. https://doi.org/10.5281/zenodo.14553015
10.5281/zenodo.14553015
