INTRODUCTION:

Rheumatoid arthritis affects around 0.5-1 % of the global population¹, with more than 20% of the Indian population suffering from one or more kinds of arthritis². It is a known cause of a multifunctional immunological disease. A genetic predisposition, age, hormones, environmental factors, smoking, and other factors may all have a role in RA. Genetic associations for RA include human leukocyte antigen-DR4³and -DRB1, and a variety of alleles called the shared epitope^.4,5 For the research of RA, various approaches have been explored. It is possible to study an experimental animal model that elucidates the development and progression of the disease as well as evaluates medications that can lessen or prevent the condition.

An ideal model would be one that closely resembles the pathophysiology and symptoms of human diseases. The adoption of an optimal animal model aids in the evaluation of therapeutic compounds for the treatment of RA⁶.

The inflammatory response at the joint and bone may be aggravated by microorganisms such as bacteria, viruses, fungus, parasites, bacterial DNA, and bacterial toxin, according to recent reports⁷. The innate and adaptive main compartments of the inflammatory response show the component cells of the inflamed rheumatoid synovial membrane⁸. We present key cytokine pathways in which dysregulated cytokine expression underlies the activation of effector cells such as neutrophils, mast cells, endothelial cells, and synovial fibroblasts through the activation of dendritic cells (DCs), T cells, B cells, and macrophages. These consequences' clinical symptoms are highlighted⁶. Ayurvedic literature describes components of specific plants used in traditional Indian treatments to alleviate painful and inflammatory illnesses like arthritis⁹. Numerous medicinal plants have been examined and proven to possess active ingredients with anti-arthritis properties¹⁰. This essay examines native herbs with an eye toward their potential for treating arthritis.

Cause:

Although the true cause and Etiology of RA are uncertain, it is thought to be an autoimmune disorder. Females have three times the frequency of guys when it comes to appearances¹¹. Diffuse RA is a condition that can occur as a result of RA. This is the most severe variety of RA, with inflammations in the lungs, pleura, and sclera, nodular lesions, and most usually in the subcutaneous tissue. Autoimmunity is a prominent prognostic factor in RA and plays a key role in the disease's progression towards severity. Many different immune-mediated chemicals promote inflammation in synovial joints¹². The aetiology is unknown, but inflammatory responses destroy articular cartilage, which is the primary cause of RA.

Symptoms:

Joint discomfort and swelling, stiffness in joints, restlessness, exhaustion, weight loss, and flu-like symptoms are all indications of this condition. In the blood of a rheumatoid arthritis patient, abnormal IgG antibodies were discovered. They respond to antigens, resulting in the development of an antigen-antibody complex, which causes synovial membrane inflammation and discomfort¹³.

Diagnosis:

The utilization of clinical imaging and laboratory tests is used in the diagnosis of RA. Anaemia, the presence of rheumatoid factor, and antibodies are all tested in the lab. Increased erythrocyte sedimentation rate and resistance to cyclic citrullinated peptides Symptomatic detection of stiffness and pain for a long time in the morning, on the other hand, provides some insight into the disease. X-rays can also assist detect RA, but they can't always tell the difference in early arthritis. To assess the progression of RA in patients, MRI and ultrasounds are used. For the validation of the disease, no such highly specific test has been devised^14,15

General treatment for rheumatoid arthritis and its limitation:

The management of pain, the avoidance of long-term joint damage, and the reduction of inflammation are all key issues to deal with when treating RA. Disease-modifying anti-rheumatic medications (DMARDs) and non-steroidal anti-inflammatory medicines (NSAIDs) have been the mainstays of treatment for the disease's symptoms and side effects. Corticosteroids, an anti-inflammatory hormone produced by the adrenal glands, are another steroidal medication used to treat RA inflammation. An optimal steroid should be able to meet the need at a low dosage while also avoiding negative effects. Both steroidal and non-steroidal medications can control symptoms in the short term, but they cannot treat or prevent disease in the long run. Aside from that, patients may experience more severe side effects, such as impacts on the kidney, liver, and heart, as a result of extended usage of such medications. Shortness of breath, nausea, infections, and allergic responses are some of the short-term side effects that have been reported. This highlights a fundamental restriction and concern when using steroidal medications to treat rheumatoid arthritis^16,17. They are ineffective in slowing the progression of the disease and curing it at its source. They are only intended to treat the major symptoms, such as pain, inflammation, and enema, as previously stated.

Rheumatoid arthritis from an Ayurvedic perspective:

According to Ayurveda, diseases are caused by improper cellular activity brought on by an excess or shortage of "Vata, " "Pitta, " or "Kapha." Toxins can also contribute to the development of disease. Body, mind, and consciousness all work together to maintain balance in Ayurveda. Many chronic diseases react well to medicine, which is why it is growing in popularity in Europe. By lowering patients' corticosteroid and analgesic usage and so improving their quality of life, ayurveda can aid in the improvement of their symptoms. Ayurvedic medicine has unquestionably assisted millions of people in leading healthier lives, which is why it is important.¹⁸ Alma-Ata, an ayurvedic disorder, is comparable to RA^19,20. Alma-Ata is connected to the gut's production of "Ama.". Ama is created as a result of a malfunctioning metabolism^21,
22. It's pro-inflammatory, causing toxicity in the intestines and a Vita imbalance in the body. People with Vita dose, according to Ayurveda, are more likely to acquire this condition²³. As a result, it can be healed by eating a diet rich in grains, legumes, green leafy vegetables, buttermilk, and other dairy products. Spices like ginger, garlic, and turmeric improve digestion and are anti-inflammatory, so they're a good choice. In Ayurveda, lukewarm water is always preferred for digestion. Boiling ginger roots in water also helps to remove toxins from the body and aid digestion. summarizes the most commonly used plants for treating and reducing RA symptoms.

Herbs Used in the Treatment of Rheumatoid Arthritis:

Herbal products have a capacity to lessen the negative effects of many illnesses, thus they have a variety of traditional uses in the treatment of various ailments. Some secondary metabolites have pharmacological effects against different diseases. These include phenolic chemicals, tannins, flavonoids, and alkaloids. In analytical studies for the treatment of diseases, researchers have documented the therapeutic effects of their organic extracts, such as ethanolic, acetonic, or methanolic extracts, in particular quantities. Rheumatoid arthritis diagnoses are on the rise, thus researchers are concentrating their efforts on finding a solution. Researchers have had success in locating herbal remedies that can lessen the signs and symptoms of rheumatoid arthritis as well as the likelihood of developing the condition^24,25,26. Some herbal medicinal plants used to treat RA are described below:

Table 1: Traditionally used plants for treating Rheumatoid Arthritis

Name of plant	Part used	Mode of use	Function	Reference
Alpinia galangal	Rhizomes	The paste of rhizome taken orally	Gives relief in pain	27
Anacyclus pyrethrum	Roots	Infusion drink is taken like tea of roots	Anti-rheumatic & Anti-arthritic	28
Aphanamixis polystachya	Bark	Oil applied on joints to help in pain	Act as analgesic	29
Callicarpa macrophylla	Flowers and fruits	Decoction taken	Anti-inflammatory, analgesic and antipy- retic effects	30
Cardiospermum halicacabum	Roots	The oil used to relieve pain and powder taken orally	Treats infection in joints by trophic organisms.	31, 32

Need of natural remedies:

Natural remedies have been utilised by the populace since time immemorial to relieve the symptoms of many diseases and are still used by many people, tribes and traditional medical practitioners for therapy. According to the WHO, herbal therapies are still used by 80% of the population. Plants and herbs have been taken in the form of infusions, raw foods, and juices, and have been observed to work effectively in patients. Simply including medicinal herbs into one's everyday diet resulted in a significant improvement in the ailment while also helping the sufferer. This shows that there is a lot of ground to cover in the subject of phytoconstituents of plants that have historically been used to treat RA.

Possible mechanism of action of herbal drugs:

Many researchers have attempted to establish a specific method that herbal medications use to target the causative components that cause RA symptoms and cure the disease from the inside out. As diseases advance through various processes and paths, herbal medicines have been observed to have multi-pathway effects by numerous researchers, some of which are detailed here.

TLRs (toll-like receptors) have been found to play an important role in inflammation in RA, stimulating the cellular activity of NF- through adapter molecules such as myeloid differentiation primary-response gene 88 (MyD88) during the outset of disease. TLR2/6, TLR4, or TLR5 agonists phosphorylate cytoplasmic IBs, which excite target cells and macrophages.

The promoter regions of inflammatory genes such as iNOS, COX-2, and IL-6 bind to NF- for transcriptional activation when this complex is degraded. COX-2 and other pro-inflammatory cytokines increase arachidonic acid metabolism, resulting in the creation of prostaglandins-E-2, which suppresses leukocyte apoptosis and even stimulates leukocyte proliferation, resulting in hyperplasia and pannus formation at the location.

Apart from that, cytokines and other pro-inflammatory factors play a key role in the disease's course. TNF-, IL-1, and IL-6 are the most common pro-inflammatory cytokines, which cause collagenase and other proteases to destroy collagen, increasing the speed cartilage degeneration. It also causes an increase in T cell, B cell, and macrophage infiltration, resulting in synovial inflammation. It means that the herbal medicine must be able to block and inactivate certain routes and complexes³³.

Many herbal medicines have been proven to alleviate oxidative stress and down-regulate pro-inflammatory cytokines. In this row, plants like Sarada Asoka, a popularly used herb with a long history of usage in RA, have shown significant anti-inflammatory activity in an in vivo model, resulting in lower levels of pro-inflammatory cytokines. Osmium, which already has a long list of medicinal potentials, effects on RA by inhibiting arachidonate metabolism and having anti-histaminic properties.

Eugenol (l-hydroxy-2-methoxy-4-allylbenzene), one of Osmium’s most potent bioactive compounds, is a playing a major role³⁴. Cannabis sativum, a notorious plant for its addictive characteristics, was also tested for RA and found to be positive. In a mouse model, cannabidiol, a main ingredient of the plant, was found to operate as an anti-inflammatory by inhibiting COX-2. Aerial portions of the Cassia plant, which has previously been used as a traditional remedy for treating RA, have shown similar action in suppressing the NF-𝜅𝛽 pathway and COX-2. In a rat model investigation, the leaves were reported to exhibit effects for swelling, cartilage degradation improvement, and leucocyte infiltration in synovial fluid³⁵.

Similar anti-inflammatory activity has been observed in Zingiber officinale, which contains the bioactive constituent 6-gingerol, which inhibits the NF- and PKC (protein kinase C) pathways and induces anti-inflammatory activity³⁶. Seme carpus Anacardium, a tree native to the sub-Himalayan region, has been shown to be effective in the treatment of RA and has anti-oxidant properties as evidenced by the inhibition of ROS in the body. Flavonoids also have an anti-inflammatory effect via inhibiting phospholipase A2, which decreases the generation of PGE2 as well as TNF- and NO levels. This all helps to prevent lysosomal enzyme rupture and release, as well as synod-vial erosion and provides a valuable resource for future research³⁷.

Artemisia absinthium, a Persian plant, is also used as a traditional plant for treating RA, and it has been shown to suppress inflammation through multiple pathways. It works by inhibiting the expression of ion’s by reducing the release of NO and PGE2. Inhibition of COX-2 expression by scopa one, a bioactive chemical present in the plant, is also a pathway followed. A. also exhibits a similar multi-path action. Experimental studies have also supported the use of Curcuma long, a widely used spice that contains curcumin. It prevents the Blocking the catabolic effect of IL-1 induced upregulation of MMP-3 and IL-1 induced decrease in type II collagen synthesis, which is a contributing factor in RA progression, inhibits the arachidonic acid cascade by inhibiting the catalytic activities of phospholipases and blocking the catabolic effect of IL-1 induced upregulation of MMP-3 and IL-1 induced decrease in type II collagen synthesis³⁸. Moringa oleifera is one of the other plants. Other plants include Moringa oleifera, which has an anti-inflammatory effect by lowering serum levels of Rheumatoid Factor (RF) and levels of the cytokines TNF- and IL-124, Nyctanthes Arbor-tristis, which lowers the inflammatory cytokines IL-1, TNF- in blood serum in an experimental set up, and Swertia chirality, which has an anti-inflammatory effect by lowering³⁹. The finest part of the strategy is that these medicines have minimal or no negative effects. Many of the above-mentioned negative effects have been found in RA patients after prolonged usage of allopathic medicines. As a result, herbal remedies could be beneficial in the treatment of such disorders. Today, several phytomedicinal plants have been detected using experimental methods and are being studied by scientists in order to develop as a natural healing strategy. The reduction of joint aches, the prevention of deformity, the prevention of erosion, the prevention of advancement, and the control of extra-articular symptoms are all goals of natural therapy.

The best aspect of the strategy is that these medicines have negligible or no negative effects. Many of the above-mentioned negative effects have been seen in RA patients following prolonged usage of allopathic medications. As a result, herbal remedies may be useful in the treatment of such illnesses. Many phytomedicinal plants have today's functions that have been found through experimental methods and are being studied by scientists to develop as a natural form of healing⁴⁰

CONCLUSION:

Rheumatoid arthritis is an autoimmune illness that causes deformity and pain in the sufferer's joints owing to inflammation. Allopathic treatments for RA have traditionally relied on disease-modifying anti-rheumatic medications, non-steroidal anti-inflammatory medicines, and corticosteroids, which reduce pain and inflammation for a limited time while in effect. When all factors are considered, the herbal approach to RA treatment might be viewed as a viable choice. Many secrets to curing any condition without creating any negative effects can be found in our folk and indigenous treasure trove of knowledge. Herbal medicines with anti-arthritic properties are currently being produced, and the potentials of its phytochemicals are being continually validated. More than 450 plant species have been identified as having anti-arthritic properties.

REFERENCES:

1. Shivanand P, Arthritis an autoimmune disorder: Demonstration of In-vivo anti-arthritic Activity. Int J Pharm Life Sci 2010; 1:38-43.

2. S Gabriel SE, Kaleb M. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009; 211:29

3. Orozco G, Barton A. Update on the genetic risk factors for rheumatoid arthritis. Expert Rev Clin Immunol. 2010; 6(1): 61-75.

4. Balsa A, Cabezón A, Orozco G, et al. Influence of HLA DRB1 alleles in the susceptibility of rheumatoid arthritis and the regulation of antibodies against citrullinated proteins and rheumatoid factor. Arthritis Res Ther. 2010; 12(2): R62.

5. McClure A, Lunt M, Eyre S, et al. Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci. Rheumatology (Oxford). 2009; 48(11): 1369-1374.

6. Patwardhan SK, Bodas KS, Gundewar SS. Effect of Fac- etal Joint Mobilization In Lumbar Spondylosis. Int J Pharm 2010; 10:216-218.

7. Kaushik, M.L., Jalalpure, S.S., J Adv Pharm Technol Res 2011, 2, 170- 176.

8. McInnes, I.B., Schett, G., Nature Reviews Immunology 2007, 7, 429-442.

9. Patil, K.R., Patil, C.R., Jadhav, R.B., Mahajan, V.K., Patil, P.R., Gaikwad, P.S., Evidence-Based Complementary and Alternative Medicine 2011, 1-7.

10. Baranwal, V.K., Irchhaiya, R., Alok, S., International Journal of Pharmaceutical Sciences and Research 2012, 3, 981-986.

11. http://arthritis.ca/getmedia/6c39edce-5b2d-498d-bd60 28d33f3e1850/Rheumatoid-Arthritis-Causes-Symptoms-and Treatments.pdf?ext=.pdf

12. Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and management. Am J Med 2007; 120:936-939.

13. Smolen JS, Steiner G. Therapeutic strategies for Rheumatoid arthritis. Nature Rev Drug Discov 2003; 2:473-488.

14. Mohanad JK, Hameed IH, Kaizal AF, Medicinal Plants Used for Treatment of Rheumatoid Arthritis: A Review. Int J Pharma Clin Res 2016; 8:1685-1694.

15. Goel A, Singh DK, Kumar S, Bhatia AK. Immunomodulating property of Ocimum sanctum by regulating the IL-2 production and its mRNA expression using rat’s splenocytes. Asian Pac J Trop Med 2010; 3:8-12.

16. Rathore B, Mahdi AA, Paul BN, Saxena PN, Das SK. Indian herbal medicines: possible potent therapeutic agents for rheu- matoid arthritis. J Clin Biochem 2007; 41:17-9.

17. Tripathy S, Pradhan D, Anjana M. Anti-inflammatory and an- tiarthritic potential of Ammania baccifera Linn. Int J Pharma Bio Sci 2010; 1:1-7.

18. http://www.ayurveda.com

19. Pandey P, Tiwari S. Therapeutic Potential of Indian Plants for the Treatment of Rheumatoid Arthritis. J Pharmacog Phyto- chem 2018; 7:37-41

20. Lewis, A. and Levy, A. Anti-inflammatory activities of Cassia alata leaf extract in complete Freund’s adjuvant arthritis in rats. West Indian Med J. 2011; 60:615– 21.

21. Al-Nahain A, Jahan R, Rahmatullah M. Zingiber officinale: A Potential Plant against Rheumatoid Arthritis. Arthritis 2014; 159089:8.

22. Kukar M. Complementary and alternative medicine use in rheu- matoid arthritis: proposed mechanism of action and efficacy of commonly used modalities. Rheumatol Int 2010; 30:571–586.

23. Rindfleisch JA, Muller D. Diagnosis and management of rheu- matoid arthritis. Am Fam Physician 2005; 72:1037-1047.

24. Singh Vishwabhan, Patel Harsh, Suvagiya Vishal, Singh Kailash (2011). Some Traditionally Used Anti-Arthritic Herbs A Review. International Research Journal of Pharmacy. 43-45:2(11).

25. Dixit K. Praveen, Mittal Suchita (2013). Herbal Sources of Anti-Arthritic Potential: A Comprehensive Review. International Journal of Pharmaceutical and Biomedical Research. 88-92: 4(2).

26. Chandini Ravikumar (2014). Herbal Remedy for Rheumatoid Arthritis. Journal of Pharmaceutical Sciences and Research. 310-312:6(9).

27. Nadkarni KM, Nadkarni AK. Indian materia medica: with Ayurvedic, Unani-Tibbi, Siddha, allopathic, homoeopathic, na- turopathic & home remedies, appendices & indexes. Bombay, India, Poupular Pakashan Pvt. Ltd. 2009.

28. Chandrasekar R, Chandrasekar S. Natural herbal treatment for Rheumatoid Arthritis – A review. Int J Pharma Sci and Res 2017; 8:368-384.

29. Srikantha MKR, Madhava N. (roga viniscaya) of Madhavakara (English translation), Chapter 22. Delhi: Chaukhambia Orien- talia 1993

30. MOHFW. Department of Indian Systems of Medicine and Homeopathy. Ayurvedic Pharmacopeia of India, Ministry of Health and Family Welfare, Government of India, 2001 (1).

31. Shen H, Tesar BM, Walker WE and Goldstein DR. Dual signal- ing of MyD88 and TRIF is critical for maximal TLR4- induced dendritic cell maturation. J Immuno 2008; 3:1849–1858.

32. Chopra A, Saluja M, Tillu G. Ayurveda-modern medicine in- terface: a critical appraisal of studies of Ayurvedic medicines to treat osteoarthritis and rheumatoid arthritis. J Ayur Integra Med 2010; 1:190–198.

33. Yan WX, Zhang JH, Zhang Y, Meng DL, Yan D. Anti-inflam- matory activity studies on the stems and roots of Jasminum lanceolarium Roxb. J Ethnopharmacol 2015; 2:335-341.

34. Umar MI. Bioactivity-guided Isolation of Ethyl-p methoxycin- namate, an Anti-inflammatory Constituent, from Kaempferia galanga L. Extracts. Molecules 2012; 17:8720-8734.

35. Jain, SK. Dictionary of Indian folk medicine and ethnobotany. New Delhi: Deep Publications. 1991.

36. Hasbarinda BH. Chemical constituents of the twigs of Mangif- era indica. Indo Am J 2008; 23:1-3.

37. Sreeshma PS, Regi Raphael K, Alby Alphons B. Pharmacog- nostic Studies of leaves of Naravelia Zeylanica (Linn) DC. South. Indian J Bio Sci 2016; 2:179-182.

38. Phadtare S, Pandit R, Shinde V, Mahadik K. Comparative Phy- tochemical and Pharmacological Evaluations of Two Varieties of Ocimum Basilicum for Antiarthritic Activity. J Pharmacog Phytochem 2013; 2:58-167.

39. Agarwal T, Singh R, Shukla AD, Waris I, Gujrati A. Compara- tive analysis of the antibacterial activity of four Piper betle va- rieties. Adv App Sci Res 2012; 3:698-605.

40. Ghani A, Medicinal Plants of Bangladesh, 2nd Ed. Asiatic So- ciety of Bangladesh, Dhaka 2003; 351-2.

Received on 25.08.2022 Modified on 09.10.2022

Res. J. Pharmacognosy and Phytochem. 2023; 15(1):77-81.

DOI: 10.52711/0975-4385.2023.00011