INTRODUCTION:

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and the etiology is multifactorial. The combination of genetic and environmental factors triggers inflammatory cascade which generates immune complexes leading to articular and extra-articular complications. Activation of T-cells leads to production of mediators of inflammation in joints. The biochemical mediators of inflammation include cyclooxygenase (COX), lipoxygenase (LOX), matrix metalloproteins (MMPs) and generation of free radicals. Generation of arthritogenic stimuli leads to release of molecular mediators of inflammation through several cell-siganaling pathways such as Extracellular-signal-regulated kinase ERK pathway, Mitogen activated protein kinase P38 MAPK pathway, and c-Jun N-terminal kinase (JNK) pathway causing expression of various proinflammatory cytokines such as tumor necrosis factor (TNFα), interleukin (IL) such as IL-1β, IL-6, and IL-17. The levels of these cytokines are increased in the synovial tissue. The cytokines and chemokines express transcription factors such as nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that stimulate receptor activated nuclear factor-kB ligand (RANKL) formation which is responsible for maturation of osteoclasts and joint deterioration in RA patients.

Non-steroidal anti-inflammatory drugs NSAIDs, glucocorticoids and disease modifying antirheumatic drugs DMARDs were the only treatment for RA before two decades. New therapeutic target interventions led to the emergence of biologic agents. The first class of biologic agents recognized for patients refractory to DMARDs were TNFα inhibitors, such as etanercept, infliximab and adalimumab. Although TNFα drugs are highly effective in RA, some patients do not respond to them. Hence newer agents like IL-1 antagonist (anakinra), cytotoxic T-lymphocyte antigen-4 CTLA-4 antagonist (abatacept) and anti-CD20 drug (rituximab) were explored. The use of these drugs requires careful monitoring in daily practice and comorbidity conditions play a major role in therapy. Additionally, higher costs and severe side effects such as life-threatening infections limit the use of newer biologics in many populations.

Since antiquity, herbal medicine has been recognized and is nature’s gift. Herbal medicine such as botanicals and nutritional supplements are becoming popular due to their safety, economy and wide availability. Several studies have demonstrated that plant extracts and/or secondary metabolites suppress the production of pro-inflammatory cytokines and chemokines and proved to have antiarthritic activity. In this review, we summarized these studies and described the antiarthritic activity of various plant extracts, and such secondary metabolites as 11-Acetyl Ketoboswellic acid and celastrol. In addition, we highlight the medical potential of these extracts and plant-derived compounds for treating of arthritis through reported clinical trials and some of the herbal formulas used traditionally. ^[1-5]

1. Some potential plants reported with antiarthritic activity

1.1 Akebia quinata (HOUTT) DECNE (Lardizabalaceae) stems are used in Japan as diuretic and antiphlogistic. The methanolic extract at 200mg/kg has proven antiarthritic activity. The extract has also inhibitory effects on vascular inflammation mediated by Tumor necrosis factor-alpha (TNFα)^{[6, 7]}

1.2 Allium sativum L (Amaryllidaceae) popular as garlic has anti-carcinogenic, antiatherosclerotic, antithrombotic, antimicrobial, antiinflammatory and antioxidant effects. Thiacremonone a sulfur compound isolated from garlic at 10mg/kg has proven anti-inflammatory and antiarthritic effects through inhibition of Nuclear Factor-kappaB (NF-κB), reduced inducible nitric oxide (iNOS) and cyclooxygenase (COX-2) ^[8].

1.3 Alpinia galanga L WILLD.(Zingiberaceae) known as blue ginger rhizome is useful in treatment rheumatoid arthritis. It has been documented that the plant extract inhibits THP-1 cells, which leads to down-regulation of expression of TNFα, Interleukin-1beta (IL-1β), COX-2, and macrophage inflammatory proteins (MIP)-α. The active component from this ginger, 1′-acetoxychavicol acetate, suppressed NF-κB activation and suppressed receptor activator ofNF-κB ligand (RANKL), osteoclastogenesis and thus prevents bone loss. In human synovial fibroblasts IL-1β induced expression of MMPs is blocked by the plant extract^{. [9, 10, 11]}

1.4 Ananas comosus L MERRILL (Bromeliaceae) known as pineapple and bromelain isolated from the plant is an anti-inflammatory enzyme and is widely used as adjuncts in post-surgical wound healing. In rodent model it was found to improve the antiarthritic effect. In many clinical trials, bromelain was found to be effective in osteoarthritis. ^[12]

1.5 Andrographis paniculata (BURM.F.)WALLICH EX NEES (Acanthaceae) known as “King of bitters” is traditionally used for skin eruptions, boils, and scabies mainly because it has blood purifying property. Andrographolide isolated from the plant has proven antiarthritic activity. It induces cell cycle arrest and apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes, which is the hallmark of rheumatoid arthritis. It was found to be a strong inhibitor of NF-κB, TNF-α, IL-6, MIP-2, iNOS and COX-2. In a 14week study in 60 RA patients, capsules containing 30% of andrographolide provided symptomatic relief^{.
[13, 14, 15]}

1.6 Anethum graveolens L (Apiaceae) is rich in quercetin. Quercetin inhibits IL-1β-induced proliferation and production of MMPs, COX-2, and PGE2 by rheumatoid synovial fibroblast. Quercetin 166mg with 133mg of vitamin C was tried in RA patients, although no changes were observed. ^[16-18].

1.7 Apium graveolens L (Apiaceae) – called as Celery, because of its taste and nutritional value. Powdered fruits with Caesalpinia bondus L Roxb seeds in equal proportion and taken twice daily by the Bhilla tribes of Maharashtra for arthritis relief. Apiin isolated from the plant down-regulated the expression of iNOS in cell line studies^{. [19, 20]}

1.7 Argyreia speciosa SWEET (Convulvulaceae) known as Woolly morning glory is a important ‘rasayana’in Indian system of medicine having antioxidant, anti-inflammatory, and antiarthritic activity. The extract has antiarthritic activity and the anti-inflammatory activity was revealed by reduction of prostaglandins^.
[21]

1.8 Artemisia absinthium L (Asteraceae) known as worm wood, aerial parts of this aromatic herb in liquid preparations, are used for treating skin wounds, boils, bumps or ulcers. 5,6,3',5'-tetramethoxy 7,4'-hydroxyflavone isolated from the plant was found to down regulate expression of inflammatory mediators via inhibition of NF-κB. ^[22,
23]

1.9 Azadirachta indica (Meliaceae) A. JUSS known as neem and is used traditionally for various ailments. Neem oil is used by the Khonds tribes of Andhra Pradesh for arthritis. Epoxyazadiradione, a limonoid isolated from the fruits of neem inhibits the proinflammatory actions of Macrophage migration inhibitory factor, and Azadirachtin targets NF-κB and inhibits it. ^{[24, 25, 26]}

1.10 Azima tetracantha (Salvadoraceae) root, root bark and leaves are used with food as a remedy for rheumatism. Its leaves were found to possess azimine, azecarpin, carpine and isorhamnitine-3-O-rutinoside, friedelin, lupeol, glutinol and β-sitosterol. Friedelin at a dose of 40mg/kg has anti-inflammatory property in rodent models of arthritis and antioxidant activity could be attributed to it. ^[27]

1.11 Bacopa monnieri (L.) PENNELL (Scrophulariaceae) known as brahmi is a creeping plant found throughout India. It contains bacoside-A, which suppressed inflammatory cytokines, betulinic acid caused inhibition of NF-κB and down-regulated expression of IL-6 in peripheral blood mononuclear cells (PBMCs). The extract decreased foot pad swelling and improvement of joint architecture in rodent models of arthritis ^{[28, 29, 30]}.

1.12 Boerhavia diffusa Linn. (Nyctaginaceae) known as punarnava and the main chemical ingredients of this plant include alkaloids (punarnavine), rotenoids (boeravinones A to J) and flavones. Malasar tribes of Coimbatore use the decoction of roots along with the roots of Tinospora cordifolia, Erythroxylon monogynum and Alpinia galanga, taken internally for arthritis. Punarnavine reduced the levels of proinflammatory cytokines in cell line studies and rodent models^{. [31, 32]}

1.13 Boswellia serrata Roxb (Burseraceae) known as frankincense, Salai guggul and peeled bark yields gum-oleo resin, the extracts of it is used traditionally as antiarthritic, astringent, stimulant, expectorant, and antiseptic. Boswellia extracts (BE) inhibit leukotriene biosynthesis, lipopolysaccharide (LPS) induced TNFα production, and the microarray analysis revealed TNFα induced expression of MMP-3, MMP-10 and MMP-10 were inhibited. Acetyl-11-keto-beta-boswellic acid (AKBA) potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and its expression. Different formulations of the BE extract have been reported for antiarthritic activity such as Aflapin (enriched in AKBA), and 3-Acetyl-11-keto-beta-boswellic acid loaded-polymeric nanomicelles for topical application. Up to 1000mg/kg bodyweight, boswellia was found to be non-toxic in rats and primates. However, the clinical trials of BE in RA patients revealed no measurable efficacy. ^[33-38]

1.14 Brassica alba L (Brassicaceae) is known as white mustard used for culinary purpose. 3,3'-Diindolylmethane is a natural compound found in brassica plants, attenuates arthritis and osteoclastogenesis by inhibiting the expression of RANKL. ^[39]

1.15 Calotropis gigantea L. R.BR. (Apocynaceae) called as crown flower, used in the treatment of abdominal tumors, boils, syphilis, tuberculosis, and rheumatism. Lupeol isolated from the latex and administered at the dose of 50mg/kg for 4weeks reduces the level of proinflammatory cytokines in animal models of arthritis. ^[40]

1.16 Calotropis procera R.Br (Asclepiadeae) is known as Sodom apple. The methanolic extract of the plant at 50-500mg/kg has revealed antiarthritic activity in rodent models of chronic inflammation, inhibits prostaglandin-E (PGE2) ^[41]

1.17 Camellia sinensis L O.KUNTZE (Thecaceae) White, green, oolong, and black teas are produced from its leaves, popular for its antioxidant properties, because of polyphenos present in it. Epigallocatechin-3-gallate from green tea modulates the activities of B lymphocytes in rodent models of arthritis ^[42].

1.18 Cannabis sativa L (Cannabaceae) is called marijuana and there are several reports about cannabinoids from the plant. Flowers and seeds are used for medicinal purpose. Cannabis oromucosal spray significantly decreased pain and disease activity was improved at 5^th week^[43].

1.19 Cardiospermum halicacabum L (Sapindaceae) is known as balloon plant. It is traditionally used in rheumatism, chronic bronchitis, and stiffness of limbs. Rutin isolated from the plant increases Glutathione reductase and prevents collagen degradation in arthritic models of inflammation. The other anti-inflammatory constituents from the plant are luteolin-7-O-glucuronide, apigenin-7-O-glucuronide and chrysoeriol^.[44,
45]

1.20 Cedrus deodara (ROXB.) LOUD (Pinaceae) known as devadaru and the aqueous extract of the volatile oil from the wood has proven antiarthritic activity, which may be due to blockade of leukotrienes ^[46].

1.21 Celastrus paniculatus (Celastraceae) is a large, woody climber known as Thunder God of Vine. The aerial parts, seeds and seed oil have great therapeutic value. Bhilla tribes of Maharashtra use the seed oil for the massage of painful joints. In vitro studies revealed that celastrol isolated from the plant inhibits NF-κB signaling, IL-17A induced expression of MMP-9 and migration of Rheumatoid Arthritis Fibroblast like synovicites. It inhibits IL-1β in rodent models of arthritis. ^{[19, 47, 48].}

1.22 Chrysanthemum indicum L. (Asteraceae) is a wild herb and has a long history of use as a traditional medicine, mainly for the treatment of inflammation, hypertension and respiratory diseases in Korean and Chinese medicine. The antioxidant activity and apoptosis of rheumatoid arthritis fibroblast like synovicytes (RAFLs) of the total flavonoids of the plant was proved in adjuvant arthritis in rats. ^[49]

1.23 Cissampelos pareira L (Menispermaceae) roots are used locally to cure gastrointestinal complaints such as diarrhea, dysentery, and ulcers. The important compounds isolated from the plant are pareirubrine A, hyatinin methochloride and cissamperine. The aqueous ethanolic extract has reported antiarthritic activity. Alkaloidal fractions of the plant have reported antioxidant activity, which may have a potential role in inflammation^.
[50]

1.24 Citrus paradisi MACF (Rutaceae) is known as grapefruit. The flavonoids present in it are naringin, hesperidin and 7,3'-dimethoxy hesperetin. All these flavonoids have supportive evidence for antiarthritic activity in In vitro and In vivo studies^.[51-54]

1.25 Cleome gynandra L (Cleomaceae) called as cat’s whisker is a weed and traditionally the whole plant is used in the treatment of tumor, anti-inflammatory and lysosomal stability actions. The leaf extract has antiarthritic action and antioxidant activity could be attributed to it^{. [55, 56]}

1.26 Clerodendrum phlomidis L.F (Fabaceae) is medicinally used for inflammation, diabetes, nervous disorder, urinary disorders as well as a bitter tonic. The isolated compounds are pectolinaringenin, scutellarein, clerodin, and clerodendrin. The ethanolic extract was found to have antiarthritic activity through lysosomal membrane stabilization. ^[57]

1.27 Commiphora wightii (Burseraceae) called as Guggul, has been in use medicinally since Vedic period for treatment of a number of diseases. Guggulosterone is a plant steroid derived from the oleo-gum resin causes inhibition of NF-κB in RAFLs, suppress inducible nitric oxide synthetase (iNOS), down-regulates expression of COX-2, MMP-1, MMP-9, and RANKL induced osteoclastogenesis ^[58-61].

1.28 Costus speciosus (KOEN. EX RETZ.) SM is known as Crape ginger. It is used traditionally by Chutia, Deori, Ahoms, SonowalKocharis, Tea-tribes, Karbis and Bodos tribes of Assam. Fresh root is crushed and mixed with Curcuma domestica Valeton, common salt and cow milk is boiled and filtered and taken orally. Korku, Gond, Bhils, Bhilalas, Naik, Mankar and Nihal tribes of Maharashtra use the rhizome extract internally for arthritis. The methanolic extract of the plant in doses of 400 and 800 mg/kg had antiarthritic activity. Costunolide, a sesquiterpene lactone has been isolated from the plant is a NF-κB inhibitor. ^[62-64].

1.29 Curcuma longa L (Zingiberaceae) popularly known as turmeric, is extensively used in Indian food. Turmeric contains three curcuminoids: curcumin, demethoxy curcumin and bisdemethoxy curcumin. Curcumin (diferuloylmethane) is the primary constituent which suppresses TNF-α induced NF-κB activation and leads to reduced expression of COX-2, MMP-9. It also suppresses IL-6 activation. Regarding arthritis, curcumin has apoptotic effect in RAFLs, TNFα suppression, protects chondrocytes. Because of the low bioavailability of curcumin, many new drug delivery systems are in the research portal for curcumin ^[65-69].

1.30 Dioscorea acultea L (Dioscoreaceae) tuber slices is traditional Chinese medicine for analgesic, anti-inflammatory, antineoplastic and antiosteoporotic effects. Diosgenin, a plant steroid, induces apoptosis in human rheumatoid arthritis synoviocytes with COX-2 overexpression in RA synovial cells ^[70].

1.31 Ephedra sinica STAPF (Ephedraceae) known as Ma Huang has been traditionally used as sympathomimetic, anti-inflammatory, hypoglycemic and antitussive/ antiasthmatic effects. Ephedrine is a well known alkaloid of the plant. The plant extract used as herb-acupuncture in rats and in U937 cells showed antiarthritic activity^{[71, 72].}

1.32 Ficus carica L. (Moraceae), is the common Fig, and the leaves of this plant have been used as folk medicine for hemorrhoids, neuralgia, warts, diarrhea and carbuncles. The leaves of this plant contain terpenoid, saponin and flavonoid compounds. The extract of the plant had proven anti-osteoclastogenic activity in In vitro studies ^[73].

1.33 Gaultheria yunnanensis (Franch.) Rehder (Ericaceae) is a kind of traditional Chinese herbal medicine used for the treatments of rheumatoid arthritis, swelling and pain. The analgesic and anti-inflammatory activity of Gaultherin, a salicylate derivative, was proved in rodent models of inflammation ^[74].

1.34 Gentiana macrophylla (Gentianaceae) is a Chinese plant and the crude extract has been used as antiulcerogenic, anti-inflammatory, and analgesic. Gentiane isolated from the plant, given at the dose of 3-100mg/kg administered orally, had suppressed TNFα in LPS challenged rats ^[75].

1.35 Glycine max L. MERR (Fabaceae) called as soybean is richest source of isoflavones such as genistein, daidzein and glycitein, and have beneficial role in cancer, obesity, cardiovascular conditions, diabetes, Alzheimer's disease and menopausal symptoms. In rodent models, genistein and daidzein at 20mg/kg dose have proven antiarthritic activity by inhibiting mitogen activated protein kinase (MAPK) signal transduction and proinflammatory cytokine expression ^{[76, 77].}

1.36 Harpagophytum procumbens DC called as Devil’s claw is used historically as an analgesic, a remedy for fevers and allergies, and as a stimulant for gastric enzymes and digestion. The tuberous roots of the plant are used for medicinal purposes. The major chemical component thought to be responsible for the anti-inflammatory activity is harpagoside, a monoterpene glucoside and the chondroprotective and analgesic effects of harpagoside are attributed to inhibition of COX-2, leukotrienes, TNFα and IL-1β ^[78].

1.37 Hemidesmus indicus L. SCHULT (Apocynaceae) is known as Indian sarsaparilla. The root has been used for various diseases such as leprosy, leucoderma, leucorrhoea, syphilis, chronic rheumatism, asthma, bronchitis, gravel and other urinary diseases. In animal models of arthritis the extracts of have antiarthritic activity, which may be related to the antioxidant activity phenolic content ^{[79, 80].}

1.38 Leucas aspera (Willd.) SPRENG, Linn. (Lamiaceae) is known as dronapushpi is used traditionally as an antipyretic and insecticide. Leaf juice is taken with honey, twice daily by the Kandha tribes of Orissa for arthritis. The ethanolic extract modulated the levels of inflammatory markers in arthritic rat model ^{[81, 82, 83].}

1.39 Lithospermum erythrorhizon L (Boraginaceae) called as purple gromwell is known for its red pigments from the roots and used as dyestuffs for fabrics, and in ointment as anti-inflammatory in China and other countries. Shikonin, a naphthoquinone isolated from the plant, inhibited the cartilage degrading enzymes and protected the joints in animal studies. ^[84]

1.40 Matricaria chamomilla L (Asteraceae) is star among medicinal plants and is useful as anti-inflammatory, antiseptic, and antispasmodic. In vitro studies revealed that polyphenols from the plant down-regulates the expression of TNFα and IL-6. Matricaria reticulata is useful in alleviating mouth ulcers resulting from methotrexate treatment ^{[85, 86].}

1.41 Moringa oleifera Lam (Moringaceae) commonly called as drum-stick tree. Chutia, Deori, Ahoms, Sonowal-Kocharis, Tea-tribes, Karbis, and Bodos tribes of Assam use crushed root with molasses and powdered clove, which is macerated with water and the extract is taken after breakfast for 3-7 days for arthritis. Aurantiamide acetate and dibenzyl urea isolated from the plant has anti-inflammatory activity and inhibiting the production of TNF-alpha and IL-2. The ethanolic extracts of the root and leaf reduced the levels of proinflammatory cytokines in animal models of arthritis ^{[62, 87, 88].}

1.42 Nigella sativa L (Ranunculaceae) called as black cumin is used to treat bronchial asthma, headache, dysentery, infections, obesity, back pain, hypertension, gastrointestinal problems, and eczema. Many compounds have been isolated from the plant such as thymoquione, thymol, thymohydroquinone, and dithymquinone. Thymoquinone is the most abundant constituent, is a very effective antiarthritic compound which suppresses NF-κB, MMP-9, MMP-13 and TNF-α, IL-1β and modulates oxidative stress in animal models of arthritis ^{[89, 90, 91].}

1.43 Nyctanthes arbor-tristis L (Oleaceae) called as Night-flowering jasmine. The flowers are used extensively in Ayurvedic medicine for the treatment of various diseases such as sciatica, chronic fever, rheumatism, and internal worm infections, and as a laxative, diaphoretic, and diuretic. Oral administration of leaf and fruit extracts reduced the expression of various cytokines, such as TNF-α, IL-1β and IL-6, in arthritic mice^[92].

1.44 Ocimum sanctum (Lamiaceae) popular known as holy basil has several medicinal properties. Most of the plant parts are used and medicinal properties are attributed to ursolic acid, eugenol and isoeugenol. Ursolic acid modulates expression of (T helper) Th1 and Th2 cells, which leads to reduction in reduction in TNF-α ^{[93, 94].}

1.45 Olea europa L (Oleaceae) known as olive tree. The major constituent of the leaves and unprocessed olive drupes is oleuropein, is a polyphenol found in olive oil and has proven antiarthritic property in mice model. In vitro studies revealed the reduction in cytokine and chemokine production by hydroxyltyrosol isolated from olive extract^{[95, 96]}.

1.46 Paeonia lactiflora Pall popularly known as Chinese peony is a herbaceous flowering plant. Paenoniflorin is the most abundant compound. In acute and chronic models of inflammation, total glycosides of peony have decreased PGE2, leukotrienes, iNOS and in animal models of arthritis, paeoniflorin has immunosuppressive effects. Though the antiarthritic effects of paeoniflorin is lesser than disease modifying Antirheumatic drugs (DMARDs), it was found to be a safer alternative^{. [97, 98]}

1.47 Piper longum L (Piperaceae) known as long pepper and the fruits are used for its medicinal value. Piperine isolated from the plant has various biological activities such as antineoplastic, anti-protozoal and antiarthritic property. It is used by Tagin tribes of Arunachal Pradesh for arthritis. In collagen-induced arthritis rat model oral dose of 100mg/kg has ameliorated oxidative stress, reduced the levels of pro-inflammatory mediators and increased level of anti-inflammatory mediators. 30mg/kg i.p alleviated synovial hyperplasia and mononuclear infiltration. Moreover, piperine also inhibited IL-1β induced proliferation of RAFLs and suppressed AP-1.^[99-102]

1.48 Plectranthus ambonicus (LOUR.) SPRENG (Lamiaceae) is a perennial herb used for skin disorders in India, anti-inflammatory in Taiwan and traditionally used for treatment of RA. In the rodent models the extract of the plant has decreased the foot pad swelling, decreased TNFα and other mediators of inflammation. Rosmaric acid isolated from the plant has proven anti-osteoclatogenic activity. ^[103,
104]

1.49 Plumbago zeylanica L (Plumbaginaceae) is known as doctor bush. The extracts of Plumbago zeylanica have been used in China and other Asian countries as folk medicine for the treatment of cancer, rheumatoid arthritis and dysmenorrhoea. Plumbagin isolated from the plant suppresses NF-κB, IL-6 and modulated the response of Th1 cells in rodent model of arthritis. ^{[105, 106]}

1.50 Pongamia pinnata (L.) PIERRE (Fabacaeae) Leaf juice is used for relief of flatulence, diarrhea and cough. Hot infusion of leaves is applied as bath in rheumatic pain, and cleaning foul ulcers and sores. Leaf extract inhibits NF-κB induced expression of TNF-α in arthritic rats. Seed oil applied externally by Baiga, Gond, Kariya and Panka of Madhya Pradesh for arthritis relief. ^[107-109]

1.51 Prunus Species (Rosaceae) called as stone fruit, cherries is a woody plant used for its timber commercially. Cyanidin and anthocyanins isolated from the plant has antiarthritic activity improved the antioxidant status and decreased the levels of proinflammatory cytokines in animal models of chronic inflammation. ^[110]

1.52 Rosa canina L (Rosaceae) commonly known as dog rose and has high phenolic contents, which as antioxidant, antimutagenic and anticarcinogenic properties. 5g rose hip powder for 6 months improved disease activity in RA patients. ^[111]

1.53 Salacia reticulata (Celastraceae) roots and stems of plant are used for the prevention of rheumatism and diabetes. It contains unique compounds such as salacinol, kotalanol, and mangiferin. The extract of the plant has antiarthritc properties revealed through animal models and inhibits IL-1β, and MMPs. ^[112,
113]

1.54 Saussurea lappa Clarke (Compositae) is traditionally used for asthma, inflammation and rheumatism. The ethanolic extract of the plant possess antiarthritic activity in animal models and blocked TNF-α and IL-6 production in LPS induced Th1 cells. Costunolide isolated from the plant inhibits TNF-α induced expression of NF-κB. ^{[21, 114]}

1.55 Semecarpus anacardium L (Anacardiaceae) is used in Ayurvedic and Siddha systems of medicine. The nut extract of the plant has phenolic compounds having medicinal properties such as antiarthritic, antineoplastic and antiinfective. In animal models the extract decreased TNFα and inhibited NF-κB in healthy and RA patient cell lines. ^{[115, 116]}

1.56 Silybum marianum GAERTN (Asteraceae) commonly known as milk thistle and the extract of it are widely used for liver disorders, owing to its purported hepatoprotective properties. A mixture of flavolignans called as silymarin isolated from the plant has proven antiarthritic activity mediated through inhibition of leukotrienes^{. [117]}

1.57 Sphaeranthus indicus L (Asteracaeae) is widely used in Ayurvedic system of medicine to treat vitiated conditions of epilepsy, mental illness, hemicrania, jaundice, hepatopathy, diabetes, leprosy, fever, pectoralgia, cough, gastropathy, hernia, hemorrhoids, helminthiasis, dyspepsia and skin diseases. 7-hydroxyfrullanolide, isolated from the fruits is a sesquiterpene lactone and inhibits NF-κB and has antiarthritic potential, proven in In vitro and In vivo studies. ^[118]

1.58 Strychnos nux-vomica L (Loganiaceae) called as poison nut is used in the treatment of anemia, lumbago, asthma, bronchitis, constipation, diabetes, malarial fever, skin disease, paralysis, muscle weakness, and appetite loss. Brucine and brucine-N-oxide has reported anti-inflammatory effects revealed through reduced PGE2 in animal models of arthritis. ^[119]

1.59 Swertia chirayita ROXB. EX (FLEMING) KARST (Gentianaceae) known as felworts is a critically endangered herb known for its anti-inflammatory, antioxidant properties, and considered to be a bitter tonic, febrifuge, and laxative and is used in fever, burning of body, intestinal worms, and skin diseases. Mangiferin, a secoiridoid glycoside isolated from the plant had been proven to down-regulate the expression of proinflammatory cytokines such as TNFα, IL-1β and upregulating IL-10 in arthritic mice model^.[120]

1.60 Tanacetum parthenium (Asteraceae) called as feverfew, is a medicinal plant traditionally used for rheumatoid arthritis. The active principle includes sesquiterpene lactones, importantly parthenolide. Parthenolide a NF-κB inhibitor could contribute to the antiarthritic activity of the plant. Even though, the plant has traditional used in RA, clinical trials have not proved this. ^{[121, 122]}

1.61 Terminalia chebula Retz. (Combretaceae), locally called thunder god of vine and used as stomachic, tonic, carminative, expectorant, anthelmintics, antidysenteric, alternative, and antispasmodic. The plant extract suppresses the expression of TNFα, IL-1β and IL-6.Chebulagic acid isolated from the plant, has antiarthritic effects in animal models of arthritis. ^{[123, 124]}

1.62 Tinospora cordifolia (WILLD.) HOOK.F. and THOMS.(Menispermaceae) is called as Guduchi, has several medicinal properties. It is used by Kandha tribes of Orissa for arthritis in the following formulation as Stem decoction with honey in empty stomach for one month, stem decoction with sesame oil for external application and juice from roots with Ricinus communis and Vanda ruxburgii taken with equal amount of water in empty stomach for 7 days. Alcoholic extract of TC at a dosage of 25μg/ml and Beta-ecdysone isolated from the plant has shown improvements in osteoblastic activity and mineralization of bones. This plant has entered clinical trials, a combination with Zingiber officinale based as polyherb has antiarthritic activity in a 24-week investigator-blind, parallel efficacy, three-arm study in comparison with Hydroxychloroquine. ^{[81,
125-128]}

1.63 Toddalia asiatica (L.) LAM (Rutaceae) known as Orange climber is traditionally used for pain and inflammatory conditions. The reduced levels of proinflammatory cytokines such as TNFα, IL-1β and IL-6 in animal models have represented its antiarthritc potential. ^[129]

1.64 Trewia polycarpa BTH. and HK.F. (Ericaceae) roots are used medicinally. The extract has free radical scavenging activity and anti-inflammatory activity in rodent models^.
[130]

1.65 Trigonella foenum-graecum L (Fabaceae) known as fenugreek and research has shown that the seeds can inhibit cancer of the liver, lower blood cholesterol levels and also have an antidiabetic effect. In arthritic animal models the antioxidant activity of the seeds has been proven. It down-regulates TNF-α induced expression of NF-κB and MMP-9. ^{[131, 132]}

1.66 Tripterygium wilfordii Hook F (Celastraceae) is used for rheumatoid arthritis by Traditional Chinese Medicine. In clinical trials, the efficacy of the plant extract in RA patients had been demonstrated. The phytoconstituents isolated from the plant are tripterine and triptolide. Tripterine causes down regulation of TNFα and IL-1β, and triptolide prevents bone destruction^.[133-137]

1.67 Uncaria tomentosa (Willd. ex Schult.) DC (Rubiaceae) is popularly known as cat’s claw and the plant extract has various medicinal uses such as anti-inflammatory, immunomodulatory, pro-apoptotic, and antioxidant. As an adjunct to conventional therapies, the extract proved to reduce the tender joint count and improve disease activity in RA patients. ^[138]

1.68 Urtica dioica L (Urticaceae) is popularly known as stinging nettle. Leaf, flower, sees and roots of the nettle are used medicinally. 13-Hydroxyoctadecatrienic acid isolated from the leaf extract has antirheumatic activity by suppressing MMPs in human chondrocytes. ^[139]

1.69 Vitex negundo L (Verbenaceae) is a woody, aromatic shrub having medicinal value is a shrub. For treatment of arthritis root decoction twice daily in empty stomach is used by Kandha tribes of Orissa, external application of warm leaves by Khasi, Jaintia, and Garo tribes of Meghalaya and Korku, Gond, Ghaiki and Bhaira tribes of Madhya Pradesh use boiled leaves in water. Agnuside an iridoid glycoside from the plant had anti-inflammatory activity mediated through suppression of Th1/Th2 mediated cytokines. Docking studies had proved antiinflammatory activity of Tris (2,4-di-tert-butylphenyl) phosphate, isolated from the leaves of the plant. ^{[81, 140, 141]}

1.70 Vitis vinifera L (Vitaceae) is called as grapes. It contains resveratrol and proanthocyanidins, which inhibit the matrix degrading enzymes and prevents bone destruction in animal models of arthritis. ^[142-145]

1.71 Withania somnifera DUNAL (Solanaceae) also known as aswagandha or Indian ginseng, used in anxiety, neurological disorders, inflammation, Parkinson’s disease and also as adjunct for chemotherapy. Much of ashwaganda’s pharmacological activity has been attributed to two main withanolides, withaferin A and withanolide D. A typical dose of ashwagandha is 3-6 grams daily of the dried root, 300-500 mg of an extract standardized to contain 1.5 percent withanolides, or 6-12 ml of a 1:2 fluid extract per day. Korku, Gond, Bhils, Bhilalas, Naik, Mankar and Nihal of Madhya Pradesh use stem juice with water and Bhilla tribes of Maharashtra uses the plant powder with one cup of water once daily for the treatment of arthritis. The plants extract suppressed proinflammatory cytokines TNF-alpha, IL-β. ^{[19, 146-148]}

1.72 Zingiber officinale ROSC (Zingiberaceae) called ginger, is used in India and China for variety of purposes such as headaches, nausea, rheumatism, and colds. It is used by the Bhilla tribes of Maharashtra for treatment of arthritis and the formulation used is powdered ginger with Apium graveolens fruits and seeds of Caesalpinia bondus L without seed coat, taken in equal proportion. 6-Shogaol inhibits proinflammatory signaling and expression of cytokines, nitric oxide and suppression of rat paw edema in animal studies. Essential oil from the rhizome is also used as massage for relief of pain. ^{[19, 149, 150]}

The plants which are used by Indian tribes for rheumatism, but not scientifically validated for antiarthritic activity are Cissus quadrangularis, Hedychium spicatum, Juglans regia, Luffa echinata, Ricinus communis, Vetiveria zizanioides, and Wattakaka volubilis. ^{[24, 81, 146, 152-154]}

TABLE-1: Herbal drugs reported Pre-Clinically for treatment of arthritis (In vivo studies)

Herbal drug	Family	Parts used in arthritis	Compound isolated / Extract	*In vivo* model	Mechanism of action	Reference
Akebia quinata (HOUTT) DECNE	Lardizabalaceae	Stem	Methanolic extract of whole plant	AIA	Inhibition of TNFα	[5][6]
Ananas comosus (L.) MERR.	Bromeliaceae	Stem	Bromelain	CIA	Inhibition of TNFα	[12]
Argyreia speciosa SWEET	Convulvulaceae	Roots	Ethanolic extract	AIA	Decrease PGE2 production	[21]
Azima tetracantha LAM	Salvadoraceae	Leaves, roots	Friedelin	AIA	Free radical scavenging	[27]
Boerhavia diffusa L	Nyctaginaceae	Roots	Punarnavine	LPS induced Balb/c mice	Inhibition of TNF-α, IL-1beta, and IL-6	[31][32]
Brassica alba (L.) RABENH	Brassicaceae	Seeds	3,3'-Diindolylmethane	AIA	RANKL inhibition	[39]
Calotropis gigantea (L.) R.BR.	Apocynaceae	Latex	Lupeol	AIA	Decreases TNF-α, IL-1β, IL-6 and increases IL-10	[40]
Calotropis procera R.Br	Asclepiadeae	Latex, leaves, roots, root bark and flowers	Methanolic extract	AIA	Decreases PGE2, TNF-alpha, and nitric oxide	[41]
Camellia sinensis (L.) O.KUNTZE	Thecaceae	Leaves	(-)-Epigallocatechin-3-gallate	CIA	Inhibition of signaling mediated by B cell-activating factor belonging to the TNF family	[42]
Cannabis sativa	Cannabaceae	Flowers	Cannabidiol	RA patients	TNFα inhibition	[43]
Cardiospermum halicacabum L	Sapindaceae	Leaves	Ethanolic extract	AIA	Antioxidant	[44][45]
Cedrus deodara (ROXB.) LOUD	Pinaceae	Wood oil	Aqueous extract	AIA	Inhibition of leukotriene synthesis	[46]
Chrysanthemum indicum L	Asteraceae	Flower	(TFC)	AIA	Antioxidant and apoptosis of RAFLs	[49]
Cissampelos pareira L	Menispermaceae	Root	Aqueous ethanolic extract	AIA	Antioxidant	[50]
Citrus paradisi MACF	Rutaceae	Fruit	Naringin Hesperidin 7, 3'-dimethoxy hesperetin	CIA AIA	Antioxidant activity and RAFLs apoptosis	[51][52] [53][54]
Cleome gynandra L.	Cleomaceae	Leaves	Ethanolic extract	AIA	TNFα inhibition and Antioxidant activity	[55][56]
Clerodendrum phlomidis L.F	Fabaceae	Leaves	Ethanolic extract	AIA	Lysosomal membrane stabilizaton	[57]
Costus speciosus (KOEN. EX RETZ.) SM.	Costaceae	Aerial parts	Methanolic extract	AIA	NF-κB inhibition	[62][63] [64]
Gaultheria yunnanensis	Ericaceae	Stem	n-Butanol extract	AIA	Suppression of TNF-α and IL-1β	[74]
Gentiana macrophylla	Gentianaceae	Whole plant	Gentiane	LPS induced rats	Inhibition of TNFα and IL-6	[75]
Glycine max (L.) MERR	Fabaceae	Legume	Genistein / Dazidzein	CIA	Down-regulation of MAPK signal transduction	[76][77]
Harpagophytum procumbens DC	Pedaliaceae	Roots	Harpagoside	CFA	Inhibition of COX-2, leukotrienes, TNFα and IL-1β	[78]
Hemidesmus indicus (L.) SCHULT	Apocynaceae	Roots	Hydroalcoholic extract	AIA	Antioxidant activity	[79][80]
Leucas aspera (WILLD.) SPRENG	Lamiaceae	Whole plant	Ethanolic extract	AIA	TNFα suppression and antioxidant activity	[81][82] [83]
Lithospermum erythrorhizon L	Boraginaceae	Roots	Shikonin	CIA	Inhibition of MMPs	[84]
Moringa oleifera LAM.	Moringaceae	Leaves	Aurantiamide acetate 4 and 1,3-dibenzyl urea 5	AIA	Down-regulation of RF, TNF-alpha, IL-1, and IL-6	[62][87] [88]
Nyctanthes arbor-tristis L	Oleaceae	Whole plant	Aqueous extract	AIA	TNFα inhibition	[92]
Ocimum sanctum	Lamiaceae	Whole plant	Ursolic acid	AIA	TNFα inhibition	[93][94]
Paeonia lactiflora Pall	Paeoniaceae	Roots	Paeoniflorin	AIA	Inhibition of IL-1, IL-6, PGE2	[97][98]
Plectranthus ambonicus (LOUR.) SPRENG	Lamiaceae	Leaves	Rosmaric acid	CIA	TNFα and RANKL suppression	[103] [104]
Plumbago zeylanica L	Plumbaginaceae	Roots	Plumbagin	CIA	Stimulates Th1 cells and antiinflammaoty cytokines	[105] [106]
Pongamia pinnata (L.) PIERRE	Fabaceae	Seeds	Hexane extract	AIA	Suppression of NF-κB	[107] [108] [109]
Prunus sp	Rosaceae	Fruits	Cyanidin Anthocyanins	AIA	Antioxidant activity	[110]
Silybum marianum GAERTN	Asteraceae	Whole plant	Silymarin (mixture of flavonolignans)	AIA	Leukotriene inhibition	[117]
Strychnos nux-vomica L.	Loganiaceae	Seeds	Brucine and Brucine-N-Oxide	AIA	Blocking MAPK signaling	[119]
Swertia chirayita ROXB. EX (FLEMING) KARST	Gentianaceae	Whole plant	Mangiferin	AIA	Suppression of TNF-alpha, IL-1beta, IL-6 and elevation of IL-10	[120]
Terminalia chebula RETZ. and WILLD	Combretaceae	Seeds	Chebulagic acid	CIA	TGFβ elevation	[123] [124]
Toddalia asiatica (L.) LAM	Rutaceae	Roots	Ethanolic extract	CIA	Decrease in TNF-α, IL-1β, IL-6 and IL-10 elevation	[129]
Trewia polycarpa BTH. and HK.F.	Ericaceae	Roots	Alcoholic extract	AIA	Antioxidant activity	[130]
Trigonella foenum-graecum L.	Fabaceae	Seeds	Mucilage	AIA	Decrease IL-1α, IL-1β, IL-2, IL-6 and TNF-α levels	[131] [132]
Vitex negundo L	Lamiaceae	Leaves	Agnuside	AIA	Modulate T-cell-mediated cytokines (Th1/Th2)	[81] [140] [141]
Vitis vinifera L	Vitaceae	Fruits	Reservatrol Proanthocyanidin	CIA	Inhibiting Th17 and B-cell function	[142] [143] [144] [145]

AIA, adjuvant-induced arthritis; CIA, collagen-induced arthritis; FIA, formalin-induced arthritis; LPS, lipopoysaccharide; NF-κB, nuclear factor-kappaB; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin (IL)-1β; IL-6 interleukin (IL)-6; IL-10, interleukin (IL)-10; MCP-1, monocyte chemotactic protein-1; PGE2, prostaglandin E2; MMP, Matrix metalloprotein; AP-1, Activator protein-1; RAFLs, Rheumatoid arthritis fibroblast-like synovicytes; NO, nitric oxide; RANKL, receptor activator of NF-κB ligand; MAPK, Mitogen activated protein kinase; Th-1, T-helper cell-1; Th-2, T-helper cell-1; Th-17, T-helper cell-17

TABLE-2:Herbal drugs reported Pre-Clinically for treatment of arthritis (In vitro studies)

Herbal drug	Family	Parts used in arthritis	Compound isolated / Extract	*In vitro* model	Mechanism of action	Reference
Alpinia galanga (L.) WILLD	Zingiberaceae	Rhizome	1′-acetoxychavicol acetate	Human synovial fibroblasts	Suppress IL-1β induced MMPs	[9][10] [11]
Andrographis paniculata	Acanthaceae	Roots, leaves,flowers and seeds	Andrographolide	RAFLs	RAFLs apoptosis	[13][14][15]
Anethum graveolens L	Apiaceae	Leaves	Quercetin	RAFLs	Inhibits synovial fibroblasts proliferation and MMPs, COX-2, and PGE2 production	[16][17][18]
Apium graveolens L	Apiaceae	Leaves	Apiin	LPS-activated J774.A1 cells	Decrease iNOS	[19][20]
Artemisia absinthium L	Asteraceae	Whole plant	5,6,3',5'-tetramethoxy 7,4'-hydroxyflavone	LPS induced RAW 264.7 and LPS-treated human RAFLs	RAFLs apoptosis	[22][23]
Azadirachta indica A. JUSS	Meliaceae	Whole plant	Epoxyazadiradione Azadirachtin	LPS induced RAW 264.7 cells	Inhibition of MMIF, NF-κB	[24][25] [26]
Commiphora wightii	Burseraceae	Resin	Guggulosterone	RAFLs	Inhibition of NF-κB, iNOS, and RANKL	[58][59] [60][61]
Dioscorea aculeata L	Dioscoreaceae	Tuber	Diosgenin	RAFLs	RAFLs apoptosis	[70]
Ficus carica	Moraceae	Leaves	Hexane soluble fraction	RAW264.7 cells and macrophages	Inhibitor of osteoclastogenesis in RANKL	[73]
Matricaria chamomilla L	Asteraceae	Flowers	Aqueous extract	THP1 macrophages	Inhibition of proinflammatory biomarkers	[85][86]
Tanacetum parthenium	Asteraceae	Whole plant	Parthenolide	RAFLs	NF-κB inhibition	[121] [122]
Urtica dioica L.	Urticaceae	Leaves	13-Hydroxyoctadecatrienic acid	Human chondrocytes	Suppression of MMPs	[139]

IL-1β, interleukin (IL)-1β; RAFLs, Rheumatoid arthritis fibroblast-like synovicytes; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; MMIF, Macrophage migration inhibitory factor; NF-κB, nuclear factor-kappaB; RANKL, receptor activator of NF-κB ligand; THP-1, T-helper cells-1

TABLE-3 : Herbal drugs reported Pre-Clinically for treatment of arthritis (In vitro and In vivo studies)

Herbal drug	Family	Parts used in arthritis	Compound isolated / Extract	*In vivo* model	*In vitro* model	Mechanism of action	Reference
Allium sativum L	Amaryllidaceae	Bulb	Thiacremonone	AIA	LPS induced RAW264.7	NF-κB inhibition	[8]
Bacopa monnieri (L.) PENNELL	Scrophulariaceae	Leaves	Baocside-A Betulinic acid	CIA	LPS induced peripheral blood mononuclear cells	TNF-α, IL-6 and nitrite reduction, NF-κB inhibition	[28][29][30]
Boswellia serrata Roxb	Burseraceae	Resin	Acetyl-11-ketobeta- boswellic acid	RA patients	Human microvascular endothelial cells	Inhibition of TNF-α and MMPs	[33][34][35][36][37][38]
Celastrus paniculatus WILLD	Celastraceae	Seed	Celastrol	AIA	LPS-stimulated human RA-FLSs	Decreases RANTES, MCP-1, TNFα and IL-1β, NF-κB and MMPs	[19][47][48]
Curcuma longa L	Zingiberaceae	Rhizome	Curcumin	CIA	RAFLs	RAFLs apoptosis	[65][66][67][68][69]
Ephedra sinica STAPF	Ephedraceae	Whole plant	Aqueous extract	AIA	LPS induced macrophage	Suppression of TNFα, IL-6	[71][72]
Nigella sativa L	Ranunculaceae	Whole plant	Thymoquinone	AIA	RAFLs	Suppression of TNFα, IL-1β	[89][90][91]
Olea europea L	Oleaceae	Leaves	Hydroxyl tyrosol Oleuropein aglycone	CIA	LPS induced RAW264.7	NF-κB inhibition	[95][96]
Piper longum L.	Piperaceae	Fruits	Piperine	CIA	RAFLs	Decreases IL-1β, TNF-α, PGE2 Increases IL-10	[99][100] [101][102]
Salacia reticulata WIGHT	Celastraceae	Bark	Aqueous extract	CIA	MTS-C H7 cells	Decreases IL-1β and anti-osteoclastic	[112][113]
Semecarpus anacardium L. F	Anacardiaceae	Seed	Nut milk extract	AIA	LPS activated RAW 264.7	Decreases NF-κB, TNFα, NO	[115][116]
Sphaeranthus indicus	Asteraceae	Whole plant	7-hydroxy frullanolide	CIA	LPS stimulated PMNs	NF-κB inhibition	[118]
Tinospora cordifolia (WILLD.) HOOK.F. and THOMS.	Menis permaceae	Whole plant	Alcoholic extract	RA patients	Human osteoblast-like cells MG-63	Osteogenesis and anti-osteoporotic	[81][125] [126][127] [128]
Tripterygium wilfordiiHOOK F	Celastraceae	Whole plant	Triptolide Tripterine	RA patients	Human osteoblast-like cells MG-63	TNFα and IL-1β inhibition	[133][134] [135][136] [137]
Withania somnifera DUNAL	Solanaceae	Roots	Withaferin A	CIA	LPS activated RAW 264.7 RAFLs	NF-κB and AP-1 inhibition	[19][146] [147[148]
Zingiber officinale ROSC	Zingiberaceae	Rhizome	6-Shogaol Gingerol	AIA	LPS activated RAW 264.7 Macrophages	Reduction of TNFα, IL-1β, NO	[19][149] [150]

NF-κB, nuclear factor-kappaB; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin (IL)-1β; IL-6 interleukin (IL)-6; IL-10, interleukin (IL)-10; MCP-1, monocyte chemotactic protein-1; PGE2, prostaglandin E2; MMP, Matrix metalloprotein; AP-1, Activator protein-1; RAFLs, Rheumatoid arthritis fibroblast-like synovicytes; NO, nitric oxide; RANKL, receptor activator of NF-κB ligand

TABLE – 4: Clinically proved medicinal plants for rheumatoid arthritis

Herb	Clinical trial design	Result	Reference
*Monoherb*
Andrographis paniculata	Prospective, randomized, double blind, and placebo-controlled study	Insignificant improvement in joint pain	[14]
Boswellia serrata	Placebo controlled	Insignificant improvement in joint pain	[38]
Cannabis sativa	Placebo controlled	Significant improvement in pain relief and disease activity	[43]
Rosa canina	Placebo controlled	Measures of disease activity, quality of life, physical function and physician global assessment all improved	[111]
Tanacetum parthenium	Placebo controlled	Greater improvement in grip strength	[122]
Tripterygium wilfordii	Comparative	Significant improvement in disease activity
Uncaria tomentosa	Placebo controlled	Adjunct to DMARDs, greater reduction in tender joint count	[138]
*Combinations*
Tinospora cordifolia and Zingiber officinale	Comparative study	Significant improvement in pain relief and disability score	[127]

2. CONCLUSION:

Rheumatoid arthritis is a multifactorial disease and excessive production of some inflammatory mediators may lead to the clinical features of the disease. Natural herbs could be better antiarthritic agents which act at the different stages of the process of inflammation. It is clear from the above description that herbal extracts and their phytoconstituents target specific defined inflammatory mediators in arthritis. The use of plant products in treatment of arthritis is based on clinical and pharmacological trials in animal models and cell-line studies. Thus plant and phytomedicine are important remedies in arthritis and various phytoconstituents like flavonoids, saponins, tannins, terpenoids, xanthonoids, lignans and phenolic compounds showed their antiarthritic activity. Herbs are reservoir of potentially useful chemical compounds, which could serve as lead molecules for modern drug research. Thus the future depends on the effective use of medicinal plants to improve therapeutic outcome in rheumatoid arthritis.

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Received on 01.02.2014 Modified on 28.02.2014

Res. J. Pharmacognosy & Phytochem. 6(2): April-June 2014; Page 51-65