Antirheumatic mechanisms of action of
Rheumatoid arthritis (RA) is a chronic inflammatory and debilitating joint disorder that causes severe impairment and reduces the quality of life. The available synthetic medicines used as standard therapy for RA have numerous side effects that can compromise their therapeutic outcomes. Thus, the demand for alternative and complementary medicines is increasing. A search of English articles in PubMed, Scopus, Google Scholar, and Web of Science databases was carried out on probable mechanisms of action of herbs with the antirheumatic property. Herbal medicines stated in folk medicine face acceptance concerns by the medical community because of the lack of scientific documents regarding their physio-pharmacological mechanisms. This chapter aims to review the possible antirheumatic effects of various herbs, including Rosmarinus officinalis L., Curcuma longa, and Crocus sativus, their related mechanisms, and preclinical applications, in order to recall the therapeutic properties of herbal medicine. However, more clinical trials are required to confirm the safety and efficacy of these antirheumatic herbal medicines.
- rheumatoid arthritis
- herbal medicine
- folk medicine
- complementary drugs
- physio-pharmacological effects
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that can strike men and women at any age . About 1% of the world’s population has been affected by RA, which has resulted in progressive articular damage, permanent impairment, and even reduced life expectancy . Genetic and environmental factors have important roles in the aetiopathogenesis of RA . The pathophysiology of RA is complex and mainly focuses on autoimmune response and inflammation . The reactive oxygen species (ROS) damage proteins such as collagen and denature immunoglobulins that both might become autoantigens in RA . Autoantibodies against immunoglobulin G (IgG) (also called rheumatoid factors (RFs)) and autoantibodies against citrullinated peptides (ACPAs) are two types of autoantibodies that can cause complement activation in RA patients [6, 7]. It was suggested that increased circulating ACPAs can promote bone loss by activating macrophages, producing B cells, organizing immune complexes or binding membrane citrullinated vimentin [8, 9, 10, 11] which consequently ease the shift from autoimmunity to inflammation. Inflammation of the synovial membrane in RA is made up of both innate and adaptive immune cells . The majority of immune responses are regulated by cytokines and chemokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF) which can induct or intensify the inflammatory response of the synovial compartment .
Disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) are currently available drugs for RA . Antirheumatic medications that are currently available for RA treatment target the inflammation and tissue swelling resulting from the disease. However, the majority of patients still experience extreme pain and physical impairment. These drugs are ineffective in preventing cartilage degradation and joint damage . It was also reported that taking two or more biologic DMARDs at the same time, or a biologic DMARD with a nonbiologic DMARD, increases the risk of severe infections or cancer . Other investigations have also illustrated the cardiovascular  and ocular  adverse effects of antirheumatic drugs. Therefore, the development of safe, fast-acting antirheumatic medicines is required.
Complementary and alternative medicine methods are now thought to provide adjuvant therapies to improve the chances of full remission of RA [19, 20]. Several herbal medicines have displayed pre-clinical and clinical antirheumatic properties including
Thus, searching for herbal medicines with antirheumatic properties could be an advantageous method to find effective antirheumatic medicines with fewer side effects. The detailed information about medicinal herbs and their physio-pharmacological mechanisms of action is summarized in this chapter.
The present chapter mainly emphasizes the published original articles implicating the therapeutic and beneficial effects of herbs on rheumatoid arthritis. The data (Google Scholar, PubMed, and Scopus) search has been carried out by searching related keywords, including “rheumatoid arthritis”, “rosemary”, “
2.1 Herbal antirheumatic medicines
In folk medicine, numerous plants have been used because of their antirheumatic properties. Researchers are currently focusing on evaluating and characterization of different plants and their components to treat RA. The aim of this section of the chapter is to review the mechanism of action of a number of medicinal plants that have antirheumatic properties.
Rosmarinus officinalisL. (rosemary)
A former study indicated that administration of water-soluble compounds of rosemary reduced oxidative stress (by enhancing the glutathione (GSH) level and the GSH/glutathione disulfide (GSSG) ratio) and inflammation (paw edema, number of leukocytes in the femorotibial joint cavities, secondary lesions score, adrenal glands, inguinal lymph nodes, and popliteus lymph nodes weights) in rats with adjuvant-induced arthritis . Carnosic acid, a major phenolic compound isolated from rosemary (5 mg/kg, 2 weeks, i.p.), administration to collagen-induced arthritis rats inhibited inflammation response and joint destruction by decreasing the amounts of TNF-ɑ, IL-1β, IL-6, IL-8, IL-17, matrix metalloproteinase-3 (MMP-3), and receptor activator of nuclear factor kappa-Β ligand (RANKL)  (Table 1). Moreover, it was observed that a methyl ester derivative of rosmarinic acid, a constituent of rosemary (50 mg/kg/day, 15 days, i.p.), has a potent anti-arthritic property in collagen-induced arthritis mice via its anti-inflammatory and immunosuppressive effects .
|Herbal medicine||Antirheumatic Mechanism(s)||Reference|
|↑ GSH level|||
|↑ GSH/GSSG ratio|
|↓ Number of leukocytes in the femorotibial joint cavities|
|↓ TNF-α, IL-1β, IL-6, IL-8, IL-17, MMP-3, RANKL|||
|↓ Erythrocyte sedimentation rate|||
|↓ C-reactive protein||[25, 26]|
|↓ PGE2, COX-2, TNF-α, and IL-1|
|↑ Bax, caspase 3, 9|||
|↓ Erythrocyte sedimentation rate|||
|↓ C-reactive protein|
|↓ TNF-α, IFNγ|
|↓ Lipid peroxides|
|↑ Catalase and glutathione peroxidase||[30, 31, 32, 33]|
|↓ IL-1β, IL-6, IL-17, IL-8, NF-κB|
|↑ SOD, GR|
Another study has reported that rosmarinic acid triggers apoptosis via mitochondrial pathway in activated T cells taken from rheumatoid arthritis patients .
Curcuma longaL. (turmeric)
A clinical trial was carried out on 45 patients with RA to investigate the antirheumatic effect of curcumin at the dose of 500 mg for 8 weeks. Curcumin improved disease activity and the American college of rheumatology scores . Another clinical trial reported that curcumin in a turmeric matrix (250 mg, twice daily, 90 days) was an advantageous agent in managing RA by its analgesic and anti-inflammatory properties. Curcumin improved erythrocyte sedimentation rate, C-reactive protein, visual analog scale, rheumatoid factor, and American College of Rheumatology responses in comparison with the control group . It was also seen that administration of CuroWhite™, a novel hydrogenated curcuminoid formulation, at the dose of 250 mg and 500 mg for 3 months ameliorated RA by its anti-inflammatory and antinociceptive effects which was confirmed by improving erythrocyte sedimentation rate, rheumatoid factor, visual analog scale, and C-reactive protein . A recent clinical study reported that administration of curcumin (200–1000 mg) to patients with RA decreased pain, fatigue, stiffness, and swelling . The results of a clinical trial indicated that the prescription of BioSOLVE Curcumin™ (250 mg, 12 weeks) to patients with RA improved the American college of rheumatology-20, Western Ontario and McMaster universities osteoarthritis index and visual analogue scale score .
A turmeric extract devoid of essential oils was given to Wistar female rats in an animal model of streptococcal cell wall-induced RA. Injections of an extract containing 4 mg/kg/day total curcuminoids intraperitoneally for four days prior to arthritis induction significantly reduced joint inflammation in both the acute (75%) and chronic (68%) phases . A previous investigation stated that the administration of
The findings of an
The data of an
Crocus sativusL. (saffron)
A clinical trial was carried on 66 women with RA to assess the effect of saffron (100 mg/day, 12 weeks) supplementation on their metabolic profiles and clinical outcomes. According to the obtained data, saffron considerably reduced the number of swollen and tender joints, pain intensity, and disease activity score compared to baseline values. Moreover, erythrocyte sedimentation rate was significantly improved and high-sensitivity C-reactive protein, TNF-α, interferon-gamma (IFNγ), and MDA levels reduced .
A former clinical trial was carried out on 6 patients with RA who took ginger powder (0.5–1 g/day, 3 months). It was found that all six patients reported pain relief, improved joint mobility, decreased swelling, and morning stiffness after three months of continuous ginger intake. There were no side effects recorded by any of the participants, and they all seemed to be happier and more engaged in their daily lives . Another study investigated the effect of ginger on 56 RA patients. The findings revealed that after taking ginger (50 g/day raw/fresh, 3 months-2.5 years) more than three-quarters of participants reported pain and swelling relief to varying degrees. Also, all the subjects with muscular discomfort experienced pain relief. The authors suggested that at least one of the mechanisms by which ginger exerts its beneficial effects is thought to be linked to inhibition of prostaglandin and leukotriene biosynthesis, implying that it acts as a dual eicosanoid biosynthesis inhibitor . The results of another study demonstrated that ginger powder (1500 mg, 12 weeks) administration ameliorated RA by reducing disease manifestations through controlling immunity factors, for instance enhancing the gene expression of forkhead box P3 (FoxP3), as well as attenuating RAR-related orphan receptor gamma (RORγt), and T-bet genes expression .
Ginger extract was found to be an advantageous anti-inflammatory agent in an
Nigella sativa(black seed, black cumin)
The efficiency of
|Herbal medicine||Antirheumatic Mechanism(s)||Reference|
|↓ Prostaglandin and leukotriene|||
|↓ RORγt, and T-bet||[48, 50]|
|↓ IL-iβ, IL-2, IL-6, TNF-α, NF-κB, TGF-β, hs-CRP, and anti-CII antibodies|
|↓ JAK3 phosphorylation|
|↑ CD4+CD25+ T cell, CD4+/CD8+ ratio|||
|↓ TNF-α, IL-iβ|||
|↓ PGE2, TNF-a, IL-ib, IL-6, IFN-c, TNF-α-induced phospho-p38 and phospho-JNK|||
|↓ MPO, elastase activity, lipid peroxidation, articular nitrite content|
|↑ GSH and SOD|
|↓ NFκB, TLR2, and TLR4|||
|↓ Oxidative stress|||
|↓ Blood leukocytosis and erythrocyte sedimentation rate|||
|↓ Free radical levels|||
|↓ IL-iβ, IL-6, IL-8, and COX-2|||
Evaluating the effects of thymoquinone, the volatile oil of black cumin (2.5, 5 mg/kg, 14 days, p.o.), on RA model in rats disclosed that signs of inflammation on the claw and the amounts of TNF-α, as well as IL-1β decreased in treatment groups . Thymoquinone (5 mg/kg, 21 days, p.o.) treatment in the collagen-induced arthritis in Wistar rats could considerably reduce the amounts of pro-inflammatory mediators including PGE2, TNF-a, IL-1b, IL-6, Interferon-c (IFN-c), and increased IL-10 level. Thymoquinone also decreased arthritis scoring and improved bone histology . Administration of the aqueous methanolic extract of black seed (400, 500 mg/kg, 20 days, p.o.) to arthritic rats decreased myeloperoxidase (MPO), elastase activity, lipid peroxidation, articular nitrite content, and increased GSH and SOD amounts . In another rat model of RA,
Camellia sinensis(green tea)
Evaluating the therapeutic effects of green tea (0.5, 1.0 g/kg, 24 days, p.o.) on articular/extra-articular difficulties in rat adjuvant-induced arthritis revealed that the arthritis severity and complications besides oxidative stress ratio in synovial fluid were significantly reduced . In another
Herbs are spread in different geographical and ecological throughout the world. Since the olden days several traditional herbs have been utilized for treating plenty of ailments. The number of medicinal plants that have antirheumatic properties is comparable to potent synthetic antidepressants. The antirheumatic effects of plants have been linked to their antioxidant, anti-inflammatory, analgesic properties. Furthermore, polyherbal formulations might be more effective due to their possible additive and/or synergistic effects and could be employed for ameliorating mild to moderate RA. As a result, it is possible to conclude that medicinal plants are at the center of nature and that more research is required to determine their therapeutic value.
|ACPAs||autoantibodies against citrullinated peptides|
|CD4+ T cell||T helper cells|
|CII||collagen type II|
|DMARDs||disease-modifying anti-rheumatic drugs|
|FoxP3||forkhead box P3|
|hs-CRP||high-sensitivity C-reactive protein|
|iNOS||inducible nitric oxide synthase|
|JAK3||Janus kinase 3|
|JNK||c-Jun N-terminal kinases|
|MAPK||mitogen-activated protein kinase|
|NFATC1||Nuclear Factor of Activated T Cells 1|
|NF-κB||nuclear factor kappa B|
|RANK||Receptor activator of nuclear factor kappa B|
|RANKL||receptor activator of nuclear factor kappa-Β ligand|
|RORγt||RAR-related orphan receptor gamma|
|ROS||reactive oxygen species|
|TGF-β||transforming growth factor-beta|
|TLR||toll like receptor|
|TNF||tumor necrosis factor|