Use of Herbal Medications for Treatment of Osteoarthritis and Rheumatoid Arthritis

Arthritis is a chronic condition that affects nearly a quarter of the United States population. Osteoarthritis (OA) and rheumatoid arthritis (RA) are two major forms of arthritis associated with severe joint pain and reduced quality of life. Various pharmacological interventions may be utilized for arthritis treatment when non-pharmacological therapy is insufficient. However, pharmacological therapy can be associated with serious side effects and high costs. Therefore, alternative therapies have been under investigation. Herbal medications have shown the potential for safe and effective management of arthritis. For this review, we attempt to summarize the mechanisms, safety, and efficacy of herbal treatments for OA and RA. After searching electronic databases, we identified nine herbs among 23 clinical trials used for the treatment of OA or RA patients. Improvement of OA and RA symptoms, pain, and inflammation was demonstrated. The herbs exhibited strong anti-inflammatory and anti-oxidant activities, contributing to a reduction in inflammation and tissue damage. Several herbs elucidated new mechanisms for OA and RA treatment as well. Though these herbs have shown promise for OA and RA treatment, more studies and clinical trials are required for determining safety and efficacy, bioactivity, and optimal bioavailability.


Introduction
Arthritis is a common health issue that affects millions of people in the United States [1]. Patients suffering from arthritis struggle with severe joint pain and nearly half of all adults with arthritis experience persistent pain [1,2]. More than 100 types of arthritis have been identified [3]. Two of the most common types are osteoarthritis and rheumatoid arthritis. Both osteoarthritis and rheumatoid arthritis impair joint structure and function but differ in symptoms, pathophysiology, and treatment (Table 1).
Osteoarthritis (OA), also known as degenerative joint disease, is the most common form of arthritis [4]. OA is a biomechanical and inflammatory disease influenced by several factors such as mechanical and oxidative stress, injury, age, obesity, and metabolic disease [5]. OA is characterized by joint cartilage degeneration, changes in the underlying bone, and synovitis [6]. Pro-inflammatory and pro-catabolic mediators are found localized in synovial fluid and hydrolytic enzymes, such as matrix metalloproteinases (MMPs), are associated with cartilage degeneration. Extracellular matrix breakdown can trigger the accumulation of innate immune cells that lead to inflammation and tissue destruction [7]. Signaling pathways and responses, such as those involving nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK), have also been found to play a role [5]. OA has a slow

Materials and Methods
Electronic databases including PubMed, Google Scholar, and ClinicalTrials.gov were searched using general keywords such as "herb", "arthritis", "pain", "inflammation" and "clinical trial". We also conducted our search by using specific herb names. Only papers published after the year 2000 with full English text were included. We excluded clinical trials that tested formulations with 4 or more combined herbs. A total of 23 clinical trials including 9 herbs: Boswellia spp., Curcuma spp., Eremostachys laciniata, Eucommia ulmoides, Matricaria chamomillia L., Paeonia lactiflora, Tripterygium wilfordii Hook F, Withania somnifera, and Zingiber officinale were reviewed. The results of these clinical trials are summarized in Table 2.

Results
A search for safer alternatives to pharmacological therapy in OA and RA management has gained momentum in the 21st century (Table 2). Natural medicines found all over the world are actively being investigated for their safety and efficacy. Recently, studies have reported novel mechanisms of herbal therapy in targeting arthritis pain and inflammation. Moreover, positive clinical outcomes have been reported in response to herbal treatment. This section will provide an overview of a significant role in treating OA and RA.

Clinical Trials Using Single Herb
Boswellia, also known as frankincense, has been used for centuries in traditional Ayurvedic medicine. This herb exhibits anti-inflammatory activity, including inhibition of microsomal prostaglandin E2 (PGE2) synthase-1 and 5-lipoxygenase, reducing production or activation of inflammatory mediators such as matrix metalloproteinase (MMP)-9, MMP-13, cyclooxygenase (COX)-2, and nitric oxide (NO), as well as analgesic and anti-arthritic effects [23,24]. Boswellia is thought to exert its beneficial effects on arthritis by improving the knee joint gap, reducing osteophytes, and attenuating inflammatory mediators, such as C-reactive protein and hyaluronic acid, associated with knee OA [25,26].
The safety and efficacy of Boswellia serrata have been investigated in several studies. Majeed et al. found that OA patients receiving oral B. serrata extract for 8 weeks demonstrated significant improvement in their Visual Analog Scale (VAS), Japanese Knee Osteoarthritis Measure (JKOM), and their Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in comparison to placebo [26]. Another clinical trial found that oral supplementation of Boswellia extract for more than 4 months also significantly improved physical function by reducing pain and stiffness in OA patients compared to placebo, without causing serious adverse events [25]. Most recently, Razavi et al. found that the topical application of Boswellia Carterii B. (oliban oil) was associated with a significant improvement in OA pain and symptoms in comparison to control and diclofenac groups. However, activities of daily living, sport and recreation, and knee-related quality of life did not improve significantly [27].
Roots of Curcuma are used as a spice commonly known as turmeric. Curcumin, a polyphenol extract of turmeric, is well known for its anti-inflammatory and antioxidant effects, and it has a long history of use in traditional Chinese and Ayurvedic medicine [28]. The anti-inflammatory activity of Curcuma may be attributed to multiple mechanisms [29]. Treatment with Curcuma has been found to strongly inhibit the production of inflammatory mediators, such as interleukin (IL)-1, tumor necrosis factor-alpha (TNF-α), IL-8, NO, and a variety of MMPs, via diminishing the activation of NF-κB, protein kinase B (Akt), and MAPK signaling pathways [29,30]. Curcuma has also demonstrated a COX-2 inhibition, leading to a reduction of prostaglandin synthesis [31] Recently, Curcuma extracts and curcumin have been studied extensively for their anti-osteoarthritic effects. Kuptniratsaikul et al. demonstrated that patients randomized to Curcuma domestica experienced significant improvement in WOMAC scores in comparison to baseline over a 4-week period and less abdominal pain and discomfort compared to ibuprofen [32]. Another trial demonstrated that curcumin had comparable efficacy, but better safety and fewer adverse effects than diclofenac [33]. Curcumin was also associated with a weight-lowering effect, an anti-ulcer effect, and no requirement for histamine H2-receptor antagonists (H2 blockers) [33]. The short-term effects of highly-bioavailable curcumin (Theracurmin) on knee OA were investigated in a randomized, double-blind, placebo-controlled prospective study [34]. After 8 weeks, Theracurmin significantly reduced knee pain VAS scores and celecoxib dependence compared to placebo, with no significant effect on JKOM scores. Slight increases in triglycerides and creatinine as well as decreases in red blood cells and cholinesterase levels were observed in only a few patients [34]. A recent study reported that curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin, combined with diclofenac showed a greater improvement in pain and functional capacity with better tolerability in patients with knee OA [31].

Eremostachys laciniata
Decoctions of the roots and flowers of the Iranian herb, Eremostachys laciniata, is usually given to alleviate inflammatory conditions, including arthritis [35]. The mechanistic action of this herb is unclear. However, one study reported that the treatment with either crude methanol extract or fractions of E. laciniate resulted in a reduction in the inflammatory response induced by carrageenan in rat paw [36]. The aqueous extract of E. laciniate has also shown promising antioxidant activity as indicated by a strong DPPH radical-scavenging activity and reduction of H 2 O 2 -or HOCl-luminal chemiluminescence [37].
One study has investigated the effects of topical E. laciniata application on arthritis pain and symptoms [35]. This single-blinded, randomized clinical trial indicated that the application of 0.5% E. laciniata ointment to affected joints over 2 weeks significantly reduced VAS pain scores for arthritis and RA patients when compared to the application of control ointment. In comparison to a 0.5% piroxicam ointment, pain scores were lower for arthritis and RA patients applying E. laciniata for 1 week, indicating a better initial therapeutic response. However, after 2 weeks, pain scores were similar between E. laciniata and piroxicam groups. Over the whole study period, E. laciniata treatment was associated with a greater reduction in joint inflammation in comparison to piroxicam treatment. The researchers also determined that iridoid glycosides were the most prevalent isolates from their E. laciniata extracts and proposed that the anti-inflammatory activity observed in their arthritis patients may have been due to these compounds [35].
Most recently, Eucommia, in combination with meloxicam, exhibited greater effects on pain relief and patient satisfaction compared to the meloxicam monotherapy group [44]. Currently, a 12-week, multicenter, randomized, double-blind placebo-controlled clinical trial is underway to assess the safety and efficacy of an E. ulmoides extract in patients with mild OA [45]. Overall efficacy comparable to diclofenac for OA; weight-lowering, anti-ulcer effect, and reduced requirement for H2 blockers. [33] Curcumin (Theracurmin) curcumin n = 18; placebo n = 23 Curcumin 180 mg/day oral 56 days Reduced OA knee pain VAS scores, but no effect on JKOM scores vs. placebo; Reduced celecoxib dependence. [34]

Eremostachys laciniata
Eremostachys laciniata EL n = 67; piroxicam n = 70 0.5% topical ointment 14 days Reduction in VAS pain scores and joint inflammation for arthritis and RA vs. control and piroxicam; quicker therapeutic response than piroxicam at 1 week; comparable response to piroxicam at 2 weeks  Reduced knee pain on standing and after walking, WOMAC index, and request of rescue medication; improved quality of life. [57] 3.1.5. Matricaria chamomilla L.
Matricaria chamomilla, also known as chamomile, has been used for centuries to treat joint pain [46,47]. The dried flower part of the plant has historically been used in the treatment of rheumatic pain and inflammation [47]. Now, chamomile is on the FDA's "generally recognized as safe" herbs list [46]. As a member of the Asteraceae; Compositae family, Chamomile has two common varieties, German chamomile, and Roman chamomile [58]. The most popular formulation of chamomile is herbal tea [58]. Chamomile contains several phenolic compounds such as apigenin, quercetin, patuletin, luteolin, and glucosides. These compounds show anti-inflammatory action by reducing cytokines and PGE2, which play a role in the pathogenesis of arthritis [47,58].
A randomized, controlled clinical trial was performed to study the safety and efficacy of topical chamomile oil compared to diclofenac and placebo in patients with knee OA [46]. In comparison to diclofenac and placebo, chamomile significantly decreased the need for acetaminophen (the rescue drug) without adverse events, but it did not influence WOMAC questionnaire domain responses [46]. Another trial found that daily consumption of 6 g of chamomile tea was associated with a reduction in tender joints and erythrocyte sedimentation rate compared placebo for RA patients [47].

Paeonia lactiflora
Radix Paeonia, the dried root of P. lactiflora Pallas, has a history of traditional use in Chinese medicine [59]. Decoctions of Radix Paeoniae have been used in the treatment of RA and other inflammatory/autoimmune disorders [59]. Water/ethanol extracts of Radix Paeoniae Alba contain total glucosides of paeony (TGP), consisting mainly of paeoniflorin [60]. Previous studies have demonstrated an inhibition of the production of PGE2, leukotriene B4, NO, ROS, and other pro-inflammatory mediators by TGP and paeoniflorin [59]. Paeonia has also demonstrated anti-inflammatory activity by reducing microvascular permeability and the infiltration of inflammatory cells [59]. The paeoniflorin component of TGP may also inhibit osteoclast differentiation and TNF-α-induced apoptosis via inhibition of NF-κB [61,62].
In a randomized clinical trial, the hepatotoxicity of a combination of methotrexate (MTX), leflunomide (LEF), and TGP with a combination of just MTX and LEF was compared [6]. At the midpoint and end of the study, the combination including TGP was shown to be just as efficacious, with significantly less hepatotoxicity. The hepatoprotective effects of TGP may be associated with its anti-inflammatory ability to reduce TNF-α, IL-6, and C-Reactive Protein (CRP) [60].

Tripterygium wilfordii Hook F
Tripterygium wilfordii Hook F (TwHF) is a Chinese herb that has demonstrated immunosuppressive effects and has historically been used in the treatment of RA. Numerous preclinical studies have shown that extracts from the root of TwHF inhibit the expression of pro-inflammatory cytokines and mediators, adhesion molecules, and matrix metalloproteinases by macrophages, lymphocytes, synovial fibroblasts, and chondrocytes [63,64]. TwHF can also induce apoptosis in lymphocytes and synovial fibroblasts and inhibit their proliferation. The immunosuppressive, cartilage protective, and anti-inflammatory effects of TwHF extracts are well demonstrated, making it a good alternative for patients with RA refractory to conventional therapy [65].
Various extraction methods have been used in an effort to reduce TwHF toxicity and maximize its therapeutic benefit. In initial studies, extractions proved a therapeutic benefit, but frequent adverse events and occasional severe toxicities were reported [66][67][68]. However, one study found that an ethyl acetate (EA) extract (at doses between 180 mg/day and 570 mg/day) and a polyglycoside preparation inhibited joint swelling and suppressed adjuvant arthritis with less adverse events in comparison to other preparations [48,49]. In 2003, Cibere et al. reanalyzed the data from clinical trials conducted before 2002 and confirmed that topical Tripterygium wilfordii appeared to be efficacious in RA [69]. Lv et al. conducted a randomized controlled clinical trial to compare the efficacy and safety of TwHF with MTX in the treatment of RA patients for 24 weeks [70]. They found that patients treated with TwHF alone or in combination with MTX showed a better outcome in achieving the American College of Rheumatology (ACR) 20, 50, and 70 response criteria. A reduction in the 28-Joint Count Disease Activity Score was also shown. Furthermore, the benefits of TwHF monotherapy were observed up to 18 months after study completion [70,71]. Another study found that patients treated with TwHF extract demonstrated a higher response rate and a decreased expression of IL-6 compared to patients receiving sulfasalazine [50]. Several clinical trials have been completed just recently or are ongoing and examining the therapeutic benefits of TwHF in RA (ClinicalTrials.gov).

Withania somnifera
Withania somnifera (Ashwagandha) is an Ayurvedic medicine known for its anti-inflammatory and analgesic effects. W. somnifera extract has been found to inhibit the production of TNF-α, IL-1β, and IL-12 by diminishing the activation of NF-κB and activator protein 1 (AP-1) signaling pathways [72]. W. somnifera extract also slowed the degradation of bovine Achilles tendon type I collagen by inhibiting the activity of collagenase [73]. Treatment with W. somnifera decreased swelling, redness, deformity, and ankylosis in a collagen-induced arthritis rat model [74]. The anti-arthritic activity of W. somnifera may be attributed to its ability to reduce ROS, TNF-α, IL-1B, IL-6, MMP-8, NF-κB activation, and increase IL-10 secretion [75].
Sumantran et al. demonstrated that an aqueous extract of W. somnifera showed a significant chondroprotective effect on damaged human OA cartilage via diminishing the gelatinase activity of collagenases [51]. A recent study has demonstrated its analgesic effects in patients with knee OA [52]. In this 12-week clinical trial, treatment with 125 or 250 mg of W. somnifera extract was associated with significant reductions in the mean WOMAC and Knee Swelling Index in comparison to baseline and placebo. A significant reduction in VAS scores for pain, stiffness, and disability was also observed. The higher dose showed efficacy earlier (at 4 weeks), better physician global assessments (excellent vs. good vs. fair), and less need for rescue medication with paracetamol compared to low dose and placebo [52].

Zingiber officinale
Zingiber offcinale, commonly known as ginger, is strongly associated with relieving inflammatory symptoms [54]. The anti-inflammatory activities of ginger have been widely investigated in patients as well as in vitro and in vivo models. Treatment with ginger has reduced the production of PGE2, NO, IL-1β, IL-12, TNF-α, monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) [76]. Ginger has also inhibited the expression of MHC class II molecules, interferon-gamma (IFN-γ), and IL-2 resulting in inhibition of the antigen-presenting activity of macrophages and T cell function [76]. Aryaeian et al. found that ginger inhibited T cell proliferation and activation by reducing the expression of T-bet and increasing GATA-3 production [77]. Further, studies demonstrated that ginger modulated the activation of NF-κB, COX-1, COX-2, peroxisome proliferator-activated receptor gamma (PPARγ), and lipoxygenase [53,54,77].
Several clinical trials have been performed to assess the effects of ginger on OA pain-relief. Haghighi et al. found that patients treated with 30 mg of ginger extract had lower VAS scores and gelling or regressive pain compared to placebo [56]. Similar results were reported by other clinical trials. One trial revealed that 250 mg ginger orally was superior to placebo at reducing VAS pain scores and morning stiffness [53]. Another study reported that two tablets of 500 mg of ginger daily improved VAS pain scores, significantly increased patient satisfaction, and was associated with no difference in side effects in comparison to control [55]. Another study revealed that ginger extract was associated with reducing knee pain and WOMAC indices, although it was associated with gastrointestinal side effects [57]. Later, Amorndoljai and colleagues found that topical ginger extract significantly improved knee pain, stiffness, physical function, and patient global assessments following 12 weeks of knee OA treatment [54,78].

Clinical Trials Involving Herbal Combinations
There is evidence of synergistic effects when different herbs are combined, including improvement in therapeutic outcomes and safety. Oral supplementation with B. serrata, combined with N-acetyl-D-glucosamine and ginger for 6 months, was found to significantly improve pain-free walking distance and WOMAC signs/symptoms for patients with moderate knee OA in comparison to standard OA management, without safety or tolerability issues [79]. Boswellic acid combined with methylsulfonymethane has been found to improve knee OA pain management and functional recovery and reduce the intake of anti-inflammatory drugs [80]. In a 3-month randomized, placebo-controlled trial comparing the efficacy of curcumin and boswellic acid (Curamin) with curcumin (CuraMed) and placebo, Curamin significantly improved physical performance tests and WOMAC joint pain indices compared to placebo. Moreover, the effect size observed with the curcumin-boswellic complex was greater than that of curcumin alone [81]. Another study examined the effects of a combination of C. longa and B. seratta (CB). They found that CB (500 mg twice daily) was more effective than celecoxib (100 mg twice daily) as demonstrated by improvement in pain scores, walking distance, and joint line tenderness, with effects comparable to celecoxib for alleviating crepitus and increasing joint-range of movement [82]. In both curcumin-boswellia complex trials, tolerability was high, and no serious adverse events were reported [82,83]. In a multicenter, open-label study, a complex of Curcumalonga, Harpagophytum procumbins (Devil's claw), and bromelain reduced VAS scores from baseline for acute and chronic OA patients and provided clinically relevant joint pain improvement, with greater tolerability and no serious adverse events [83]. The effects of ginger on arthritis have also been studied in combination with other herbs. A pilot study with a quasi-experimental design evaluated the effects of a ginger and Acmella oleracea complex on pain and inflammation after 4 weeks [84]. Data showed significant WOMAC, Tegner Lysholm Knee Scoring, physical activity, and fat-free mass improvements. There was a significant decrease in pain intensity in both knees as detected by VAS in both knees and no significant side effects [84].

Other Herbs with Potential for OA and RA Treatment
A few other medicinal plants have been investigated in preclinical studies using cellular and animal models, but have not been tested in clinical trials involving humans. Nevertheless, the mechanisms elucidated by these preclinical trials provide insight into the therapeutic potential of these natural medicines for OA and RA. Species of Angelica, Cinnamon, Glycyrrhiza, and Saposhnikovia have been widely used in traditional Chinese medicine and known for their anti-inflammatory and pain-relieving effects [85][86][87][88]. These herbs diminish the expression of inflammatory mediators, such as IL-1, IL-6, TNF-α, PGE2, and COX-2, via modulation of NF-κB activation and kinase activity in in vitro and in vivo arthritis models [88][89][90][91]. Furthermore, treatment with these herbs has been found to improve cartilage structure and texture, normalize bone remodeling, and inhibit osteoclastogenesis in animal arthritis models. Such findings suggest the beneficial use of these herbs for treating arthritis in human patients.

Discussion
In this review, we have summarized clinical trials demonstrating the effect of herbal medicines when used for OA and RA treatment. We found nine herbs that show promise in improving arthritis symptoms by providing pain relief and a reduction in the inflammatory response and oxidative stress ( Table 3). The major mechanisms of action of these herbs include modulation of inflammatory signaling pathways and regulation of immune cell activity. Though different in pathology and clinical symptoms, both OA and RA are associated with inflammation and oxidative stress. In the pathogenesis of the degenerative joint disease, OA, inflammatory cytokines, such as IL-1, IL-6, and TNF-α, promote the synthesis of collagenase and MMPs resulting in the degradation of collagen type II. RA is a systemic autoimmune disease, in which cytokines play critical roles in regulating the function of macrophages, T cells, and B cells. When used for arthritis, herbs have been found to provide anti-inflammatory and antioxidant activity. Such herbs inhibit pro-inflammatory signaling pathways, including NF-κB, MAPK, and Akt, and enhance anti-inflammatory pathways, such as PPARγ. Therefore, the synthesis of pro-inflammatory cytokines, chemokines, NO, and PGE2 are diminished, while the production of anti-inflammatory cytokines, such as IL-10 and TGFβ, are promoted. As a result, these herbs reduce the activation of immune cells and the activity/production of collagenase and MMPs. These changes can lead to an improvement in OA and RA symptoms. Herbs may also synergistically improve the efficacy of traditional drugs, such as MTX and diclofenac, with a low risk of adverse effects [31].
The herbal medicines that we reviewed may positively impact the management of OA and RA and may be associated with minimal adverse effects. However, several studies reported that herbs caused some side effects, such as hepatotoxicity, gastrointestinal upset (diarrhea, nausea, vomiting, and abdominal pain), dizziness, fatigue, cutaneous reactions, elevated levels of serum aminotransferase, male reproductive toxicity, and alterations in menstruation [31,41,92]. Future studies should investigate the appropriate dosage and duration of herbs for treating OA and RA. Low bioavailability, due to poor absorption, rapid metabolism, or elimination of active components, may also limit the use of herbal medicines [81]. Several approaches have been tested to increase the bioavailability of different herbs [78,81,93]. Recently, nanoparticle-based delivery systems have been applied to ginger extracts to increase its efficacy when used for OA treatment [78]. Mixed purified curcuminoids with turmeric volatile oil have also been found to increase the bioavailability of curcumin in human and animal models [81]. However, the bioavailability of other herbs utilized for OA and RA treatment is poor, and future studies are needed to develop techniques to overcome this issue.

Conclusions
Current pharmacological therapy options recommended for OA and RA are associated with variable efficacy and safety, especially for the treatment of chronic pain and inflammation. Certain herbal medicines may be used as a complementary therapy to work with or reduce the need for pharmacological agents. Treatment with herbal medicines may also offer a safer alternative with equal or superior efficacy.
The anti-arthritic mechanisms of herbs include inhibition of pro-inflammatory and pro-catabolic mediators such as cytokines, PGE2, MMPs, ROS, apoptotic proteins via signaling pathways (NF-κB, RANKL, and PI3K/Akt). These activities may contribute to improvement in OA and RA joint pain, inflammation, swelling, structure, and function, with minimal adverse effects.
For future research, more trials are needed to determine the clinical safety and efficacy of herbal medicine in arthritis and other chronic pain conditions. Further studies on herbal chemical compounds and isolates may also help to provide more targeted therapy options. Lastly, the development of natural product formulations with ideal bioavailability and kinetics will be necessary for optimizing treatment.

Conflicts of Interest:
The authors declare no conflict of interest.