Aloe vera gel has been thought to potentially have a role as a topical agent in RA due to its anti-inflammatory properties [9]. In a study performed by Subhashis et al. [10], heat-induced hemolysis of red blood cells (RBC) and hypotonicity-induced hemolysis of RBC were evaluated in rats receiving an aloe vera homogenate. These specific measures were chosen because lysis of lysosomal vesicles results in the release of enzymes that can induce an inflammatory response, which is the main driver of RA. Inhibiting lysis of the membrane has the potential to reduce the progression of inflammation. Concentrations of aloe vera homogenate used were 600, 800 and 1000 ug/mL of gel. Topical indomethacin served as a comparator within this trial. Results of the study [10] indicate that Aloe vera protects human RBCs from hypotonicity-induced hemolysis with the most protective effect at 1000 ug/mL. The percentage of inhibition was 74.89% at 1000 ug/mL, which was similar to that of indomethacin (80.52%). Aloe vera also proved efficacious in inhibiting heat-induced hemolysis in RBC, however was about half that of indomethacin (20.86% vs 43.98%). The results of this study [10] indicate a potential benefit of Aloe vera gel in reducing inflammation, and Aloe vera is a widely available product that can be bought in stores or grown at home.

Perillyl Alcohol (POH) is a plant-based compound that has some data to support its use as a topical agent in rheumatoid arthritis. One in-vitro/in-vivo study [11] looked at the topical application of POH in arthritic rats. The in-vitro results indicated that POH suppressed reactive oxygen species and other signals that regulate stress and inflammation pathways. In addition, pro-inflammatory cytokine levels decreased after administration of POH ultimately resulting in a decrease in inflammation. Paw volumes, histological evaluation, and X-ray reports were utilized and aided in identification of a decrease in inflammation and bone erosion. While the results of this study [11] are promising, an increased number of trials are needed to recommend POH for the treatment of RA.

Aleurites moluccana leaves have been used for decades in the treatment of asthma, hepatitis, headache, and inflammatory processes [12]. The main anti-inflammatory mechanism of A. moluccana is thought to be a reduction in leukocyte migration, leading to decreasing numbers of cytokines and chemokines [13]. Mendes Hoepers et al. [13] sought to evaluate topical anti-inflammatory properties of A. moluccana in mice. Ear edema was induced utilizing croton oil to simulate inflammation. A semisolid dosage form of A. moluccana was instilled into the ear of the mouse and levels of tumor necrosis factor (TNF), interleukin-1b (IL-1b), and chemokine keratinocyte chemoattractant (CXCL1/KC) were measured. TNF, IL-1b, and CXCL1/KC are all indicators of pro-inflammatory processes. In evaluating CXCL1/KC, IL-1b, and TNF levels, significant reductions were observed at 62.29%, 38.36% and 53.75% respectively. Reduction in edema was also observed and compared to a positive control of dexamethasone. It was found that A. moluccana reduced edema by 35.77% in comparison to 97.62% with dexamethasone. Ultimately this study [13] demonstrated the topical anti-inflammatory effects of A. moluccana through multiple mechanisms.

Calendula officinalis, commonly known as marigold, is a traditional medicine known for its potent anti-inflammatory activity when taken orally [14]. Little data delves into the topical anti-inflammatory properties of Calendula officinalis. A single study out of Romania [15] assessed the anti-inflammatory effect of a topical formulation containing diclofenac, methyl salicylate and lyophilized Calendula officinalis in rheumatoid arthritis. One-hundred and fifteen participants were included in this randomized, prospective study and were assigned to either active or placebo groups. The topical application was given twice a day for 14 days and Visual Analogue Scale (VAS) and ultrasound were utilized to measure outcomes such as pain throughout the 14 days of the trial. The baseline VAS score for both the active and placebo group was approximately 6 in patients with shoulder pain attributed to RA. By the 14^th day, the experimental group had a VAS score of 2.36 vs placebo at 5.48 and was statistically significant.. Ultrasound was used to assess differences in the thickness of the synovial membrane. At baseline, the synovial membrane thickness in the shoulder was about 3.3 mm in both active and placebo groups. At day 14, the active group had a synovial thickness of 1.32 vs 3.2 in the placebo group, which was statistically significant, and a 59% decrease in the thickness of the synovium. The results of this study¹⁵ are promising if there were to be an NSAID/methyl salicylate/Calendula officinalis topical formulation, however, there is no direct evidence that topical Calendula officinalis can be utilized as monotherapy as an option for RA.

Achyranthes is a flowering plant used in Chinese medicine as an antiviral, anti-inflammatory, and analgesic agent [16]. Immunohistochemistry in arthritis models have shown that Achyranthes inhibits the effects of IL-6-mediated matrix metalloproteinases [17]. In-vivo models have showcased a decrease in cartilage erosion, subchondral plate thickness, cartilage degeneration, and synovium inflammation [17]. In an animal model, Achyranthes proved to decrease paw swelling, bone degradation, as well as the proliferation of inflammatory cells [18]. No topical studies have been performed using Achyranthes, so the effects of using Achyranthes species for the topical treatment of RA remain unknown.

In Chinese medicine, Guizhi Shaoyao Zhimu decoction is considered a first line therapy in the treatment of RA [19]. An in-vivo model evaluated toe swelling, arthritis score, and inflammatory cytokine levels in collagen-induced arthritis (CIA) rats [20]. The results of the study demonstrated a reduction in both toe swelling and arthritis score. Serum levels of various inflammatory cytokines, including TNF-alpha, IL-1B, IL-6 and IL-17a, all decreased with Guizhi Shaoyao Zhimu in-vivo administration. There is no data to support the use of Guizhi Shaoyao Zhimu topically; however it is still widely used outside of Western medicine.

Curcumin is an active compound found in turmeric, which is a common spice that has been used for centuries in cooking and traditional Chinese medicine [21]. Turmeric has an abundance of oral data showcasing an anti-inflammatory effect which has sparked interest in its research [21]. Little data evaluating topical turmeric as an anti-inflammatory exists. Future research should address the topical role of turmeric in inflammatory conditions, as currently there is no evidence to suggest its effectiveness when used topically.

Wutou decoction is a common preparation used in Chinese medicine for the treatment of RA. When given orally via decoction, Wutou has showcased an inhibition of NF-kB mediated inflammatory response in a CIA rat model [22]. When administered intragastrically, wutou lowered swelling in the hind paws of rats with RA, in addition to ROS suppression [23]. These studies demonstrate the effectiveness of wutou for reducing inflammation when used orally, but more studies are necessary to see these effects for topical use.

Paeoniflorin is the major active compound of total glycoside of paeony which is traditionally extracted from the Chinese Peony flower in traditional Chinese medicine [24]. It has been used to treat pain and inflammation over thousands of years. When injected into animal models with collagen induced arthritis, joint destruction was suppressed [25]. In addition, a decreased arthritis score, ankle/ paw swelling, and suppression of the proliferation of FLS, T, and B lymphocytes was observed [25]. Decreases in reactive oxygen species and proinflammatory cytokines and chemokines were also observed [25]. While this ancient flower has been used over the years, there is no data to support its use as a topical agent in RA.

Tripterygium wilfordii Hook F (TWHF) is a traditional Chinese herb that has been used for thousands of years in the treatment of joint pain [26]. It’s mechanism of action is thought to work through an inhibition of adhesion molecules, matrix metalloproteinases, and pro-inflammatory cytokines and mediators, in addition to inducing apoptosis of lymphocytes and synoviocytes ultimately inhibiting their proliferation [26]. Recently, TWHF has been studied as a topical agent in RA due to reproductive side effects associated with its oral use [26]. Cibere et al. [27] conducted a 6-week, randomized, double blind placebo controlled trial with 61 RA patients that used intention-to-treat analysis. The primary outcome was a modified American College of Rheumatology-20 (ACR-20) criteria response rate. Secondary outcomes focused on tenderness, swollen joint count, and morning stiffness. The odds of achieving a modified ACR response was 8.1 in the TWHF group when compared to placebo. TWHF was successful in reducing tender and swollen joint count and morning stiffness. Two other studies that included nearly 250 patients found similar results to that of Cibere et al. [28] [29]. Improvement in tender joint and swollen joint count was observed in addition to a higher ACR50 response among patients using TWHF. Self-reported joint pain relief in a study conducted by Jiao et al. [29] was 90.8% in the TWHF group in comparison to 69% in the placebo group. Minimal adverse events were noted with the topical application of TWFH with the most common of skin allergy, which was not significantly different from what was observed in the placebo group [28] [29]. These randomized, double blind, placebo-controlled trials showcase promising data for the topical use of TWHF in RA patients.

Capsaicin is a common over-the-counter cream that is recommended for various types of pain, mainly neuropathic [30]. Capsaicin has an anti-inflammatory mechanism of action that works by depleting substance P [31]. By activating the TRPV1 receptor every day with the application of capsaicin, substance P becomes depleted and the nociceptors no longer respond to stimuli [32]. Substance P is commonly implicated in the pathogenesis of inflammation and pain making this a strong target for RA pain [31]. Data for capsaicin specifically in RA patients is not robust and showcases minimal benefit. One review included various studies that favored capsaicin over placebo in the treatment of RA pain [33]. However the review concluded that while this data may favor capsaicin, the evidence is weak to support its ability to treat RA pain. Ultimately, capsaicin’s minimal side effect profile makes it an option for add-on therapy in patients with persistent pain and an inadequate response to other topical agents. The main side effect associated with capsaicin is its local burning sensation upon its application due to it being derived from chili peppers. Overall, capsaicin may be a good option for patients who have not experienced relief from other topical agents and who are capable of handling the side effects associated with application.

Cannabidiol (CBD) is a natural ingredient of interest for treating a large number of conditions due to its anti-inflammatory action [34]. CBDs’ anti-inflammatory action is complex and works through activation of the endocannabinoid system, specifically the cannabinoid type 1 and 2 receptors [34]. Activation of these receptors decreases cytokine production and immune cell mobilization [34]. While data is more robust for the oral use of CBD in inflammatory conditions, new research has begun exploring the role of CBD as a topical agent. Topical administration of CBD bypasses its poor oral bioavailability, gastrointestinal side effects, and any concerns that CBD may impact higher brain function [35]. A study performed by Hammell et al. [35] utilized a mouse model to evaluate the role of transdermal CBD in reducing inflammation and pain in arthritis. Results showcased a significant reduction in joint swelling at day 4 in addition to improvements in limb posture scores which included spontaneous pain, immune cell infiltration, and thickening of the synovial membrane. A dose-dependent reduction in pro-inflammatory biomarkers was also seen in this study. Major side effects have not been reported with the topical use of CBD. As such, CBD is a promising option for patients to reduce RA pain, and is often recommended as a natural option for symptom relief.

Berberine is an alkaloid isolate that can be extracted from a variety of plants such as Berberis vulgaris, Mahonia aquifolium, and Coptidis Rhizoma. Berberine has been used for centuries in Chinese medicine and is thought to have antibiotic, antitumor, antiplatelet, and anti-inflammatory properties [36]. Various in vitro and in vivo studies have showcased berberines potential benefit in treating symptoms associated with RA. One study found that berberine can suppress synovial joint inflammation via inhibition of FLS, one of the major contributors to the worsening of RA [38]. Another cell culture study identified that IL-21 could induce autophagy which would ultimately promote proliferation of the FLS cells [37]. Berberine was able to block the induction of autophagy therefore blocking the proliferation of FLS. Berberines role in targeting FLS, a major component of RA potentiation, has been elucidated in culture data and showcases its potential therapeutic effect. Culture data is difficult to use in support of berberine as the topical use of berberine would face the major issue of absorption through the skin. A study conducted by Elkomy et al. [39] evaluated the topical use of berberine. Specifically, this study looked at boosting the transdermal system of berberine by encapsulating it in chitosan, a surface-modified bilosome nanogel. A rat model was used and both ex-vivo and in-vivo models were utilized. The ex-vivo model looked at the permeation of the compound with the enhanced liposome and found that this modality enhanced permeability and extended the release time of berberine. This could be potentially useful when formulating topical berberine for over-the-counter use in order to ensure its adequate absorption through the skin. The in vivo portion of this study assessed paw edema, to which a 24.4% reduction was seen at the 12-hour time point. While the data for topical berberine is limited and there have not been any studies conducted on humans, the relatively benign safety profile of berberine makes it a potential adjuvant product for RA.