Adjunctive Therapies in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis is an autoimmune pathology that follows a chronic course characterized by the involvement of the synovial membrane of joints all over the body. Clinically, the disease is characterized by persistent and painful immune-mediated inflammation, which culminates in bone deformations and joint movement limitation. Alternative therapies, such as garlic, ginger, curcumin, and resveratrol, are beneficial given their anti-inflammatory properties. These alternative therapies are a secondary option for treating the clinical manifestations of rheumatoid arthritis, helping to improve the patient’s quality of life further and preventing future complications.

1. Introduction

Rheumatoid arthritis is a chronic autoimmune inflammatory joint disease characterized by systemic involvement of the synovial membrane of small and medium-sized joints. It manifests clinically as a persistent, painful inflammatory process, culminating in bone deformities that often produce fatigue and severe limitations in mobility [1,2]. Types of arthritis include osteoarthritis and ankylosing spondylitis [3].

The disease can lead to complications such as fever, insomnia, anxiety, depression, pulmonary fibrosis, anemia, leukopenia, ocular sclerosis, leg ulcers, and more [2,4]. The prevalence is up to 1.2% worldwide [5].

This article aims to review clinical and preclinical trials in which ginger, omega-3, curcumin, resveratrol, and garlic (Allium sativum) have shown promising results as adjuvants to the current approved treatment for rheumatoid arthritis.

There are more medicinal plants that can help improve the symptoms of rheumatoid arthritis [3]; however, we will focus on these five compounds to analyze their mechanism of action and the evidence from preclinical and clinical studies.

2. Current Treatment of Rheumatoid Arthritis

The current clinical practice guidelines by the Spanish Society of Rheumatology for the management of patients with rheumatoid arthritis recommend that each treatment be individualized following disease progression, damage to additional organs or systems, if any, and adverse pharmacological effects due to any selected treatment; without neglecting the primary therapeutic objective, which is to control the clinical manifestations, associated comorbidities, and consequences produced by the progression of the disease. Therefore, three main groups of drugs are usually used: Disease-Modifying Anti-Rheumatic Drugs (DMARDs), glucocorticoids, and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), each having a specific function in managing the disease [4].

Despite these treatments, pharmacological treatment alone is inadequate for the management of this disease; therefore, it is essential to include other measures that may help stop the progression of the disease, such as physical activity, dietary modifications, vitamins, and alternative or complementary therapies, such as natriuretic, and foods such as garlic and ginger (Figure 1), which have been shown to have benefits in clinical and preclinical trials [6].

3. Garlic as an Adjuvant Treatment for Rheumatoid Arthritis

Garlic (Allium sativum) is one of the most widely used foods worldwide. It contains bioactive compounds such as allicin, alliin, ajoene, diallyl thiosulfate (allicin), diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), E/Z-ajoene, S-allyl-cysteine (SAC), and S-allyl-cysteine sulfoxide (alliin). Seven studies demonstrate that black garlic is effective.

It has particular antioxidant, anti-inflammatory, neuroprotective, analgesic, and anti-fatigue effects, antimicrobial activity, modulating the immune system, cardiovascular protection, antihypertensive activity, anti-hyperlipidemic activity, and anticancer activity, which have been studied in different pathologies, such as obesity, diabetes, cardiovascular diseases, cancer, and infectious diseases [7].

3.1. Mechanism of Action of Garlic

While the exact mechanism is not known, it is suspected that garlic’s anti-inflammatory properties can be attributed to its modulation and expression of the Nrf2-ARE pathway (nuclear erythroid 2-related factor and antioxidant response element) or due to its capacity to inhibit cyclooxygenase-2 (COX-2) and the NF-κB pathway [8].

Garlic can increase the secretion of anti-inflammatory cytokines and, conversely, inhibit pro-inflammatory cytokines such as TNF-α, IL-12, IL-8, IL-6, IL-10, and IL-1β by blocking NF-κB, essential factors in the inflammatory process. It also increases the production of IL-10, an anti-inflammatory cytokine [9].

Similarly, aged garlic extract creates a better environment where immune cells can undergo apoptosis, which could support the idea that diet plays a role in monitoring inflammatory processes by generating an initial response to potential pathogens, helping to resolve this signal-induced inflammation. Additionally, garlic provides antioxidants, protecting tissues and organs from internal agents in an inflammatory process [10].

3.2. Preclinical Studies

In vitro, using diallyl trisulfide, a garlic compound, inhibited cell proliferation, induced apoptosis, and downregulated TNF-α-induced IL-8, IL-6, and IL-1β production in fibroblast-like synoviocytes derived from patients with rheumatoid arthritis [11].

Likewise, female BALB/c mice with induced breast cancer fed 1 mL/kg body weight of garlic extract added to endurance exercise were observed to have decreased levels of IL-6, IL-8, and IL-17 and increased IL-10 levels [9].

3.3. Clinical Studies

Few studies have been conducted on this subject in patients with rheumatoid arthritis. However, according to a meta-analysis, only one study matches the quality characteristics required to avoid bias, according to the Cochrane Collaboration tool and the Jadad scale [12].

This group’s findings showed that 1000 mg per day of garlic, given over eight weeks, decreased post-activity pain, improved the health assessment questionnaire (HAQ) score, decreased serum malondialdehyde (MDA) concentration, and increased total antioxidant capacity. The same group also published a study demonstrating the capacity of garlic to decrease CRP and TNFα levels and improve disease indicators such as DAS-28, pain intensity, joint pain, tenderness, and fatigue among patients with RA [8] (Table 1).

These findings suggest that garlic could be used as a therapeutic adjuvant to improve patient quality of life with RA due to its multiple properties. However, more studies are required to determine its application in clinical practice and better to document all potential beneficial effects [13].

Several studies have shown that garlic components or derivatives can modulate the expression of different cytokines; for example, animal studies using rats with periodontitis provided 1 mM of diallyl sulfide observed decreased TNF-α expression [12].

Likewise, human studies on patients with inflammatory bowel disease using daily garlic extract at different doses also decreased the expression of inflammatory cytokines, such as TNFα, IL-1α, IL-6, IL-8, and IFNɣ. Furthermore, patients on peritoneal dialysis decreased by more than 10 µg/mL in IL-6, PCR, and erythrocyte sedimentation rate (ESR) in serum levels when given 400 mg of garlic extract daily [14] (Table 1).

Table 1. Garlic in clinical trials.

Author/Year	Study Population	Intervention	Base/Final	Changes in the Mean	References
Moosavian S, Paknahad Z, Habibagahi Z	70 patients with active RA	Tablets containing 500 mg of dry garlic powder 8 weeks	TAC: (26.58 ± 77.30 nmol of Trolox equivalent/mL)	TAC ↑	[8]
			MDA: (−0.82 ± 1.99 nmol/mL vs. 0.36 ± 2.57 nmol/mL	MDA ↓
			HAQ: −11.96 ± 13.43 mm frente a −0.06 ± 13.41 mm	HAQ ↓
Zare, 2019	42 peritoneal dialysis patients	400 mg twice a day for 8 weeks	IL-6: 2.2 vs. 0.7	IL-6 ↓	[14]
			CRP: 13 vs. 2	CRP ↓
			ESR: 45.3 vs. 35.4	ESR ↓

Source: created by authors. TAC: total antioxidant capacity, RA: rheumatoid arthritis, MDA: malondialdehyde, HAQ: health assessment questionnaire, CRP: C-reactive protein, IL-6: interleukin 6. The arrows signify an increase or decrease corresponding to each marker.

Table 1. Garlic in clinical trials.

Author/Year	Study Population	Intervention	Base/Final	Changes in the Mean	References
Moosavian S, Paknahad Z, Habibagahi Z	70 patients with active RA	Tablets containing 500 mg of dry garlic powder 8 weeks	TAC: (26.58 ± 77.30 nmol of Trolox equivalent/mL)	TAC ↑	[8]
			MDA: (−0.82 ± 1.99 nmol/mL vs. 0.36 ± 2.57 nmol/mL	MDA ↓
			HAQ: −11.96 ± 13.43 mm frente a −0.06 ± 13.41 mm	HAQ ↓
Zare, 2019	42 peritoneal dialysis patients	400 mg twice a day for 8 weeks	IL-6: 2.2 vs. 0.7	IL-6 ↓	[14]
			CRP: 13 vs. 2	CRP ↓
			ESR: 45.3 vs. 35.4	ESR ↓

Source: created by authors. TAC: total antioxidant capacity, RA: rheumatoid arthritis, MDA: malondialdehyde, HAQ: health assessment questionnaire, CRP: C-reactive protein, IL-6: interleukin 6. The arrows signify an increase or decrease corresponding to each marker.

4. Ginger as an Adjunctive Treatment for Rheumatoid Arthritis

Ginger (Zingiber officinale Roscoe) has long been used as a food, spice, supplement, and flavoring agent in traditional medicines due to its beneficial characteristics, such as pharmacological activity. Ginger was reported to have numerous effects [15].

The structural features of gingerol and shogaol are responsible for most of their pharmacological anti-inflammatory activities. However, variations in its composition can be observed depending on how it is stored and processed [15].

Ginger components are involved in biological processes, including the following:

• Apoptosis;
• Cell growth and DNA repair;
• Gene expression and regulation;
• Cell structure and movement;
• Immune function and inflammation;
• Nervous system function [15].

Ginger is a widely used herbal remedy with numerous health benefits. Traditional medicine systems, like India or China, have incorporated this nutraceutical in the treatment of conditions including the following:

• Respiratory issues: asthma, cough;
• Digestive problems: diarrhea, loss of appetite;
• Heart conditions;
• Infections: fever;
• Metabolic disorders: diabetes;
• Nervous system disorders: difficulty urinating;
• Immune system disorders: rheumatoid arthritis, inflammation, rheumatism [16].

Evidence shows that ginger may be beneficial in certain diseases such as psoriasis and cancer and in reducing inflammatory processes such as arthritis, ulcerative colitis, Crohn’s disease, and lupus. Certain bioactive compounds within ginger, such as 6-shoagol, zingerone, and 8-shoagol, have been shown to decrease the expression of NF-κB in patients with psoriasis; therefore, short-term administration of these substances could be considered complementary treatment options in this disease [17].

Ginger consumption in combination with other dietary polyphenols has been shown to help significantly improve disease activity scores in 28 joints and levels of inflammation or oxidative stress in diseases such as rheumatoid arthritis [18].

4.1. Mechanism of Action of Ginger

Ginger has been shown to decrease the expression of NF-κB in patients with psoriasis [17].

Meanwhile, the anti-inflammatory activities of ginger, by regulating the immune response in the cellular phase in rheumatoid arthritis, give rise to similar effects to NSAIDs by inhibiting the COX-2 and LOX pathways but without damage to the stomach mucosa. This is attributed to the fact that it generates a form of salvation through the enzyme paraoxonase-1, canceling lipid oxidation since chronic inflammation caused by free radicals from oxidative stress can generate tissue destruction [17], which is why ginger should be considered as far as rheumatoid arthritis treatment is concerned.

In other instances, it has shown the ability to relieve joint pain associated with rheumatoid arthritis and also demonstrated the ability to inhibit the synthesis of prostaglandins, which are essential for the inflammation process [18].

4.2. Preclinical Studies

Compounds found in ginger, like 6-shogaol, have shown promise for treating various inflammatory conditions. 6-shogaol showed promise as a natural treatment for rheumatoid arthritis by suppressing the growth, movement, and invasiveness of rheumatoid arthritis fibroblasts, reducing inflammatory markers, and promoting cell death [3].

A murine model study showed that cedrol (a compound in ginger) has anti-inflammatory properties. Cedrol, a compound extracted from ginger, was discovered to be a potent inhibitor of the JAK3 signaling pathway, a protein involved in inflammation. This could lead to new treatments for rheumatoid arthritis [19].

4.3. Clinical Studies

Ginger could mitigate rheumatoid arthritis by upregulating FoxP3 genes and downregulating RORγt and T-bet genes [20] (

Table 2. Ginger in clinical trials.

Author/Year	Study Population	Intervention	Base/Final	Changes in the Mean	Reference
Aryaeian N, Shahram F, Mahmoudi M	70 patients with active RA.	1500 mg daily as 2 capsules of ginger powder for 12 weeks	NF-κB: 46 vs. 40	NF-κB ↓	[20]
			DAS28: 4.73 vs. 3.44	DAS28 ↓

Source: created by authors. DAS28: disease activity score assessing 28 joints, NF-κB: Nuclear factor-kappa-light-chain-enhancer of activated B cells, RA: rheumatoid arthritis. The arrows signify a decrease corresponding to each marker.

).

An herbal formulation for rheumatoid arthritis containing Zingiber officinale, alongside other plants, has demonstrated comparable efficacy to celecoxib in the treatment of rheumatoid arthritis symptoms [21].

A combined therapy using ginger, acupuncture at ST36, and anti-rheumatic drugs was more effective in treating rheumatoid arthritis with peptic ulcers than alone or with acupuncture [22].

5. Omega-3 as an Adjunctive Treatment for Rheumatoid Arthritis

Omega-3 and omega-6 fatty acids are members of the family of long-chain polyunsaturated fatty acids. The main omega-3 fatty acids obtained through the diet are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA); foods such as fish and other seafood are rich in EPA and DHA, while seed oils or nuts such as walnuts are the main sources of ALA [23].

Omega-3 fatty acids participate in the structural composition of phospholipid cell membranes, enabling the absorption of fat-soluble vitamins, regulating cholesterol metabolism, and synthesizing physiological mediators, including eicosanoids [24,25].

After oral ingestion, omega-3 is absorbed in the first portion of the small intestine, where its bioavailability depends on the omega-3/omega-6 ratio and increases in proportion to its concentration. Once absorbed, fatty acids take various pathways. They can be transported to the liver and bound to lipoproteins for storage in adipose tissue, oxidized for energy, or incorporated into cell membrane phospholipids for eicosanoid synthesis [25].

The doses used in clinical studies are highly variable, from 1 g up to 7 g per day, with better results generally seen with higher doses, which are only achievable with supplements and not through dietary intake alone [26].

5.1. Mechanism of Action of Omega-3

The anti-inflammatory potential of omega-3 in rheumatoid arthritis is attributed to the synthesis of eicosanoids, which are products of the oxygenation of omega-6 and omega-3 fatty acids by cyclooxygenase and lipoxygenase enzymes. Eicosanoids derived from omega-6 fatty acids, the main ones being arachidonic acid, have a pro-inflammatory and pro-aggregatory effect, while those derived from omega-3, such as prostaglandin E3 (PGE3), prostaglandin I3 (PGEI3), thromboxane A3 and leukotriene B5 (LTB5), are anti-inflammatory and antiaggregatory. Being products of the same enzymes, a diet in a higher proportion of EPA and DHA interferes with the enzymatic conversion of arachidonic acid into pro-inflammatory prostaglandins [2,24,27]. Consequently, it decreases cytokine production [28].

Specialized pro-resolving lipid mediators derived from omega-3 fatty acids, such as resolvins, protectins, and maresins, also play an essential role in resolving inflammation in rheumatoid arthritis by shortening the life span of neutrophils, inducing macrophage phagocytosis of apoptotic cells, and facilitating their removal from inflammatory tissues [29,30].

5.2. Preclinical Studies

Many preclinical studies will focus on a lipid mediator produced by soybean lipoxygenase from DHA, which reduces inflammation, joint damage, and cartilage loss in the ankles. This may be due to its effects on specific proteins involved in inflammation and immune responses, suggesting that lipid mediators could be a helpful treatment for rheumatoid arthritis, as they improve joint health and restore normal blood levels [31].

In another study, omega-3 fatty acids may help reduce arthritis by increasing the number of regulatory T cells. These cells can help control inflammation while reducing IL-17 (a proinflammatory cytokine). Eating more foods rich in omega-3 fatty acids could help treat rheumatoid arthritis [32].

5.3. Clinical Studies

Omega-3 fatty acids, especially long-chain ones, are an ally in preventing rheumatoid arthritis. Long-term studies have revealed that adequate consumption of these nutrients through supplements or foods such as fatty fish can significantly reduce the risk of developing this autoimmune disease. These findings underscore the importance of a balanced diet rich in anti-inflammatory foods to maintain good joint health [33].

One study included 70 patients with active rheumatoid arthritis who were given oral supplements containing 1.8 g of EPA and 2.1 g DHA for 12 weeks; results at the end of the study showed a decrease in average morning stiffness from 128 min to 40 min. Likewise, there was a decrease in the reporting of the number of tender joints from 21 to 5, and inflammation was documented in 3 joints in the omega-3 group compared to 10 joints in the control group. Furthermore, upon physical evaluation by a doctor, patients using omega-3 supplements also reported a significant reduction in pain overall [34].

In experimental models, supplementation with krill oil, a type of planktonic crustacean rich in omega-3 fatty acids, reduced inflammatory cell infiltration in the synovial membrane and decreased joint erosion [35].

Human studies have linked omega-3 supplementation with improvements in symptoms such as pain and swelling, decreased morning stiffness time, strength recovery, and reduced number of swollen and tender joints. These changes have the added benefit of resulting in decreased use of NSAIDs and other drugs [30,34,36].

Fish oil supplementation and exceptionally high levels of EPA in plasma have decreased therapeutic failure in cases where triple therapy with DMARDs is required. It is also associated with an increased likelihood of remission of rheumatoid arthritis. Given these benefits, diets high in omega-3 fatty acids and low in omega-6 are suggested as a complement to drug therapy to reduce the dose and number of drugs required to adequately manage symptoms and disease progression [34,37].

Omega-3 has shown effects in decreasing swollen joint count, decreasing the use of analgesics, and Ritchie articular index for pain. [38,39,40] (

Table 3. Omega-3 clinical trials for rheumatoid arthritis.

Author/Year	Study Population	Intervention	Base/Final	Changes in the Mean	References
Bahadori B, Uitz E, Thonhofer R et al. (2010)	23 patients with active RA	2 weeks of treatment: 0.20 g of fish oil emulsion per kg of body weight 100 mL of this preparation contained 6.5 g of ω-3 PUFA	Swollen joint count: 10 vs. 1	Swollen joint count ↓	[38]
Rajaei E, Mowla K, Ghorbani A, et al.	60 patients with active RA	12 weeks Groups: omega-3, 2 omega 3 capsules per day containing 1.8 and 2.1 g of EPA and DHA	Number of swollen joints: 10 vs. 3	Number of swollen joints ↓	[39]
			Use of analgesics: 25 vs. 7	Use of analgesics ↓
Geusens P, Wouters C, Nijs J, et al.	69 patients with active RA	6 capsules with 1 g of fish oil (2.6 mg of ω-3) 12 months	Ritchie articular index for pain: 27.8 ± 5.1 vs. 13.8 ± 4	Ritchie articular index for pain ↓	[40]
			Painful joints: 20 ± 4 vs. 11 ± 2	Painful joints ↓

Source: created by authors. DHA: docosahexaenoic acid, EPA: eicosapentaenoic acid, RA: Rheumatoid Arthritis, PUFA: Polyunsaturated fatty acids, ω-3: omega-3. The arrows signify a decrease corresponding to each marker.

).

6. Resveratrol as an Adjunctive Treatment for Rheumatoid Arthritis

Most autoimmune diseases are characterized by severe inflammation caused by an imbalance between pro-inflammatory and anti-inflammatory cytokines and chemokines. Therefore, controlling inflammation is one of the principal pillars of managing autoimmune diseases. Some natural compounds, such as resveratrol, have been widely studied for their anti-inflammatory properties [41].

Resveratrol (3,4′,5 trihydroxy stilbene) is a natural phytoalexin produced by some spermatophytes or specific plants in response to environmental stress. It is also found in certain foods, such as grape skins, peanuts, and red wine. Resveratrol plays an essential biological role as a potent antioxidant in promoting nitric oxide production, as an antiplatelet agent, and as an inhibitor of low-density lipoprotein oxidation, thus providing a cardioprotective effect. In addition, specific anti-cancer and anti-inflammatory properties have recently been attributed to it [42]. Furthermore, it has been shown to decrease plaque formation in certain neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease [43].

Absorption of resveratrol occurs at the intestinal level, and once in the blood, it is found as glucuronic, sulfated, and accessible. The free form binds to albumin and LDL lipoproteins for transport. It has low bioavailability, but despite this, it has shown promising results. Resveratrol’s most abundant metabolite, sulfated trans-resveratrol, interacts with drugs metabolized by CYP2C9 [44]. This suggests that it could cause a drug interaction if administered with another substance metabolized by the same receptor.

6.1. Mechanism of Action of Resveratrol

Resveratrol´s mechanism of action in the treatment of autoimmune diseases is through interaction with certain pathways and molecular targets, such as the following:

• Adenosine monophosphate-activated protein kinase (AMPK);
• Cyclooxygenase type 2 (COX-2);
• Mitogen-activated protein kinase (MAPK);
• Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB);
• Nuclear erythroid 2-related factor 2 (Nrf2);
• Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway;
• Silent information regulator 1 (SIRT1);
• Signal transducer and activator of transcription (STAT3);
• Aryl hydrocarbon receptor (AhR);
• The Wnt/β-catenin pathway;
• The peroxisome proliferator-activated receptor γ (PPARγ) [45,46,47,48].

Due to its simple chemical structure, resveratrol can interact with various receptors and enzymes, thus regulating different pathways [49].

Resveratrol exerts an antioxidant and anti-inflammatory role by reducing the levels of reactive oxygen species, particularly in the case of rheumatoid arthritis. Resveratrol inhibits the Jun N-terminal kinase (JNK) pathway and plays essential regulatory functions throughout life [50]. It also regulates the p38 MAPK (Mitogen-activated protein kinase) signaling pathways; p38 MAPK signaling helps protect cells from damage caused by harmful substances [51].

Key players in RA pathogenesis include the following:

• JNK inhibition mitigates bone erosion.
• p38 MAPK inhibition lessens synovial inflammation, cartilage erosion, bone damage, and angiogenesis, which is crucial for chronic synovial inflammation.

Resveratrol’s suppression of HIF-1α expression underlies its anti-angiogenic effects, leading to decreased vascular endothelial growth factor (VEGF) production [52].

This nutraceutical also inhibits cell proliferation by cell cycle arrest in the G0 phase and induces apoptotic cell death by activating caspases. In addition to activating specific caspases, resveratrol induces apoptosis by upregulating sirtuin-1 expression, disrupting mitochondrial membrane potentials in synovial cells, and releasing cytochrome C [53].

6.2. Preclinical Studies

Specific beneficial effects have been demonstrated with the use of once-daily resveratrol at a dose of 400 mg/kg in an experimental rat model with induced arthritis using bovine collagen type II. One of the main benefits was the decreased infiltration of inflammatory cells within the synovial membrane and decreased proinflammatory cytokines such as IL-1B, IL-6, MCP-1, and TNF- α. Other effects included the reduction in oxidative stress with a decrease in malondialdehyde production and an increase in superoxide dismutase, a downregulation of the HIF-1α protein responsible for transcriptional induction of angiogenesis, as well as attenuation of synovial hyperplasia, which is characteristic of rheumatoid arthritis through cell cycle arrest and induction of apoptosis in fibroblast-like synoviocytes [54].

A systematic review and meta-analysis demonstrate the efficacy of resveratrol in reducing the manifestations of arthritis in experimental rat models; results show a decrease in paw volume and the rate or severity of arthritis, likewise highlighting the resolution of oxidative stress and cartilage loss in rats [55].

As a dietary supplement, resveratrol can activate a cellular process called non-canonical autophagy. This process helps reduce inflammation and may prevent the overgrowth of synovial tissue, a key feature of rheumatoid arthritis. These findings suggest that incorporating resveratrol into your diet could be a promising way to prevent or manage rheumatoid arthritis [56].

6.3. Clinical Studies

A clinical trial involving 100 patients with rheumatoid arthritis found that daily supplementation with 1 g of resveratrol for three months significantly reduced the following:

• Joint swelling and tenderness;
• Inflammatory markers include C-reactive protein, erythrocyte sedimentation rate, undercarboxylated osteocalcin, matrix metalloproteinase-3, tumor necrosis factor alpha, and interleukin-6 [57] (

  Table 4. Resveratrol in clinical trials.

  Author/Year	Study Population	Intervention	Base/Final	Changes in the Mean	Reference
  Khojah H, Ahmed S, Abdel-Rahman M, et al.	100 Egyptian patients with RA	Test group: daily capsule with 1 g of resveratrol for 3 months.	DAS28: 4.98 ± 1.07 vs. 3.02 ± 0.77	DAS28- ESR ↓	[57]
  			SJC-28: 3.8 ± 1.0 vs. 1.5 ± 0.8	SJC-28 ↓
  			RF positivity (% of patients): 92.7 vs. 85.4	RF positivity (% of patients) ↓
  			PCR: 2.9 ± 0.9 vs. 1.8 ± 0.5	PCR ↓

  Source: created by authors. DAS28: disease activity score assessing 28 joints, PCR: C-reactive protein, RF: rheumatoid factor, SJC-28: swollen joint count-28, RA: Rheumatoid Arthritis. The arrows signify a decrease corresponding to each marker.

  ).

7. Curcumin as an Adjunctive Treatment for Rheumatoid Arthritis

Turmeric is a perennial herb belonging to the genus Curcuma in the family Zingiberaceae. Curcumin is considered a potential therapeutic and nutraceutical agent, and, together with other curcuminoids such as demethoxycurcumin and bisdemethoxycurcumin, forms one of the main bioactive substances of turmeric, which is a plant native to India, commonly used in the preparation of curry. These substances have been shown to have anticancer, antimicrobial, anti-inflammatory, and anti-aging properties. Curcumin is generally used as a natural colorant in food, cosmetics, and textiles, as an additive to certain foods, and even as an insect repellent [58,59].

Curcumin, a compound found in turmeric, has been shown to have a wide range of health benefits. These include antioxidant, anti-inflammatory, anti-angiogenic, and anti-tumor properties without causing significant side effects [60].

In a clinical trial, it was observed that the administration of a formula based on Piper nigrum, Curcuma longa, and Zingiber officinale twice daily for four weeks significantly decreased levels of prostaglandin E2, a marker of inflammation, with an efficacy comparable to that of naproxen [61].

Previous research has demonstrated that curcumin has the following benefits:

• Reduces inflammation;
• Lowers blood cholesterol and triglycerides;
• Improves blood sugar control.

These effects suggest that curcumin may be protective against chronic diseases [62].

Recent studies have specifically highlighted curcumin’s potential for alleviating symptoms of rheumatoid arthritis and inflammatory bowel disease.

By inhibiting inflammatory reactions, curcumin can help reduce pain and swelling associated with these conditions [63,64].

7.1. Mechanism of Action of Curcumin

Curcumin´s main mechanism of action, associated with its anti-inflammatory effects in rheumatoid arthritis, is based on a decrease in inflammatory mediators, induction of proapoptotic molecules, and inhibition of osteoclasts [65]. This is achieved through the inactivation of NF-KB, which subsequently decreases the amount of proinflammatory cytokines. Furthermore, curcumin reduces the number of inflammatory lymphocytes such as Th1 and Th17 and increases the number of regulatory T lymphocytes; proinflammatory mediators are also reduced by regulating cyclooxygenase and lipoxygenase enzymes. The osteoclastic function of monocytes and lymphocytes is mitigated by inhibiting RANK, the receptor activator of NF-KB [66].

Curcumin is widely used and generally well tolerated; however, its absorption is minimal in most cases, undetectable in serum [67]. Its low bioavailability is due to poor absorption, rapid metabolism, and systemic elimination. High doses of up to 12 g/day have been reported to be used with good tolerance but with minimal results [62].

Due to these pharmacodynamic limitations, alternatives have been sought to achieve greater bioavailability and take advantage of its therapeutic potential. A study in patients with active rheumatoid arthritis reported a tenfold increase in bioavailability of a new form of curcumin in a natural turmeric matrix consisting of curcuminoid, turmeric essential oil, and water-soluble turmeric fractions; doses of 250 or 500 mg were administered twice daily for three months. Compared to the placebo group, the results showed a significant change with both doses regarding symptomatic improvement and decreased inflammatory biochemical markers such as ESR, CRP, and RF [68] (

Table 5. Curcumin in clinical trials.

Author/Year	Study Population	Intervention	Base/Final	Changes in the Mean	References
Amalraj A, Varma K, Jacob J, et al.	36 patients with active RA	250 mg of curcumin product as the low dose	Low-dose	Low-dose	[68]
			DAS28: 4.51 ± 0.64 vs. 2.14 ± 0.16	DAS28 ↓
			PCR: 0.97 ± 0.15 vs. 0.68 ± 0.10	PCR ↓
			RF: 123.3 ± 36.9 vs. 24.4 ± 5.7	RF ↓
			VAS: 7.01 ± 0.86 vs. 2.63 ± 0.74	VAS ↓
		500 mg of curcumin product as the high dose 3 months	High-dose	High-dose
			DAS28: 5.29 ± 0.54 vs. 1.80 ± 0.36	DAS28 ↓
			PCR: 1.21 ± 0.18 vs. 0.59 ± 0.08	PCR ↓
			RF: 150.6 ± 41.7 vs. 23.8 ± 6.0	RF ↓
			VAS: 7.99 ± 0.71 vs. 2.21 ± 0.45	VAS ↓
Chandran B, Goel A.	45 patients in India diagnosed with active RA	500 mg of curcumin 8 weeks	DAS28: 6.40 ± 0.73 vs. 3.55 ± 0.73	DAS28 ↓	[69]
			VAS: 68.5 ± 17.14 vs. 27.5 ± 9.35	VAS ↓
			PCR: 5.34 ± 4.12 vs. 2.56 ± 1.8	PCR ↓

Source: created by authors. DAS28: disease activity score assessing 28 joints, RF: rheumatoid factor, PCR: C-reactive protein, VAS: Visual Analog Scale, RA: rheumatoid arthritis. The arrows signify a decrease corresponding to each marker.

). Curcumin is not only a safe and effective therapy, but its efficacy is also comparable or even greater in relieving pain when compared to the use of NSAIDs such as diclofenac [69] (Table 5).

7.2. Preclinical Studies

Studies in animal models of arthritis have demonstrated that curcumin isolated from Curcuma longa exerts anti-inflammatory effects by modulating various molecular pathways. Specifically, curcumin inhibits the activation of Toll-like receptors (TLR2) and the expression of transcription factors such as NF-κB, leading to a decrease in the production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF-α, and IFNγ. These effects are attributed to curcumin’s ability to stimulate the expression of Nrf2 and inhibit the phosphorylation of IκB-α [70].

8. Discussion

The administration of garlic in a clinical setting can reduce the levels of pro-inflammatory molecules such as TNF-α, IL-6, CRP, and ESR [14]. Preclinical animal studies demonstrated similar decreases in IL-6, IL-8, and IL-17 with oral administration in mice with cancer [9].

Turmeric administration has been used safely and with no adverse effects to treat systemic lupus erythematosus. At the same time, rheumatoid arthritis has been shown to decrease levels of DAS28, ESR, and CRP [63,64]. Curcumin increases apoptotic expression and inhibits osteoclast activity [65].

By modulating various molecular pathways in inflammatory processes, curcumin can decrease the production of substances that damage the joints. Clinical studies have demonstrated that curcumin is comparable to conventional medications for treating rheumatoid arthritis but with a more favorable safety profile. However, its low bioavailability represents a challenge for its therapeutic use, which has driven research into new formulations to improve its absorption [71].

Conversely, ginger’s main anti-inflammatory activities occur by regulating the immune response in the cellular phase, as in the case of rheumatoid arthritis [17]. In a study, ginger was found to alleviate joint pain associated with rheumatoid arthritis and to inhibit the synthesis of prostaglandins, which are essential components of the inflammatory process [18].

Omega-3 supplementation has been shown to exert its greatest effects at high doses from 1 g to 7 g daily [26]. In comparison, Huang expresses that a lower dose of two capsules of omega-3 daily containing 1.8 g EPA and 2.1 g DHA can decrease morning stiffness, the number of tender joints, and pain significantly in patients with RA [34].

Resveratrol significantly reduces inflammatory markers such as PCR, TNF-α, and IL-6 levels while decreasing joint inflammation and pain [57]. Since oral administration of resveratrol helps to control systemic and synovial disease, its effects could be highly relevant in managing rheumatoid arthritis [56].

Non-pharmacological treatments for RA have shown some efficacy, but the results are still limited. Although statistically significant, the observed improvements are small and do not always reach the clinically relevant threshold. Additionally, different non-pharmacological treatments seem to act through different mechanisms, making it difficult to draw general conclusions and limiting the possibility of recommending a single therapeutic approach. More research is needed to determine which non-pharmacological treatments are most effective and for whom [72].

Finally, these bibliographical reviews allow for a broad understanding of currently known information regarding rheumatoid arthritis and further advances in the knowledge of complementary medicinal substances, which can help to improve prevention and treatment strategies for patients suffering from this disease.

9. Conclusions

Complementary medicinal products with known pharmacological impact should be considered when treating various ailments. The various nutraceuticals discussed in this review have been highly relevant in treating rheumatoid arthritis, particularly in conjunction with established pharmacological treatments.

The doses at which these products exert their optimal benefit in treating rheumatoid arthritis vary greatly. Resveratrol was adequate with 1 g daily, but more clinical trials are necessary. In this review, only one study was found to be of sufficient quality to be included.

Curcumin was studied at doses from 250 to 500 mg, and both products showed significant anti-inflammatory effects. Conversely, omega-3 has adequate effects with the administration of 1.8 g of EPA and 2.1 g of DHA by improving morning stiffness and decreasing the number of sensitive joints and overall inflammation.

While preliminary research suggests that complementary medicinal products with known pharmacological effects may be beneficial in treating rheumatoid arthritis, more clinical trials are needed to determine optimal dosages and long-term safety.

10. Future Directions

Concerning this growing evidence, further evaluation of the immunomodulatory effects of curcumin should be conducted in clinical trials to treat rheumatoid arthritis.

This review analyzes only five nutraceuticals (garlic, resveratrol, ginger, curcumin, and omega-3). However, a wide range of foods and nutraceutical products can be studied further, both for prevention and as complementary treatments, such as green tea, krill oil, black tea, and olive oil, among many others.

It is also essential to study the different pharmaceutical forms in which these nutraceuticals can be presented and the doses required to evaluate effectiveness, efficacy, or possible adverse effects.

This review article seeks to stimulate further research into natural therapies for rheumatoid arthritis, expand the therapeutic armamentarium available to patients, and enhance their quality of life.

Integrating complementary medicinal products with known pharmacological effects may benefit a personalized approach to treating rheumatoid arthritis. Individualized dosing and careful monitoring are essential to optimizing outcomes.