Rheumatoid arthritis (RA) is a common autoimmune arthritis disease, characterized by a chronic recurrent symmetrical polyarthritis (1). In most cases, rheumatoid arthritis has an insidious onset with one or more swelling joints at the beginning of the disease (2). Proximal interphalangeal, metacarpophalangeal, wrist and foot joints are more common to suffer from swelling (3). Rheumatoid arthritis patients also have symptomatic joint congestion and edema, tenderness, stiffness, joint pain. Most joint swelling and redness occur in the morning and evening in acute attacks, fluid exudation occurs in chronic phase, and joint muscle atrophy and joint deformity are likely accompanied in the late stage of the disease (4). In addition, rheumatoid arthritis can lead to some complications such as fever, insomnia, anxiety, depression, pulmonary fibrosis, anemia, leukopenia, ocular sclerosis, leg ulcers (5). Chronic inflammation in rheumatoid arthritis leads to damage to cartilage and bone, resulting in cartilage erosion, bone degeneration, and joint deformity and loss of range of motion (6). One study in Danish adults reported that the average prevalence and incidence of rheumatoid arthritis was approximately twice as high in women as in men (7). Rheumatoid arthritis not only bring physical harm, but also affect mental health (8). The disease leads to unbearable repeated pain and endless medication to patients and is also known as the “invisible killer”. Nevertheless, rheumatoid arthritis can achieve good control of symptoms and avoid joint deformity by early diagnosis and treatment (9).

Rheumatoid arthritis is very ‘sneaky’, often undetectable and easily confused with other diseases in its early stage, and can get progressively worse over time (10). The clinical treatment for rheumatoid arthritis includes pain medication, physical therapy and, in some cases, essential surgery. The existing disease-modifying antirheumatic drugs (DMARDs) can be broadly divided into three categories: conventionally synthesized DMARDs (e.g., methotrexate), targeted synthetic DMARDs (e.g., pan-JAK and JAK1/2 inhibitors), and biological DMARDs (e.g., (TNF) -α inhibitors, IL-6R inhibitors) (11). DMARDs for rheumatoid arthritis treatment have the potential to greatly improve disease symptoms and prevent disease progression. Meanwhile, DMARDs produce gastrointestinal toxicity and side effects of cardiovascular disease and result in high economic costs (12). Different formulations of traditional Chinese medicine (THM) have been shown to have anti-rheumatoid arthritis effects and improve some symptoms. The traditional Chinese medicine prescriptions for rheumatoid arthritis have the potential to improve the symptoms and delay the progression of this chronic disease (13).

Turmeric is a perennial herb belonging to the genus Curcuma in the family Zingiberaceae. Curcumin is the most important chemical component of turmeric, which can exert antioxidant, anti-inflammatory, anti-angiogenic and anti-tumor pharmacological effects without significant adverse effects (14). Previous studies have shown that curcumin and curcuminoids in turmeric could provide good protection against many chronic diseases in the body by inhibiting inflammatory responses, lowering blood lipids, and improving blood sugar (15). Curcumin in turmeric can effectively inhibit inflammatory reactions and reduce symptoms such as pain and swelling. In recent years, it was found that curcumin could alleviate some symptoms in some autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (16). The researchers have conducted numerous studies to evaluate the pharmacological effects and clinical applications of turmeric and curcumin on rheumatoid arthritis treatment (17).

In this systematic review and meta-analysis, we investigated the effectiveness and safety of curcumin on the treatment of rheumatoid arthritis based on 10 randomized controlled trials (RCTs). We summarized and analyzed both laboratory test factors and clinical test indicators to evaluate the anti-inflammation and immunomodulatory function of supplementary curcumin on rheumatoid arthritis treatment.

This systematic review and meta-analysis involved a total of ten studies and indicated that curcumin supplementation is one of the effective treatments for rheumatoid arthritis. The articles included in the analyses were generally different, but all passed through a complete statistical school. Although there was heterogeneity in the included articles, meta-analysis showed that factors such as patient age, rheumatoid arthritis history, serum abnormalities and threshold did not alter estimates of prognosis. The results of the current study showed that curcumin supplementation was effective in reducing clinical symptoms in the treatment of rheumatic diseases, and the use of curcumin supplementation in rheumatoid arthritis patients could reduce the possibility of unpleasant consequences.

Rheumatoid arthritis is this systemic inflammatory arthritis with a lifetime prevalence of up to 1% worldwide (29). Rheumatoid arthritis is an autoimmune disease and the pathophysiological mechanisms are complex, mainly affecting systemic joints and may present with varying degrees of extra-articular manifestations (30). It is characterized by a high incidence of cardiovascular disease, particularly in women and people with a history of smoking (31). Therefore, early diagnosis seems to be extremely important for the intervention and management of rheumatoid arthritis (32). It is expected to explain the pathogenesis of rheumatoid arthritis by focusing on novel genes and the close interaction between genetic factors and epigenetic mechanisms (33). It has been found that autoantibody isotypes and their molecular and physicochemical components may become potential therapeutic targets and strategies for the disease underlying immune processes (34). The response of some rheumatoid arthritis patients to antirheumatic drugs (DMARDs) remains limited in mitigating and preventing disease activity (35). Patients with rheumatoid arthritis tend to have extra-articular manifestations associated with more active and severe rheumatoid arthritis. The extra-articular features remain a major challenge in diagnosis and treatment for the disease, as they are associated with poor prognosis and required early recognition and timely management. The required effective alternative treatments are important to address this new challenge (36).

Curcumin, a pure natural compound derived from the roots of turmeric, is one of the most active components of polyphenolic curcuminoids (37). Zn (II) -curcumin compound has been found to exert anticancer effects on a variety of molecular mechanisms through Nrf2 regulation (38). Curcumin is effectively usedfor obesity therapy because it is a lipophilic molecule that can rapidly penetrate cell membranes, and may be associated with lipid metabolism, gut microbiota, and anti-inflammatory potential (39). Advanced encapsulation or loading of curcumin in the form of nanocurcumin has been shown to improve its therapeutic potential of multifaceted effects in the management of chronic diseases (40). It has been suggested that curcumin combined with photodynamic therapy could cause cell cycle arrest and inhibit apoptosis-mediating factor stimulation on disease cell viability, proliferation and migration (41). Curcumin is also known as “seasoning of life” by its well-known antibacterial, anti-inflammatory, antioxidant, antitumor, antifungal and pro-apoptotic effects (42).

Curcumin has been shown to improve symptoms and delay disease cycles in rheumatoid arthritis patients by inhibiting mitogen-activated protein kinase family, extracellular signal-regulated protein kinase, activator protein-1, and nuclear factor κB signal pathway in rheumatoid arthritis (43). Curcumin treated by rheumatoid arthritis patients with taking 250-1500 mg/day over 8-12 weeks can improve dysfunctional immune cells (including TH1, TH17, Treg and B cells) and reduce the clinical symptoms of the disease (44). It has been found that curcumin has therapeutic effects on collagen-induced arthritis (CIA) by inhibiting NF-κB signaling pathway and promoting macrophage apoptosis (45). Cur-TF combination with targeted delivery and enhanced efficacy of curcumin could improve clinical, histologic and radiographic scores, and reduce proinflammatory cytokines in rheumatoid arthritis patients (46). Curcumin has been found toaffect IL-10 secretion and immunoregulation to modulate the neurodegenerative diseases by promoting anti-inflammatory and immunosuppressive function (47). Curcumin supplementation enhances the anti-inflammatory capacity of the eicosanoid pathway in rheumatoid arthritis patients by modulating serum lipid levels to a normal state (48). It has been reported that curcumin improved the effect of fibroblast-like synoviocytes in rheumatoid arthritis by modulating the inc00052/miR-126-5p/PIAS2 axis and inhibiting Janus kinase 2 (JAK2)/signal transducer (49). Interestingly, curcumin suppressed inflammatory cell infiltration into synovium via rapamycin (mTOR) target pathway and suppressed the proinflammatory cytokine levels in rheumatoid arthritis rheumatoid arthritis (50). On the other hand, curcumin inhibits activation of PI3K/AKT signaling pathway and the expression of proinflammatory cytokines TNF-a, IL-6, and IL-17 (51). Therefore, curcumin can be used as a preventive measure in individuals at high risk of early or developing rheumatoid arthritis (52).

In this systematic review and meta-analysis, we found that curcumin could improve ESR, CRP, DAS, RF, VAS, TJC, and SJC in patients with rheumatoid arthritis. Our findings suggest that rheumatoid arthritis patients in the experimental group supplemented with curcumin benefit more than patients in the control group. For rheumatoid arthritis patients, functional improvement of total proteins by curcumin is uncertain. The current study suggest that curcumin supplementation may be an effective method to enhance anti-rheumatic immunity. In our study, no serious adverse events were found in ten studies. The mild side effects such as constipation, diarrhea, rash, nausea, and vomiting may occur during intervention with curcumin. No statistically significant difference was found in the curcumin group and the control group, suggesting that curcumin supplementation is safe for intervention in rheumatoid arthritis.

In our study, high heterogeneity was found and then the random-effects model was used. The causes of the heterogeneity were complex and mainly divided into the following types: clinical heterogeneity, ethnic heterogeneity and methodological heterogeneity. In our study, most of the results in the experimental group were statistically significant. It was also clear that curcumin has great potential in the treatment of rheumatoid arthritis, overcoming the dosing barriers through nano/submicron carrier-based delivery techniques and maximizing the efficacy of anti-rheumatic drugs.

This research has several restrictions: (1) Although ten RCTs were included in this study, the sample size was relatively small; (2) Most of the included RCTs did not report long-term effects of drugs and the prognosis of patients; (3) Some included original studies used unified interventions and did not distinguish patients by syndrome. (4) Although the study used total protein as a secondary outcome measure, the literature is sparse.

Modern medical research has found that the occurrence of many diseases in the human body is related to free radical formation and inflammatory response. The multiple double bonds in curcumin endow it with trapping free radical electrons, antioxidant activity and anti-inflammatory effects. Curcumin is beneficial for rheumatoid arthritis treatment. Inflammation levels and clinical symptoms in patients with rheumatoid arthritis can be improved by curcumin supplementation. Large sample randomized controlled trials on the effects of curcumin on patients with rheumatoid arthritis are needed in the future.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

HK and LH contributed equally to this study. All authors contributed to the work and approved the final manuscript.