Efficacy and safety of acupuncture therapy combined with conventional pharmacotherapy in the treatment of systemic lupus erythematosus: A systematic review and meta-analysis

Abstract

Background:

Currently, the mainstream treatments for systemic lupus erythematosus (SLE) are based on glucocorticoids and immunosuppressants, which are known to have considerable adverse effects. This meta-analysis is aimed at confirming the efficacy and safety of acupuncture therapy in combination with traditional medications in the treatment of SLE.

Methods:

Multiple databases were searched for randomized controlled trials using acupuncture therapy in combination with conventional pharmacotherapy for the treatment of SLE, from the establishment of the database to March 2023. Study selection, data collection, as well as quality assessment were conducted by 2 reviewers independently. RevMan 5.4 and Stata 17 software were used for Meta-analysis.

Results:

Seven eligible studies involving 514 patients with SLE were included. Meta-analysis demonstrated that in SLE patients, extra treatment with acupuncture was superior to drug therapy alone in improving the overall response rate (RR = 1.20, 95% confidence intervals [1.11, 1.29], P < .00001, heterogeneity P = .69, I² = 0%) and regulating immunological indicators (C3, C4, IgG, T lymphocyte subpopulation, IL-6, ds-DNA, ESR) while reducing TCM symptom scores, the SLE Disease Activity Index (SLEDAI) and the incidence of adverse events on treatment (P ≤ 0.05). Additionally, it was able to reduce BUN, Scr and 24 hours urine protein, suggesting that acupuncture treatment had a protective effect on the kidneys.

Conclusions:

Acupuncture therapy combined with conventional pharmacotherapy is an efficient and safe way in the treatment of SLE. However, the conclusions drawn from this meta-analysis have some limitations due to the small number and uneven quality of the included studies, leading to heterogeneity and bias. Thus more relevant high-quality randomized controlled trials are needed for further evaluation in the future.

1. Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystem involvement, mainly affecting young and middle-aged women, which can cause life-threatening damage to multiple organs. The cause of the disease is not known and may be related to the external environment, endocrine factors, genetic factors, drug effects, and infectious factors.^[1] Hydroxychloroquine, glucocorticoids, immunosuppressive drugs (including cyclophosphamide, azathioprine, and hydroxychloroquine), and some biological agents are currently used in the traditional treatment of this disease,^[2] but their use in clinical practice is somewhat limited by the long duration of treatment, the high number of adverse effects and the relatively high cost of the drugs.

Acupuncture is an essential component of traditional Chinese medicine treatment. Research has shown that its effects are mediated by the human central nervous system,^[3] and stimulation by acupuncture significantly modulates the activity of the limbic system, parietal and subcortical gray matter structures,^[4] and also relieves pain. Modulating the balance of distributed central networks associated with pain^[5] and the brain’s response to acupuncture stimulation involves a broad network of regions, including somatosensory as well as emotional and cognitive processing.^[6] In the treatment of SLE with traditional therapies, acupuncture is uniquely effective in relieving symptoms, controlling the disease, regulating immune function, reducing the toxic side effects of hormonal withdrawal and western drugs, and reducing complications. The clinical application of acupuncture in patients with SLE can effectively relieve pain, improve clinical symptoms, and enhance the patient’s quality of life.^[7]

Thus it is necessary to clarify the safety and efficacy of acupuncture combined with conventional pharmacotherapy versus conventional pharmacotherapy alone in the clinical application of SLE, to maximize the advantages of TCM treatment and thus improve the overall treatment effect of SLE. In this study, we retrieved randomized controlled trials (RCTs) of acupuncture therapy combined with conventional pharmacotherapy for the treatment of SLE and conducted a comprehensive analysis and investigation of the overall remission rate, SLE disease activity index (SLEDAI), and TCM symptom scores, immunological indexes, and incidence of adverse effects after treatment aiming to provide clinical treatment strategies for SLE with acupuncture as adjuvant treatment guidance and provide evidence-based medical evidence.

Therefore, it is imperative to clarify the safety and efficacy of acupuncture combined with conventional drug therapy versus conventional drug therapy alone in the clinical application of SLE in order to maximize the advantages of TCM treatment and thus improve the overall treatment outcome of SLE. In this study, we searched RCTs of acupuncture therapy combined with conventional drugs for the treatment of SLE, and conducted a comprehensive analysis of the overall remission rate, TCM symptom scores, Systemic lupus erythematosus disease activity index (SLEDAI), immunological indicators, and incidence of adverse effects after treatment, with the aim of providing evidence-based clinical treatment strategies for the acupuncture-assisted treatment of SLE medical evidence.

2. Methods

2.1. Protocol register

Study screening, eligibility criteria assessment, data extraction, and statistical analysis were performed according to a prespecified protocol that was registered prior to the start of the review (PROSPERO: CRD42022362372). The protocol was developed in accordance with the Cochrane Collaboration methodological guidelines,^[8] and the manuscript was developed in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.^[8] The protocol was not prepared.

2.2. Information sources and search

The following databases were searched: Wanfang Database, China National Knowledge Infrastructure, PubMed, Embase, Web of Science, and Cochrane Library. Retrieval time was from database establishment to March 4, 2023 (It should be noted that when this meta-analysis was initially registered on PROSPERO, the data retrieval deadline was April 2022; however, in order to ensure that the data are accurate and current, we reretrieve the data at March 4, 2023). The strategy will combine the following Medical Subject Headings and free-text words: “lupus erythematosus, systemic,” “Systemic Lupus Erythematosus,” “Lupus Erythematosus Disseminatus,” “Libman-Sacks Disease,” “Disease, Libman-Sacks,” “Libman Sacks Disease,” “Lupus Erythematosus, Systemic,” “Lupus Nephritis,” “Lupus Vasculitis, Central Nervous System,” “Lupus,” “Acupuncture,” “Acupuncture Therapy,” “Pharmacopuncture,” “Electropuncture,” “Acupoint,” “electro-acupuncture.” This search strategy was modified to particular database limitations based on the features of each database. Additionally, the list of references for the selected studies and reviews was also carefully checked to manually identify eligible articles.

2.3. Study selection

The literature search and screening were conducted by 2 reviewers independently. First, the titles and abstracts of the records were initially reviewed to identify suitable studies based on the eligibility criteria. Next, the studies that met the criteria were screened by reviewing the full text and the reasons for exclusion were noted in the excluded studies. When disagreements arose, a third reviewer arbitrated the literature.

2.4. Inclusion and exclusion criteria

Studies that only mention randomization or clinical controlled trials were also included. However, case reports, animal mechanism studies, conference abstracts, and non-RCTs will be excluded. Patients were enrolled as long as they were diagnosed with SLE according to any 1 of the generally accepted criteria.^[9–13] Gender, age, and nationality are not restricted. Types of conventional medications will be included in the research. The acupuncture approaches were defined as needle stimulation of acupoints, including manual acupuncture, electroacupuncture, thread embedding, warm acupuncture, moxibustion, and acupoint application. The control group involved medication, placebo, sham acupuncture, routine care, and so on. If the treatment group employed acupuncture in combination with other therapies, the control group should use the same therapies without acupuncture. Furthermore, RCTs comparing various types of acupuncture were omitted.

2.5. Data extraction

Using the information provided in the articles, 2 authors independently extracted data in the designed form. The data collection form involved the name of the first author, publication year, Treatment duration, sample size, the characteristics of the participants (age, gender, years, diagnostic criteria of SLE, and course of disease), interventions, outcomes, and adverse events. If there was a discrepancy, it was submitted by a third reviewer for adjudication.

2.6. Evidence quality evaluation

The quality of the evidence is assessed for each outcome using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method, and the system produces a summary table of outcomes and evidence profiles as a result. Depending on factors such as limitation, inconsistency, inaccuracy, publication bias, and indirectness. The quality of evidence was first assigned a label of “high quality,” which could then be reduced to “moderate quality,” “low quality,” or “very low quality.”^[14] If there were any discrepancies in the results, the third reviewer made the ultimate judgment.

2.7. Risk of bias in individual studies

To analyze the risk of bias in the individual studies, we used the Cochrane Collaboration’s Risk of Bias Assessment Tool for Randomized Trials.^[15] Two reviewers performed this work independently. The evaluation was performed at the study level and different opinions were agreed upon through discussion. Order generation, allocation concealment, blinding, selective outcome reporting, incomplete outcome data, and other risks of bias were assessed as adequate (low risk of bias), inadequate (high risk of bias), or inconclusive (insufficient information). Individual studies were scored using the scoring criteria for the different domains in the Cochrane Handbook.^[8]

2.8. Data synthesis

The following outcome indicators were included in studies that report one or more of them. The primary outcome indicators were the overall response rate, and the secondary outcome indicators mainly include SLEDAI, TCM symptom scores, C3, C4, IgG, IL-6, T lymphocyte subpopulation (CD4⁺, CD4⁺/CD8⁺), ds-DNA, ESR, adverse events, BUN, Scr, and 24-hour urine protein.

Statistical heterogeneity, methodological heterogeneity, and clinical heterogeneity are the 3 types of heterogeneity. At the outset, methodological heterogeneity and clinical heterogeneity were assessed. Clinical heterogeneity refers to differences in outcomes caused by different patients, therapies, and study endpoint indicators. Statistical heterogeneity between studies should be measured using Q-tests and I² scores. I² > 50% and P < .1 implies high heterogeneity between studies, while I² < 50% and P > 0.1 implies low heterogeneity.^[16] If statistical heterogeneity was low (I² > 50% and P < .1), a fixed-effects model was used to combine the data, otherwise, a random effects model was utilized. For impact indices of continuous variables, including SLEDAI, TCM symptom scores, C3, C4, IgG, IL-6, T lymphocyte subpopulation (CD4⁺, CD4⁺/CD8⁺), ds-DNA, ESR, BUN, Scr, and 24-hour urine protein, we calculated standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI). For overall response rate and adverse events, we calculated relative risk with 95% CI. To investigate the various sources of heterogeneity, we used subgroup analysis and sensitivity analysis. If necessary data were available, we performed subgroup analyses for different acupuncture interventions and different types of controls. Sensitivity analyses were used to determine the robustness of the pooled estimates. In all statistical analyses, P < .05 were considered statistically significant. All analyses were performed using RevMan V.5.3.5 (Cochrane, London, UK).

2.9. Ethics

Given it is a secondary study based on published literature, no further ethical permission is required.

3. Results

3.1. Study selection

A total of 603 studies were retrieved from the database, and an additional 15 records were included through other sources. 52 duplicate copies of records were excluded. By screening titles and abstracts, 525 articles were excluded from the remaining 549 articles. And 18 studies were found to be inappropriate by reading the full text and were therefore removed. Finally, 7 eligible studies were included in this meta-analysis (Greco et al 2008; Chen 2012; Zuo et al 2012; Wang et al 2018; He et al 2020; You et al 2022; He, 2022). The process of study selection is shown in Figure 1. Six of the included studies were published in Chinese medical journals between 2012 and 2022.

Figure 1.

PRISMA flow diagram of screening process.

3.2. Study characteristics

The general features of the included studies are shown in Table 1. Seven eligible studies included a total of 514 SLE patients. The 261 cases in the control group were treated with conventional medications, including hydroxychloroquine, prednisone, and cyclophosphamide. The 253 patients in the experimental group were treated with acupuncture combined with medication, while the control group was treated with medication only. The duration of treatment ranged from 5 weeks to 34 weeks.

Table 1.

Basic characteristics of the included studies.

Included trial	Participants(M/F; age years)		Diagnostic criteria of SLE	Course of disease(month)		Intervention		Treatment duration	Outcome index
	Experimental	Control		Experimental	Control	Experimental	Control
Greco 2008[17]	0/7; >18	1/15; >18	1997 ACR	>3	>3	ACT(Bi-weekly) plus CM	CS(2–10mg qd) plus AIM(qd)	5 weeks	1 2 3 4 7 8 9
Chen 2012[18]	8/24; 15–68, 39.3	7/25; 16–67,39	1982 ACR	4–13, 4.9	4–12, 4.7	ACT(30min qd) plus CM	DXM(10–15mg QD)	3 months	10
Zuo 2012[19]	2/58; 13–45, 25.46 ± 10.43		1982 ACR	Within 1 year: 29 cases 1–10 years: 20 cases more than 10 years: 11 cases		BAIT(SNF) plus CM	RDRT	8 weeks	14 15 16 17 18
You 2022[20]	17/16; 18–59, 34.38 ± 5.25	16/17; 19–59, 34.34 ± 5.23	1997 ACR	2–10, 4.15 ± 0.49	2–9, 4.12 ± 0.44	AA(once every 2 days) plus TCMD(200ml bid) and RNI	RNI	3 months	5 6 7 11 15 18 19 20
Wang 2018[21]	21/30; 21–77, 41.24 ± 5.21	21/30; 20–78, 41.29 ± 5.20	1997 ACR	3–12, 6.73 ± 1.24	2–13, 6.79 ± 1.28	ACT(30min qd) plus TCMD(200ml bid)	HCQ(0.1g bid) plus PED(40 mg qd)	2 months	6 7 9 10 11 21 23
He 2020[22]	22/27; 18–61, 52.47 ± 5.12	23/25; 21–62, 51.46 ± 4.13	2007 NCACM	3–6, 4.71 ± 1.25	3–6, 4.53 ± 1.81	ACT(30min qd) plus TCMD(200ml bid) and CM	HCQ (0.2 g qd) plus CTX (0.6 or 0.8 g/m2 once every 3 months)	34 weeks	3 7 10 18 19 21 22 23
He 2022[23]	23/28; 21–68, 48.61 ± 4.15	22/29; 20–69, 48.65 ± 4.23	2003 RCMA	5–28, 13.28 ± 2.07	4–29, 13.23 ± 2.11	ACT(2–3 times a week, 30min each time) plus TCMD(200ml tid) and CM	HCQ(0.1g bid) plus PED(40 mg qd)	12 weeks	3 7 8 10 11 14 20 21 23

1. AIMS2 Pain, 2. MPI, 3. SF-36, 4. FSS, 5. WHOQOL-BREF, 6. TCM symptoms scores, 7. SLEDAI Scores, 8. IL, 9. Adverse effects, 10. Overall response rate, 11. 24-hour urine protein, 12. Plasma proteins, 13. Urinary tubular type, 14. CD4/CD8, 15. IgG, 16. IgA, 17. IgM 18. C3, C4, 19. BUN, SCr, 20. ds-DNA, 21. ESR, 22. Urine PCX concentration, 23. Blood viscosity and changes in each component, 24. ALT/AST.

AA = acupoint application, ACR = American College of Rheumatology, ACT = Acupuncture Therapy, AIM = anti-inflammatory medicines, BAIT = blood acupoint-injection therapy, CM = chemical medicine of the control group, CS = corticosteroids (2–10 mg), CTX = cyclophosphamide, DXM = dexamethasone, HCQ = hydroxychloroquine sulfate, MN = minimal needling (which involves shallow insertion of needles on body areas that are not known to correspond to AC points, was the control intervention), NCACM = Nephropathy Branch of China Association of Chinese Medicine, NMPA = National Medical Products Administration, PED = prednison or prednisolone acetate, RCMA = Rheumatology Branch of Chinese Medical Association, RDRT = Rheumatism Dept routine therapy, RNI = routine nursing interventions (environmental care, dietary care, psychological care, oral care, health education), SLICC = Systemic Lupus International Collaborating Clinic, SNF = stepped needle feed (the first to third acupoint-injections are daily, the fourth to sixth acupoint-injections are every other day, and the seventh to tenth acupoint-injections are every second day), TCMD = Traditional Chinese Medicine decoction.

3.3. Trial quality

Figures 2 and 3 depict the detailed bias assessment of the included trials. 75% of the trials declared the use of random assignment methods, but only 1 explicitly stated the use of random number tables, and a few mentioned binding methods and allocation concealment. Outcome data were reported with completeness and selectivity, and only 1 study was assessed as being at high risk of bias due to data deficiencies and incomplete reporting of specified indicators. There were no other significant biases in the included studies. None of the trials described above provided raw information, so we extracted only summary data from the publisher for assessment, which may have subjected the analysis to information bias.

Figure 2.

Risk of bias summary.

Figure 3.

Risk of bias graph.

3.4. Efficacy

3.4.1. Overall response rate.

Five trials have reported the overall response rate as the primary outcome. Analysis was performed using a fixed-effects model based on a heterogeneity test (P = .69, I² = 0%). As a result of treatment, the overall response rate was higher in the experimental group than in the control group (RR = 1.20, 95% CI [1.11, 1.29], P < .00001) (Fig. 4).

Figure 4.

Forest plot of overall response rate.

3.4.2. SLEDAI, TCM symptoms scores.

Analysis of SLEDAI from 5 trials and TCM symptom scores from 2 trials were performed separately. Owing to the high heterogeneity (SLEDAI: P < .0001, I² = 84%; TCM symptom scores: P = .06, I² = 71%), a random effects model was used for both analyses. Both SLEDAI and TCM symptom scores were considerably lower in the experimental group compared to the control group (SLEDAI: SMD = –1.23, 95% CI [–1.81, –0.65], P < .0001; TCM symptom scores: MD = –3.68, 95% CI [–4.68, –2.68], P < .00001) (Fig. 5). One trial (He 2022) did not include an analysis of TCM symptom scores because it used subdivided TCM symptom scores but reported results showing that TCM symptom scores could be significantly lower in the experimental group compared to the control group. Sensitivity analyses identified studies by Greco 2008 and You 2022 as a source of heterogeneity for this pooled analysis, and excluding these 2 papers resulted in I² = 30%. Analysis of their study designs revealed that Greco 2008 did not include a herbal intervention in the experimental group, and You 2022 used the treatment method of acupoint application. Broadly speaking, acupoint application belongs to a new treatment method derived from the development process of acupuncture treatment, but it is still slightly different from the traditional acupuncture treatment, which may be the reason for its high heterogeneity.

Figure 5.

Forest plot of SLEDAI scores (A) and TCM symptoms scores (B).

3.4.3. C3, C4, IgG.

C3, C4, and IgG are indicators of humoral immunity. According to the analysis of the 3 included indicators, the heterogeneity test suggested low heterogeneity of C3 and ESR levels (C3: P = .41, I² = 0%; ESR: P = .40, I² = 0%), so a fixed-effects model was applied for both indicators. Heterogeneity test of IgG showed a high heterogeneity, so a random effects model was adopted (P = .02, I² = 80%). The differences between the experimental and control groups were statistically significant for C3, C4 and IgG (C3: MD = 0.19, 95% CI [0.13, 0.24], P < .00001; C4: MD = 0.07, 95% CI [0.06, 0.08], P < .0001; IgG: MD = –4.41, 95% CI [–7.40, –1.43], P = .004), indicating that the experimental group was effective in elevating C3 and C4 levels and reducing IgG levels (Fig. 6). Subgroup analyses or sensitivity analyses could not be performed because only 2 study contributions were included in the pooled analysis of IgG. Same as before, it is possible that the method of acupoint application in You 2022 resulted in high heterogeneity.

Figure 6.

Forest plot of C3 (A), C4 (B), and IgG (C).

3.4.4. CD4⁺, CD4⁺/CD8⁺, IL-6.

CD4⁺, CD4⁺/CD8⁺, IL-6 are all assays for cellular immunity, All of which were analyzed using a fixed-effects model due to low heterogeneities (CD4⁺: P = .74, I² = 0%; CD4⁺/CD8⁺: P = .78, I² = 0%; IL-6: P = .27, I² = 18%). The results indicated that additional use of acupuncture treatment was capable of increasing peripheral blood CD4⁺ level and CD4⁺/CD8⁺ ratio while reducing the level of IgG (CD4⁺: MD = 4.13, 95% CI [2.35, 5.90], P < .00001; CD4⁺/CD8⁺: MD = 0.15, 95% CI [0.09, 0.21], P < 0.00001; IL-6: SMD = –1.08, 95% CI [–1.46, –0.69], P < .00001), suggesting that the experimental group was more effective in improving cellular immunity (Fig. 7).

Figure 7.

Forest plot of CD4⁺ (A), CD4⁺/CD8⁺ (B), and IL-6 (C).

3.4.5. ds-DNA, ESR.

Ds-DNA is an indicator of autoantibody detection and ESR is an indicator of inflammatory response Significant heterogeneity was found in ds-DNA while low heterogeneity was found in ESR (ds-DNA: P = .02, I² = 83%; ESR: P = .55, I² = 0%). Therefore, the ds-DNA data were evaluated using a random effects model, and the ESR level used a fixed-effects model. The results showed that compared to the control group, the experimental group was more capable of reducing the production of autoantibodies effectively, thus alleviating the auto-inflammatory response (ds-DNA: MD = –15.17, 95% CI [–26.73, –3.61], P = .01; ESR: MD = –6.70, 95% CI [–7.73, –5.67], P < .00001) (Fig. 8). Pooled analyses of ds-DNA could not be performed for subgroup analyses or sensitivity analyses because the contributions of only 2 studies were included in the pooled analysis. As before, the acupoint application of You 2022 may have contributed to the high degree of heterogeneity in the study.

Figure 8.

Forest plot of ds-DNA (A) and ESR (B).

3.5. Safety

3.5.1. Adverse reaction.

The 3 included trials reported adverse reactions during treatment, including symptoms such as nausea, malaise, and headache. The studies showed moderate heterogeneity (P = .19, I² = 40%), so a fixed-effects model was used. The results showed that the experimental group had fewer side effects reported (RR = 0.38, 95% CI [0.18, 0.78], P = .009), suggesting that acupuncture has a better safety in the management of SLE (Fig. 9).

Figure 9.

Forest plot of adverse reaction.

3.5.2. BUN, Scr, 24-hour urine protein.

BUN, Scr, and 24-hour urine protein are important indicators reflecting the function of kidneys, and the development of SLE is most prone to involve the kidneys, so the 3 indicators are important for judging whether acupuncture has a protective effect on the kidneys or not. BUN and Scr levels were reported in 2 trials while 24-hour urine protein was reported in 3 trails. A fixed-effects model was used for BUN and Scr because of their low heterogeneity (BUN: P = .83, I² = 0%; Scr: P = .60, I² = 0%). And random effects model was used in 24-hour urine protein because of its high heterogeneity (P = .05, I² = 68%) Pooled analysis showed that BUN, Scr, and 24-hour urine protein levels were reduced in the experimental group compared with the control group (BUN: MD = –2.98, 95% CI [–3.34, –2.62], P < .00001; Scr: MD = –20.03, 95% CI [–25.07, –14.99], P < .00001; 24-hour urine protein: MD = –0.26, 95% CI [–0.34, –0.18], P < .00001), suggesting that acupuncture treatment had a protective effect on the kidneys (Fig. 10). Sensitivity analysis of 24-hour urine protein found He 2022 to be the source of its heterogeneity, and excluding this article reduced the heterogeneity to 0%. By analyzing its methodology, it was found that its combination of traditional Chinese medicine may contribute to a better improvement effect on 24-hour urine protein.

Figure 10.

Forest plot of BUN (A), Scr (B), and 24-hour urine protein (C).

3.6. Publication bias

An Egger test on the overall response rate showed P = .028, indicating that there was a publication bias in the studies included, which may have been due to an inadequate number of included studies and negative unpublished results.

4. Discussion

SLE is a systemic autoimmune disease characterized by systemic multiorgan involvement, recurrent relapses and remissions, and many autoantibodies in the body. SLE mainly affects women of reproductive age, with a male-to-female incidence ratio of 1:10–12.^[24] Currently, hormones and immunosuppressive drugs are mainly used to treat SLE, but these drugs have both advantages and disadvantages and have caused different degrees of complications and adverse effects while playing an effective role. For example, long-term use of high doses of hormones and immunosuppressants can cause side effects such as infection, Cushing syndrome, and osteoporosis.^[25] In contrast, acupuncture therapy attaches importance to both supporting the vital qi and eliminating the evil qi, and it can cure diseases by regulating qi and blood. Therefore, combining traditional Chinese medical therapy and chemical drugs to treat SLE has become one of the new research areas.

In recent years, acupuncture therapy has been used to intervene in SLE to shorten the treatment course, prevent disease progression, and achieve optimal therapeutic results. Results from a 2014 retrospective UK study of patients with SLE also showed that 32% of subjects (n = 806) were looking for additional support beyond conventional medication, such as massage and acupuncture.^[26] The results demonstrate that it is difficult to achieve satisfactory results in treating SLE with conventional pharmacotherapy alone. Specifically, the combination of acupuncture and traditional medication not only improved the symptoms (e.g., fatigue, depression, pain) and related immunological parameters (e.g., C3, C4, IgG, IgA) of SLE patients, but also reduced the side effects of long-term use of high doses of hormones and immunosuppressive drugs, such as infections, Cushing syndrome, and osteoporosis.^[27] According to TCM theory, fatigue in SLE patients is mainly caused by qi deficiency, and acupuncture can relieve fatigue in lupus patients by tonifying qi. A previous study confirmed that acupuncture can improve fatigue symptoms of SLE patients.^[28] In addition, TCM theory suggests that the main causes of pain in SLE patients are “pain if being blocked” and “pain if not moistened and nourished,” and acupuncture can relieve pain in SLE patients by regulating qi and unblocking qi and blood. In addition, research on the mechanism of acupuncture for SLE is ongoing. For example, some findings suggest that acupuncture can regulate IL-6 expression through the TLR4/ NF-κB pathway, thereby alleviating inflammation, which could be a potential strategy for the treatment of SLE.^[29] However, it remains to be further investigated for its specific mechanism of action.

The result of this meta-analysis showed that the group combined with acupuncture therapy presented a more satisfactory efficacy than the group that intervened with drug therapy alone, including improving the overall response rate while reducing SLEDAI scores, TCM symptom scores. In terms of Immunity indicators (Humoral immunity: C3, C4, IgG; Cellular immunity: T-cell subpopulation (CD4⁺, CD4⁺/CD8⁺), cytokines (IL-6); Autoantibodies: ds-DNA; Inflammatory indicators: ESR), the patients who intervened with both acupuncture and conventional therapy were found significantly increased in C3 and C4 levels, which improved their autoimmune status. Besides, those intervened with acupuncture have lower IgG, IL-6, ds-DNA levels, suggesting slighter autoimmune reactions. In the aspect of BUN, Scr, and 24-hour urine protein, the patients applied to both acupuncture and drug therapy had better results in reducing BUN, Scr, and 24-hour urine protein levels, suggesting the intervention of acupuncture has a protective effect on the kidneys during the treatment of SLE. In the evaluation of adverse effects during treatment, 3 studies reported adverse reactions or complications, including nausea, malaise, headache, bruising, transient bleeding, muscle aches, and low-grade fever, and no life-threatening events were reported. Additionally, the incidence of adverse reactions was significantly lower when combined with acupuncture therapy, suggesting a good safety profile for acupuncture therapy in treating SLE.

5. Limitations and implications

The existing limitations: 1) Quality of included studies: The quality of included randomized controlled trials (RCTs) is variable, which can affect the reliability and validity of the overall results. Studies with methodological flaws, insufficient blinding, or small sample sizes may introduce biases that affect the precision of estimated treatment effects; 2) Publication bias: there is some publication bias in the included studies, probably due to the existence of nonpublished negative results. studies on acupuncture for SLE were mainly initiated by Chinese scholars, and most of the study subjects were also mainly Chinese, making the possibility of bias in the results; 3) Limited number of studies: the number of relevant RCT is limited, and some ongoing experiments were not included in this Meta-analysis, which may limit the statistical power and generalizability of the findings. However, we hope that this meta-analysis will inspire more researchers to conduct relevant experiments to provide more credible evidence for this new therapy in treating SLE; 4) Lack of long-term data: the follow-up was inadequate, as the long-term outcome is essential for assessing the treatment means due to the complexity and recurrence of SLE; 5) Heterogeneity: heterogeneity in this meta-analysis stems mainly from the modality of the intervention (with or without herbal intervention, type of drug administered, frequency), the type of acupuncture (1 study used acupoint application and 1 study used acupoint injections; the acupoints used in each study were not exactly the same), and the participant (1 research involved participant of patient with lupus nephritis). 6) Limited scope of outcomes: In addition to the outcomes involved in this meta-analysis, IgA, IL-4, Th1/Th2, IFN-gamma, and other outcomes are also important indicators reflecting the development of SLE. Due to insufficient number of included studies, meta-analysis of the above indicators was not applied; The above limitations adversely affected the credibility of this meta-analysis.

Implications for clinical and research: 1) In the treatment process of SLE, patients are advised to take both acupuncture therapy and pharmacotherapy to enhance the efficacy and reduce adverse effects; 2) due to the complexity of TCM theory, the acupuncture points taken in each experiment will differ according to the actual situation. Still, it can be ensured that the acupuncture points taken in the same experiment have uniformity. This is one of the shortcomings of acupuncture therapy in clinical RCTs, and there have been articles suggesting ways to improve it.^[30] It is expected that future RCTs focusing on acupuncture can adopt the relevant suggestions. 3) Well-designed, strictly implemented, high-quality, multicenter RCTs with large sample size and uniform outcome indicators are needed to further validate the effectiveness and safety of acupuncture therapy in SLE treatment.

6. Conclusion

This meta-analysis shows that synergistic treatment by combining acupuncture therapy with conventional pharmacotherapy can significantly improve efficiency and safety. However, due to the limitations of the included studies, more well-designed, well-executed, high-quality RCTs with large sample sizes are necessary to further verify the long-term safety and efficacy of acupuncture in treating SLE.

Acknowledgments

Thank all participants for their kindly help during the formation and finalization processes of the manuscript.

Author contributions

Conceptualization: Ting Zhao.

Data curation: Hanzheng Wang, Baizhou Wang.

Formal analysis: Hanzheng Wang, Baizhou Wang.

Funding acquisition: Zi Yang, Ziyu Song, Zhijun Xie, Qice Sun, Ting Zhao.

Investigation: Jinge Huang, Qingmiao Zhu.

Methodology: Hanzheng Wang, Jinge Huang.

Project administration: Jinge Huang.

Resources: Baizhou Wang.

Software: Hanzheng Wang, Baizhou Wang.

Supervision: Zi Yang, Ziyu Song, Qingmiao Zhu, Zhijun Xie, Qice Sun, Ting Zhao.

Validation: Zi Yang, Ziyu Song, Zhijun Xie, Qice Sun, Ting Zhao.

Writing – original draft: Hanzheng Wang, Baizhou Wang, Jinge Huang.

Writing – review & editing: Hanzheng Wang, Ting Zhao.