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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 8
| Issue : 1 | Page : 153-167 |
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Therapeutics of integrative medicine ameliorate immunological disorders of the nervous system: A meta-analysis
Jin-Yun Ma1, Jennifer Cruz2, Jason Jin1, Xiao-Yan Peng1, Ai-Ming Zhang3, Xiao-Dong Cheng1
1 Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
2 Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China, Doctoral Program of Acupuncture and Oriental Medicine, The Atlantic Institute of Oriental Medicine, Florida 33301, USA
3 Department of Neurology, Min-Hang Hospital of Integrative Medicine, Shanghai 200241, China
| Date of Submission | 30-Oct-2020 |
| Date of Acceptance | 08-Jun-2021 |
| Date of Web Publication | 29-Jan-2022 |
Correspondence Address:
Prof. Xiao-Dong Cheng
Institute of Clinical Immunology, Yue-Yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/wjtcm.wjtcm_57_21
Objective: The objective of the study is to evaluate the therapeutic efficacy of integrative medicine in the treatment of immunological disorders of the nervous system. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were adopted to conduct this study, which included randomized controlled trials with a confirmed diagnosis of multiple sclerosis (MS), myasthenia gravis (MG), and Guillain–Barre syndrome (GBS), all of which were treated with integrative medicine. The effective rate, recurrent frequency, and disease score were used as the markers of outcome variables for the meta-analysis. Results: A total of 48 randomized control trials were included. The effective rates of treatment with integrative medicine were noticeably higher than those with Western medicine alone for the three diseases. The recurrence frequency for MS and the recurrence rate for MG treated with integrative medicine were reduced more than those with Western medicine alone. The Extended Disability Status Scale, acetylcholine receptor antibody, and Hughes scores for MS, MG, and GBS, respectively, treated with integrative medicine were significantly lower than those with Western medicine alone. The risks of bias in the literature evaluation showed that the quality of the included studies was not high. Conclusions: Compared to treatment with Western medicine alone, integrative medicine might ameliorate immunological disorders of the nervous system.
Keywords: Guillain–Barre syndrome; integrative medicine; meta-analysis; multiple sclerosis; myasthenia gravis
How to cite this article:
Ma JY, Cruz J, Jin J, Peng XY, Zhang AM, Cheng XD. Therapeutics of integrative medicine ameliorate immunological disorders of the nervous system: A meta-analysis. World J Tradit Chin Med 2022;8:153-67 |
How to cite this URL:
Ma JY, Cruz J, Jin J, Peng XY, Zhang AM, Cheng XD. Therapeutics of integrative medicine ameliorate immunological disorders of the nervous system: A meta-analysis. World J Tradit Chin Med [serial online] 2022 [cited 2023 Jun 2];8:153-67. Available from: https://www.wjtcm.net/text.asp?2022/8/1/153/336837 |
| Introduction | |  |
Multiple sclerosis (MS), myasthenia gravis (MG), and Guillain–Barre syndrome (GBS) are three common immunological disorders of the nervous system that are caused by autoimmune inflammatory responses. They can occur when autoantibodies attack the central nervous system (CNS), neuromuscular junctions, or the peripheral nervous system. Common pathological changes include demyelination, neurodegeneration, and neuromuscular junction injury. MS is a chronic autoimmune inflammatory demyelinating disease of the CNS. With respect to pathomechanisms, autoimmune inflammation in the early MS is primarily mediated by adaptive immune responses and involves autoreactive T cells, B cells, and antibodies, while the later, chronic stages of MS are characterized by a compartmentalized immune response in the CNS with activated microglia and macrophages.[1] Immunological disorders are clinically characterized by a lower quality of life, decreased range of motion, atrophy, fatigue, cognitive dysfunction, depression, moodiness, and loss of vision, balance, and mobility.[2] MS commonly strikes young people and requires lifelong treatment.[3],[4] MG is the most common autoimmune disorder affecting neuromuscular junctions. It is caused by autoantibodies targeting proteins of the neuromuscular junction; ~85% of MG patients have autoantibodies against the muscular acetylcholine receptor (AChR-MG).[5] The measurement of AchR antibody (AChR-ab) titers is of special significance in the diagnosis of MG. The main clinical manifestations are partial or systemic skeletal muscle weakness and fatigue, aggravated after activity, and relieved after rest. The onset of the disease is most likely to occur in men between 20 and 40 years of age and in women between 50 and 70 years of age.[6] GBS is an acute immune-mediated polyradiculoneuropathy. The main pathophysiological mechanism is complement-mediated nerve injury caused by antibody–antigen interactions in the peripheral nerves.[7] It is clinically characterized by progressive ascending symmetry paralysis, quadriplegia, and varied levels of sensory impairment. Approximately 100,000 people worldwide are afflicted by this disease annually.[8],[9] The three representative autoimmune diseases in the nervous system are primarily treated with glucocorticoids, immunosuppressants, and immunoglobulins. However, none of these drugs can completely cure these three diseases. These drugs have serious side effects. Therefore, new and more effective therapeutic approaches are needed in clinical settings.
According to the basic theories of traditional Chinese medicine (TCM), MS, MG, and GBS can be classified as “flaccidity syndrome.”[10] According to TCM, both external and internal potential pathogenic factors play important roles and are differentiated as follows: (1) hot and humid immersed, (2) the wind, phlegm, and blood stasis, (3) blood stasis obstructing collaterals, (4) qi deficiency and blood stasis; (5) liver and kidney yin deficiency, (6) spleen qi deficiency, and (7) kidney yang deficiency.[11]
TCM therapeutics are known to have neuroprotective effects in the clinic.[12],[13] Integrative medicine combines Chinese herbal medicine and acupuncture with Western medicine. Therapeutics of integrative medicine can bridge possible gaps in Western medicine and relieve the symptoms of patients with “flaccidity syndrome” such as paresthesia, bulging, numbness, tingling, nerve misfiring, zonesthesia, itching, and extremity weakness. Furthermore, it can potentially improve a patient's ability to exercise.[14] Clinical data and experience show that the therapeutic effects of integrative medicine based on syndrome differentiation and individual therapy have potential advantages. However, additional experimental data are needed to confirm the efficacy of integrative medicine. In fact, a meta-analysis we previously published showed that integrative medicine was therapeutically more effective in treating neurological autoimmune diseases compared to Western medicine alone.[15] However, a previous study analyzed the data from the two kinds of autoimmune diseases in the nervous system, MS, and GBS. In this study, we performed an updated quantitative meta-analysis to explore and confirm the clinical efficacy of integrative medicine in the treatment of MG, MS, and GBS. A total of 48 studies were included in this study, compared to 25 in the previous study. In addition, articles published between 2018 and 2019 were included in this study.
| Methods | | |
Search strategy
The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were adopted to plan and conduct this study.[16] Systematic information retrieval was performed in PubMed, the Cochrane Library, CNKI, Wan-fang, CBM, and CQVIP databases for all relevant articles, regarding the therapeutic effects of integrative medicine in treating MS, MG, and GBS.
Integrative medicine was defined as the combination of Chinese herbal medicine or acupuncture with Western medicine. The following keywords were used: (”multiple sclerosis or MS” or “myasthenia gravis or MG” or “Guillain-Barre syndrome or GBS”) and (”integrative medicine” or “combined traditional Chinese and Western medicine” or “Chinese herbal medicine” or (herb or herbal) or “traditional Chinese medicine” or “acupuncture”) and (”randomized controlled trial” or “RCT”). The search interval was set from inception to December 31, 2019, without language restrictions.
Inclusion and exclusion criteria
Inclusion criteria
Articles were included if (1) the study was a randomized controlled trial (RCT); (2) the diagnosis of MS, MG, or GBS was confirmed; (3) the therapeutic effects were based on Western medicine combined with Chinese herbal medicine or acupuncture; and (4) the study was original.
Exclusion criteria
Publications were excluded if (1) the study was a repetition of published research; (2) the sample size was smaller than 10 or unknown; (3) the outcome data were incomplete or it was not possible to extract valid data for statistical analysis; and (4) the study was an experimental research performed on animals.
Data extraction
Data extraction and literature quality assessment were independently performed by two researchers. The extracted content included author, diagnostic criteria, sample size, sex, interventions in the experimental group and in the control group, treatment time, follow-up period, demographic patient data (e.g., age, gender, and ethnicity), methods for RCT (e.g., randomization, allocation concealment, blind, dropout, and quit), interventions, control interventions, and outcomes (e.g., recurrence rate, efficient, extended disability status scale [EDSS], AchR-Ab, and Hughes score).
Risk of bias of literature evaluation
All studies were evaluated based on the risk of bias tool from the Cochrane Manual (version 5.3) for quality assessment.[17] This tool assesses the quality of the studies in seven domains: (1) random sequence generation; (2) allocation sequence concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias.
Data analysis
Review Manager software with version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis. The dichotomous data results were summarized using the risk ratio (RR) and 95% confidence interval (CI) as the effect size. Continuous data such as EDSS, AchR-Ab, and Hughes scores were summarized using mean differences (MDs) and 95% CI. The Chi-squared test and statistic I2 were chosen for heterogeneity testing.[18] A Chi-squared test level of P < 0.10 and I2 ≥50% were considered statistically significant. A random-effects model was used to pull the data when significant heterogeneity was found. Otherwise, a fixed-effect model was used.
| Results | | |
Literature retrieval
A total of 1365 records were retrieved regarding the therapeutic effects of integrative medicine based on syndrome differentiation and individual therapy for the diseases of MS, MG, and GBS. Of these records, 731 were from CNKI, 163 were from CBM, 266 were from Wan-fang, 182 were from CQVIP, 10 were from PubMed, and 13 were from Cochrane Library [Figure 1]. | Figure 1: Flowchart showing the study selection of screening records; CNKI: China National Knowledge Infrastructure; CBM: Chinese Biomedical Literature Database; Wan-fang: Wan-fang Data Knowledge Service Platform; CQVIP: Chongqing VIP
Click here to view |
After eliminating repetition references, animal studies, expert experience or discourses, review, case reports, non-RCT articles, and studies with sample size and incomplete data, 48 studies were finally included in this study: 15 on MS, 24 on MG, and 9 on GBS. These studies were published between 2000 and 2019.
Study characteristics
A total of 3646 cases of the research object were included, with a minimum sample size of 23 cases and a maximum of 240 cases. For MS, the effective rate was observed in 12 out of 15 studies; the recurrence frequency was reported in 4 of these 15 studies; and the EDSS was reported in 10 out of 15 studies. For MG, the effective rate was observed in 24 studies, and one study did not report the specific data, leaving 23; the recurrence rate was reported in 4 out of 24 studies, and one study did not report the specific data, leaving 3; AchR-Ab was observed in 10 out of 24 studies, and one study was too heterogeneous to be included, leaving 9 to be included in the statistical analysis. For GBS, the effective rate was reported in nine studies and the Hughes score was reported in three studies. The basic characteristics of the studies are presented in [Table 1] and [Table 2].
Risk of bias
The risk of bias in the literature was generally high. All studies reported the use of randomization, but only seven of them demonstrated a specific method of random number generation. Five of them used specific random allocation methods. Only 2 of the 48 studies utilized the single-blind method. Two studies reported dropout cases. Forty-eight studies proceeded with the baseline comparison between the experimental and control groups. The results showed that P values were higher than 0.05. Consistent with this, most of the included studies showed a clinical bias according to the bias risk assessment tools provided by the Cochrane Collaboration [Figure 2]a and [Figure 2]b. | Figure 2: The risk of methodological bias. (a) Risk of bias summary. (b) Risk of bias graph
Click here to view |
Outcomes
Effective rate
Effective rate of multiple sclerosis
Twelve of the 15 studies observed the effective rate.[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30] MS effective rate (R) was evaluated using the equation: R = (score before treatment − score after treatment)/score before treatment × 100%. R was not <20%, which is considered to be effective. The meta-analysis was performed using the fixed-effects model because there was no obvious heterogeneity (P = 0.32, I2 = 13%). The results showed that the combined effect quantity of RR was 1.28 (95% CI = [1.20, 1.38]) and statistically significant (Z = 6.93, P < 0.001). The effective rate of treatment with integrative medicine was higher than that with Western medicine alone [Figure 3].
Effective rate of multiple sclerosis
Twenty-four of 24 studies observed the effective rate, and valid data were extracted from 23.[26],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52] MG effective rate (R) was evaluated using the equation: R = (score before treatment − score after treatment)/score before treatment × 100%. R was not <25%, which is considered to be effective. The meta-analysis was performed using the random effects model because of obvious heterogeneity (P < 0.01, I2 = 78%). The results showed a combined effect of RR which was 1.17 (95% CI = [1.10, 1.25]). The effective rate of treatment with integrative medicine was significantly higher than that with Western medicine alone (Z = 4.90, P < 0.001) [Figure 4].
Effective rate of Guillain–Barre syndrome
Nine of nine studies observed the effective rate, and valid data were extracted from 9.[53],[54],[55],[56],[57],[58],[59],[60],[61] GBS effective rate was evaluated by the method of muscle strength of limbs increased by 1–2 grades. The meta-analysis was performed using the fixed-effects model without obvious heterogeneity (P = 0.12, I2 = 37%). The pooled analysis showed a combined effect of RR which was 1.12 (95% CI = [1.06, 1.19]). The effective rate of treatment with integrative medicine was greater than that with Western medicine alone. There were statistically significant differences between the two groups (Z = 3.95, P < 0.001) [Figure 5].
Recurrence frequency/rate
Recurrence frequency of multiple sclerosis
Four of the 15 studies were observed for their recurrence frequencies.[23],[29],[62],[63] The analysis was performed using the fixed-effect model with little heterogeneity (P = 0.21, I2 = 34%). Meta-analysis showed that the combined effect of MD was −0.47, (95% CI = [−0.60, −0.34]) and was statistically significant (Z = 6.94, P < 0.001). For the study of MS relapse prevention, the recurrence frequency in the group treated with integrative medicine was lower than that in the control group [Figure 6].
Recurrence rate of myasthenia gravis
Three of the 24 studies were observed for their recurrence rates.[26],[43],[64] The analysis was performed using the fixed-effects model with little heterogeneity (P = 0.99, I2 = 0%). Data analysis revealed that the combined effect of RR was 0.11 (95% CI = [0.05, 0.23]) and was statistically significant (Z = 5.78, P < 0.001). For the study of MG relapse prevention, the recurrence rate in the group treated with integrative medicine was lower than that in the control group [Figure 7]. | Figure 8: Forest plot of extended disability status scale score in multiple sclerosis
Click here to view |
Disease score or index
Extended disability status scale of multiple sclerosis
Nine of 15 studies were observed for EDSS.[19],[20],[22],[23],[24],[25],[27],[29],[65],[66] The random-effects model was adopted to conduct the analysis with an obvious heterogeneity (P < 0.001, I2 = 82%). The combined effect of MD was −1.24 (95% CI = [−1.76, −0.72]). The improvement in EDSS in the group treated with integrative medicine was statistically significantly higher than that in the group treated with Western medicine alone (Z = 4.66, P < 0.001) [Figure 8].{Figure 8}
Acetylcholine receptor antibody of myasthenia gravis
Ten of the 24 studies were observed for AchR-Ab.[31],[33],[36],[43],[44],[46],[47],[51],[52],[64] The heterogeneity of one study[33] was so obvious that it was excluded, and nine studies were included in this analysis. The random-effects analysis model was adopted to proceed with the meta-analysis due to a relatively obvious heterogeneity (P < 0.001, I2 = 93%). The combined effect of MD was −0.17 (95% CI = [−0.25, −0.09]). The level of reduction of AchR-Ab in the group treated with integrative medicine was statistically significantly reduced more than that in the group treated with Western medicine alone (Z = 4.01, P < 0.001) [Figure 9]. | Figure 9: Forest plot of acetylcholine receptor antibody in myasthenia gravis
Click here to view |
Hughes score of Guillain-Barre syndrome
Three of the nine studies[54],[58],[60] were observed for their Hughes score. The fixed-effects analysis model was used for pool analysis without obvious heterogeneity (P = 0.17, I2 = 43%). The combined effect of MD was −0.41, (95% CI = [−0.75, −0.07]). The degree of Hughes score in the group treated with integrative medicine was significantly lower than that in the group treated with Western medicine alone (Z = 2.33, P = 0.02) [Figure 10].
Publication bias
Funnel graphs were constructed to evaluate publication bias by RevMan5.3 The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, as shown in [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]. Funnel graphs of the effective rate of the three diseases displayed an imperfect symmetry [Figure 11], [Figure 12], [Figure 13], which indicated that there might be a publication bias. The EDSS of MS and AchR-Ab of the MG funnel plots are shown in [Figure 14] and [Figure 15]. Since the points on either side of the line seemed asymmetric, there may be a degree of subjectivity bias. We did not construct funnel graphs of recurrence frequency of MS, recurrence rate of MG, or Hughes score of GBS due to a limited number of studies. Consequently, we suspect that the publication bias regarding the three outcomes might be significant. | Figure 11: Funnel diagram of effective rate in multiple sclerosis included 12 studies
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 | Figure 12: Funnel diagram of effective rate in myasthenia gravis included 23 studies
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 | Figure 13: Funnel diagram of effective rate in Guillain-Barre syndrome included 9 studies
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 | Figure 14: Funnel diagram of extended disability status scale score in multiple sclerosis included 10 studies
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 | Figure 15: Funnel diagram of acetylcholine receptor antibody in myasthenia gravis included 9 studies
Click here to view |
| Discussion | | |
Therapeutic effect analysis
Effective rate and recurrence rate
The outcomes of the effective rate and recurrence frequency/rate showed that integrative medicine was superior to Western medicine alone in the treatment of the three diseases in both aspects. The results of these two indicators suggested that the therapeutic strategy of integrative medicine could not only effectively treat these three diseases but also prevent the recurrence of these diseases. A study investigated the type and frequency of integrative medicine use and determined whether the use of integrative medicine correlated with demographic, social, or disease-specific characteristics in the patient population.[67] They found that 99% of the surveyed patients reported the use of at least one integrative medicine for the treatment of amyotrophic lateral sclerosis. Chinese herbal decoctions and vitamins, Chinese herbal compounds, massage therapy, and acupuncture were the five most commonly used therapies. The main reason for using integrative medicine was to treat weakness and fatigue, muscle atrophy, disease development, depression, insomnia, limb pain, or numbness.
Extended disability status scale, Hughes score, acetylcholine receptor antibody
These three indicators represent the most common clinical scales and are widely used in clinical trials as evaluation indexes of MS, MG, and GBS, respectively. The meta-analysis for EDSS, Hughes score, and AchR-Ab showed that the average scores were significantly lower in the group treated with integrative medicine than in the control group treated with Western medicine alone. This demonstrated that the treatment with integrative medicine for these three diseases has a much higher efficacy compared to the treatment with Western medicine alone.
This comprehensive analysis of therapeutic effect clearly illustrated that integrative medicine therapies effectively alleviated the symptoms of autoimmune neurological diseases, regarding all three clinical scales and prevented the recurrence of MS, MG, and GBS, and the effects were better compared to Western medicine alone therapies. This indicates that the therapeutic effect of integrative medicine can improve the clinical efficacy of treating autoimmune inflammatory diseases of the nervous system with Western medicine.
Literature quality analysis
Based on the risk of bias tool from the Cochrane Collaboration, the included literature had the following characteristics: (1) Baseline situations were described for each group in detail; statistical processing results showed that both groups (integrative medicine and control) were comparable. (2) The research used the random grouping method but did not detail which one specifically. Only seven studies illustrated the application of the random number table method. (3) Two studies adopted the single-blind method, while other studies were not blinded. (4) Allocation concealment was only mentioned in five studies. (5) Two studies reported failure to follow-up and cessation. (6) Treatment and follow-up periods for all studies were not the same, treatment time ranged from 1 week to 18 months, and the length of follow-up time ranged from 6 months to 10 years. Some articles did not report the follow-up periods.
Considering all the above information, the quality of the literature included in this study was low. Therefore, this deficiency in clinical trials should be improved by providing the basis of sample size estimation and specific random allocation methods, design reasonable treatment and follow-up periods, carry out specific and reasonable, randomized, double-blind, placebo-controlled studies, and observe the long-term therapeutic effects and adverse reactions. High-quality results will support evidence-based treatment and serve as a better guide for therapies for autoimmune inflammatory diseases of the nervous system.
| Conclusions | | |
The therapeutic effect of integrative medicine might ameliorate damage and the loss of function of neurons and reduce the recurrence rate of immunological disorders of the nervous system. However, a limitation of this study is that the quality of the included literature was not high. Therefore, high-quality RCT studies on the treatment of CNS autoimmune diseases with TCM are needed.
Financial support and sponsorship
This study was supported by grants from the National Natural Science Foundation of China (No. 81973543), the Research Project of Science and Technology in Shanghai (No. 19401901600), the Education and Scientific Research Projects of 2021 in the 14th Five-Year Plan of National Higher Education of Traditional Chinese Medicine (No. YB-20-08), and the ninth “Young Talents” training program in Yue-Yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine (No. RS41.07.01.11).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]
[Table 1], [Table 2]
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