Efficacy and safety of external treatment traditional chinese medicine on the treatment of hyperthyroidism and Graves’ orbitopathy:A meta-analysis

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(1.First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion,Tianjin 300193,China; 2.Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital,Tianjin 300120,China)

[Abstract] Objective To systematically evaluate the clinical efficacy and safety of external treatment of traditional Chinese medicine (ETCM) such as acupuncture,acupoint application,auricular pressure and herbal nebulization in the adjuvant treatment of hyperthyroidism and Graves orbitopathy(GO).Methods Data related to ETCM-based clinical controlled trials on hyperthyroidism and hyperthyroidism proptosis were searched on Chinese and English article databases including Chinese Journal Full-text Database (CNKI),VIP Chinese Journal Database (VIP),Wangfang Med Online (WangFang),China Biomedical Literature Database (CBM),and PubMed from January 1980 to May 2021.Meta-analysis was performed on RevMan 5.3.Results A total of 13 articles involving 1,223 patients were included.As revealed by the results of meta-analysis,in the treatment of hyperthyroidism and hyperthyroid proptosis,ETCM improved the thyroid serological indices (FT3 and FT4)(P=0.000 5,P=0.02) and the TCM syndrome score(P=0.0004) compared with conventional treatment,and mitigated the adverse effects of the latter( P=0.02).In terms of relieving exophthalmos,it was found from the subgroup analysis that ETCM was more effective in the treatment of diseases with the duration of fewer than 20 months( P<0.000 01); Conversely,there was not any difference when the disease with the duration of more than 20 months(P=0.51).Furthermore,in terms of increasing TSH,the subgroup analysis showed a contrary result in more than 20 months(P<0.000 01).Conclusion The collected data reveal that ETCM has a better clinical effect for hyperthyroidism and GO than conventional treatment,especially in improving exophthalmos and TCM symptoms,and reducing the adverse effects caused by conventional drugs.

[Key words] Acupuncture; external treatment of traditional Chinese medicine; hyperthyroidism; Graves’ orbitopathy; Meta-analysis

Hyperthyroidism is a thyroid-specific autoimmune disease,with such main clinical features as goiter,autonomic nervous system disorders,and the increased basal metabolic rate[1].Graves’ disease (GD) is the most common cause of hyperthyroidism in clinical practice,accounting for 85% of the cases in China[2].According to epidemiological surveys,women suffer a higher incidence of GD (1.5%) than men,mostly between the ages of 20 and 40.In particular,Graves’ orbitopathy (GO),also known as hyperthyroid eye disease,is the most common extrathyroid manifestation of GD,with an incidence of approximately 25% to 50%[3],and the prevalence of orbital disease is the highest in the adult group worldwide[4].Without timely and effective treatment,GO can be prolonged into the inactive stage,thus seriously affecting life quality of patients by resulting in long-term optic nerve compression,corneal infection,perforation,and even blindness[5].However,modern medical treatment for hyperthyroidism is subject to many limits including prolonged medication duration,potential liver function damage,and white blood cell reduction.Specifically,surgical treatment is commonly rejected by the majority of people due to postoperative hypothyroidism and lifelong medication.However,only surgical treatment is recommended for GO in the International Guidelines for the Treatment of Thyroid Diseases,despite its far from satisfactory curative effect and low acceptance among patients[6].In addition to surgical treatment,treatment by common drugs including glucocorticoids,rituximab,and selenium preparationsetc.are also adopted,while these drugs are reportedly not effective for all patients and trigger frequent adverse reactions[7].

Acupuncture,massage,auricular acupoint pressing,Chinese medicine atomization,and other methods of the external treatment of traditional Chinese medicine (ETCM) have been used in clinical practice since ancient times[8].ETCM plays an important role in preventing and treating many diseases by regulating the body's qi mechanism based on a holistic concept and syndrome differentiation.It has advantages in improving the indicators of hyperthyroidism,mitigating the symptoms and signs of GO,and reducing adverse reactions,as reported in lots of clinical studies[9-10].However,due to the small sample size and significant heterogeneity,it becomes difficult to draw credible and correct conclusions and connections based on these individual studies.

Meta-analysis was performed in this systematic review to examine the effectiveness of ETCM as a adjuvant therapy during the treatment of hyperthyroidism and hyperthyroid eye diseases compared with the treatments based on conventional drugs (e.g.anti-thyroid drugs,glucocorticoid).It was expected to provide evidence for the clinical application of acupuncture and other ETCM methods for hyperthyroidism and GO.

1 Material and methodology

1.1 Criteria for inclusion and exclusion Inclusion criteria:(1) Research type:randomized controlled trials (RCTs),regardless of the use of blinding or allocation hiding; (2) Research objects:The diagnosis of hyperthyroidism met standardized diagnostic criteria,such as "Internal Medicine","Guidelines for the Prevention and Treatment of Thyroid Diseases in China" in 2007,"Guiding Principles for Clinical Research of New Chinese Medicines (Trial)·New Chinese Medicines for the Treatment of Thyroid Guidelines for Clinical Research of Hyperfunction"[11]and diagnostic criteria in other authoritative literatures; the diagnosis of GO met the 2008 European Graves’ Eye Disease Expert Group Consensus on the diagnosis of GO[12],with exophthalmos ≥18mm; under the premise of comparability,the included patients were not limited to baseline characteristics such as race,age,and gender; (3) Intervention measures:treatment groups:ETCM,like acupuncture or combined ETCM (e.g.ETCM combined with Western medicine treatment),without distinguishing the selection of acupuncture points,techniques,needle specifications,electroacupuncture,etc.; control groups:conventional Western medicine treatment or Western medicine conventional treatment plus oral Chinese medicine (except for ETCM); (4) Outcome indicators:FT3,FT4,TSH,exophthalmos,TCM syndrome integral,total effective rate,and incidence of adverse reactions.

Exclusion criteria:(1) Repeatedly published articles; (2) Animal experiment reports; (3) Sham acupuncture groups as the control; (4) Unstandardized curative effect index; (5) Non-rigorous experimental design or incomplete data; (6) Case reports,reviews,and clinical experimental studies without a control group; (7) Literature reports without effective outcome indicators.

1.2 Literature search strategy Lots of relevant study results are in English and Chinese,so articles related to randomized controlled trials (RCTs) published from January 1980 to May 2021 were searched on the below databases:PubMed,Cochrane Central Register of Controlled Trials,China Journals Full-text Database (CNKI),Wangfang Med Online (WangFang),and VIP Journal Integration Platform (VIP).Terms and keywords related to ETCM,hyperthyroidism,and graves’ orbitopathy were used,including hyperthyroids,primary hyperthyroidism,graves disease,graves ophthalmopathy,thyroid-Associated phthalmopathies,thyroid eye disease,acupuncture,moxibustion,needling,hand acupuncture,ear acupuncture,auricular acupuncture,electroacupuncture,scalp acupuncture,scalp needle,massage,acupoint application,Chinese herbal medicine atomization,and auricular acupressure.But trials whose subjects were non-related on ETCM were not included,such as laser acupuncture.Control treatments included methimazole,propylthiouracil,sodium carboxymethyl cellulose eye drops,prednisone,dexamethasone,and methimazole.

1.3 Literature Screening and Data Extraction Two researchers independently screened the articles searched,extracted the data,and conducted cross-checks.Any disagreement would be resolved by the discussion of the two or by the evaluation of a third party.Subjects and abstracts of the trials were read in NoteExpress for preliminary screening to exclude duplicate articles,and then the title,catalog,abstract,and the full text of each article were read for further information extraction to complete the data extraction table.This table mainly covered the following information:basic study information (e.g. the author name,study title,publication year,and publication status),study features (e.g. sample size,source of cases,gender distribution,course of disease,intervention,control measures,and adverse reactions),research methodology (e.g. random scheme generation,allocation hiding,blind method,incomplete result data,selective reporting,other biases,and loss of follow-ups),and outcome measures (used to gain the baseline-to-endpoint changes in anthropometric and biochemical variables).Besides,the mean and standard deviations (SDs) from each article were computed correspondingly,and the total effective rate and the occurrence rate of adverse events were compared.

1.4 Risk assessment for RCT deviation The RCTs' quality was evaluated based on Cochrane collaboration's tool for assessing the risk of bias (RoB),which were divided into three levels:high,unclear,and low[13],and assessed based on the seven factors extracted from the Cochrane net:(1) random sequence generation; (2) allocation concealment; (3) applying blind for participants and personnel; (4) applying blind for outcome assessment; (5) incomplete outcome data; (6) selective reports; and (7) other sources of deviation.If there was a proper and explicit method and description,the RoB was low; if it was not sure whether the method was appropriate,it was considered as "unclear"; otherwise,it was high.

1.5 Statistical analysis Compared with the control group and the intervention group (either treated with monotherapy or adjunctive therapy),95% confidence interval (95% CI) of mean differences (MDs) was obtained by the Review Manager Program (Revman 5.3).In addition,Zvalues andχ2-distributed Cochran'sQvalues were calculated to check the total effects and heterogeneity in trials.To evaluate the heterogeneity quantitatively,I2tests were conducted:I2=100%*(Q-degree of freedom)/Q).TheI2value of <25%,25%～50%,and >50% indicated slow,moderate and high heterogeneity,respectively.If theI2value was ≤25% and theP-value was ≥0.10,then the fixed model of the Mantel-Haenszel method was used; otherwise,a random-effects model applied.If a positive value was obtained in the primary analysis,sensitivity analysis was conducted to evaluate robustness through two methods below.First,fixed-effect and random-effect models were used to conduct a sensitivity analysis for all included trials.Second,the effect sizes of the trials included and excluded were compared to decide the effect of a specific study on the combined effect size.

2 Results

2.1 Research quality and classification Among the 448 studies on the treatment of hyperthyroidism and related complications by ETCM,13 randomized controlled trials (RCT) were included after multiple screening based on the criteria described previously (Fig 1).

Fig 1 Flowchart of literature screening

2.2 Basic features of covered studies In 13 randomized controlled trials meeting the inclusion criteria,612 participants were assigned to receive acupuncture and other external treatments (the experimental group),and 611 participants were in the control group.In most studies,the experimental group used acupuncture combined with drugs as a treatment modality.In the control group,only conventional drugs were used for treatment.The objective of these 13 trials was to evaluate the differences in thyroid serological indices and proptosis between the use of ETCMs as adjunctive therapy in combination with drugs (antithyroid drugs,glucocorticoids and tapazole) and the use of drugs alone (Table 1).RoB assessment results of the 13 trials are shown in Fig 2 and Fig 3.

Table 1 Summary of randomized controlled trials of ETCM for hyperthyroidism and related complications

Fig 2 Risk of bias graphs for all included studies

Fig 3 Risk of bias graphs for all included studies

2.3 Literature quality evaluation The Cochrane review was conducted based on the Cochrane methodology as recommended aiming at reducing the deviation risk in the review process[14].The quality of included literature was evaluated by the Cochrane collaboration network evaluation risk tool.Five articles did not specify the methods of randomization and blinding of patients; only 3 showed allocation concealment; 6 were found free of the selective outcome and its correlation with selective reporting remained unclear.

2.4 Data synthesis

2.4.1 Efficacy of ETCM as adjunctive therapy Exophthalmos reduction Seven trials[15-21]reported the efficacy of treatment for the exophthalmos reduction in GO patients.Due to the existence of high inter-study heterogeneity,the random-effects model was used to explain the heterogeneity between studies and its results were consistent with those obtained by the fixed-effects model (P<0.000 01,I2=93%).As indicated by the present meta-analysis,ETCM as an adjuvant therapy was found to be more effective than the treatment by drugs alone and had nearly no side effects (-1.38,95%CI:[-2.16,-0.59],P=0.000 6)(Fig 4).

Fig 4 Exophthalmos of two groups

Furthermore,a subgroup analysis was conducted on those studies with a disease course.The duration ≤20 months showed moderate heterogeneity (P=0.18,I2=38%) and the results of subgroup analysis demonstrated a significant difference in the efficacy (MD=-1.06 95%CI:[-1.39,-0.74],P<0.000 01).However,the subgroup with a disease course of more than 20 months (P=0.05) showed significant heterogeneity across the included studies (P<0.000 01,I2=97%).These discordant results may come from the differences in their disease duration (Fig 5).

Fig 5 Subgroup analysis of exophthalmos

2.4.2 Efficacy of ETCM as adjunctive therapy FT3 Four trials[22-25]showed that the ETCM as an adjunctive therapy (n=371) significantly outperformed control therapies (n=378) (MD=-2.11,95%CI:[-3.30，-0.92],P=0.000 5) with pronounced heterogeneity (I2=79%).The sensitivity analysis showed that the distinction between fixed and random-effects sizes was not significant when the data set was the same.Even if trials were removed one by one,considerable heterogeneity still existed,so the random-effects model was used.Overall,it was found that the drug treatments combined with ETCM decreased FT3 to a more significant extent than the treatment based on drugs alone (Fig 6).

Fig 6 FT3 of two groups

2.4.3 Efficacy of ETCM as adjunctive therapy FT4 Five trials[21-25]showed that ETCM as an adjunctive therapy (n=389) contributed to a significant decrease in overall FT4 levels (MD=-11.49,95%CI:[-21.01,-1.97],P=0.02) compared to control treatments (n=396),showing high heterogeneity (I2=99%) (Fig 7).Therefore,the random-effects model was applied.Heterogeneity was moderate in the acupuncture intervention group (P=0.42,I2=0%),but high in the auricular acupoint intervention group (P=0.04,I2=76%),which could be attributed to the use of different therapies (Fig 7 and Fig 8).

Fig 7 FT4 of two groups

Fig 8 Subgroup analysis of FT4

2.4.4 Efficacy of ETCM as adjunctive therapy TSH Five trials[21-25]showed that the TSH levels of the ETCM group (n=389) were significantly higher than those of the control group (n=396) (Z=1.04,P=0.30) with high heterogeneity (I2=100%) (Fig 9).It was found from the sensitivity analysis that the results did not change significantly after the fixed-effects model was replaced by the random-effects model,so the random-effects model was applied.And there was no difference in outcomes between ETCM and control groups (MD=-0.98,95%CI:[-2.82,0.86],P=0.30).Further subgroup analyses based on disease duration for the meta-analysis were performed due to heterogeneity.They revealed that the duration of >20 months was required to achieve significant clinically meaningful outcomes compared with the control group (MD=0.35,95%CI:[0.28,0.41],P<0.00001) and no heterogeneity existed between studies (P=0.87,I2=0%),while the subgroup with disease duration <20 months obtained contrary results (P=0.51) (Fig 9 and Fig 10).

Fig 9 TSH of two groups

Fig 10 Subgroup analysis of TSH

2.4.5 TCM syndrome integral Data from four trials[16,19,21,26]showed a significant difference in the overall TCM syndrome integral between ETCM (n=100) and control groups (n=100) and presented high heterogeneity (Z=3.53,I2=88%).The random-effects model was used to explain the heterogeneity,the results of which were consistent with those obtained by the fixed-effects model.When one trial by Wang et al[16].was deleted,the heterogeneity reduced to 67%,indicating that the specific trial resulted in the heterogeneity.And the other three trials showed the additional ETCM treatment group outperformed the control group in decreasing the TCM syndrome integral to a markedly greater degree (Z=3.53,P=0.000 4) (Fig 11).

Fig 11 TCM syndrome integral of two groups

2.4.6 Total effective rate Eight trials[17,18,20-22,24-26]showed that the total effective rate of the additional ETCM group was higher compared with the control group,with low across-trial heterogeneity (P=0.21,I2=28%),so the fixed-effects model was applied.The further meta-analysis showed that from the statistical perspective,the two groups were significantly different in the total effective rate with MD of 1.25 (95%CI:[1.16,1.35],Z=5.68,P<0.000 01) and moderate heterogeneity (I2=28%) (Fig 12),which revealed a better outcome of ETCM.

Fig 12 Total effective rate of two groups

2.4.7 Adverse reactions (ADR) Four trials[20,22,24-25]revealed the difference of adverse reactions between the additional ETCM treatment group (n=366) and the control group (n=362).The main ADRs did not include all tests mentioned but drug-induced skin rash,drug-induced Liver injury,neutropenia,leukopenia,alopecia,and sleep restriction.Thus,the main focus was put on the overall incidence of side effects.High heterogeneity across trials (I2=92%) was observed.When an individual trial was removed to perform a sensitive-analysis,there had little change of heterogeneity.With random effect sizes,it was concluded that the differences of overall adverse reactions were small between the two groups (MD=0.25,95%CI:[-0.47,-0.04],Z=2.28,P=0.02) (Fig 13).

Fig 13 ADR of two groups

3 Discussion

3.1 Analysis of research results In this review,13 randomized controlled trials (612 participants received acupuncture and other external treatment programs,and 611 participants received controlled interventions) were included.It was the first systematic assessment of the efficacy of acupuncture in treating hyperthyroidism ophthalmopathy.Compared with conventional drugs,ETCM such as auricular acupuncture and acupoint massage produced better therapeutic effects in improving exophthalmos,reducing adverse reactions,and increasing effective efficiency,consistent with previous studies.In addition,as an adjuvant treatment,ETCM significantly outperformed the control group receiving antithyroid drugs and glucocorticoids.As found by the subgroup analysis of selected indicators of hyperthyroidism such as TSH,proptosis,and FT4 according to the duration of the disease,early ETCM as an adjunctive therapy could yield additional benefits in the treatment of hyperthyroidism and related complications.

Hyperthyroidism is triggered by the excessively produced thyroid hormones in human bodies,and the synthesis and metabolism of relevant drugs are correlated with the peroxidase in the human thyroid.Antithyroid drugs (ATDs) are commonly used in modern medicine,with the mechanism of reducing the number of thyroid stimulating antibodies in blood circulation and inhibiting its response,thereby regulating the body's immune function and improving the symptoms of immune dysfunction.However,ATDs had no effect in inhibiting the autoimmune response,and some patients suffered from frequent adverse reactions and other problems including drug dependence,the low cure rate and high recurrence rate.Furthermore,hyperthyroidism may be cured fundamentally with the help of surgery and131I therapy,which however are frequently accompanied by post-treatment hypothyroidism,lifelong use of thyroid hormones and other problems.In contrast,ETCM can strengthen the immune function of the body,improve physical fitness,and mitigate symptoms by stimulating the meridians and acupoints on the body surface and promoting blood circulation.Hence,it as adjuvant therapy combined with western medicine will achieve a better effect.In traditional Chinese medicine,hyperthyroidism is mainly attributed to the stagnation of the liver,which proceeds to intermingled phlegm and blood stasis,thus causing exophthalmos.In ETCM,main efforts are made to soothe the liver,relieve depression,resolve phlegm and dissipate blood stasis.For instance,He Jinsenetal.[21]conducted acupuncture treatments for hyperthyroidism,with the focus on meridians and such acupoints as Neiguan,Jianshi,Hegu,Zusanli,Sanyinjiao,and Taixi.Good clinical effects have been achieved,reaching a rate of 95.74%.Liu Zehongetal.[27]used auricular acupuncture on Shenmen,sympathetic,cortex,heart,kidney,liver,drooping anterior,and ear vest to treat patients suffering both hyperthyroidism and insomnia,achieving a good clinical effect.Moreover,it has been found frominvitroexperiments that ETCM may contribute to the treatment by improving the body's immune monitoring and regulation functions and promoting the normalization of immune monitoring.However,further clinical evidence is still needed[23].

In the research of the mechanism of ETCM in GO treatment,GO is considered an autoimmune disease resulting from the cross-reaction between antibodies against the thyroid and the autoantigens of the eye.The pathogenesis of GO is correlated with many factors such as heredity and immunity (internal factors) as well as the environment and smoking (external factors).Moreover,immune cells,especially T cells,cytokines,orbital fibroblasts,self-antigens and antibodies,all participate in it and provide new targets for the treatment of GO.The drugs currently used in clinical practice mainly target molecules or cells in the immune-related mechanisms of GO pathogenesis,while they are not effective for all patients according to research[5].Notably,as an important adjuvant therapy,ETCM plays an important role in GO treatment.As demonstrated by previous studies,acupuncture treatment for GO can relieve ocular edema and improve the body's immunity,thereby mitigating the symptoms of GO to a certain extent[21].Nonetheless,the long disease course of GO may cause collagen deposition in the eye,thus triggering fibrosis and fat deposition.This may impede the efficacy of ETCM methods such as acupuncture[25].It reveals that early use of ETCM to intervene with GO can benefit the patient to the greatest extent.

3.2 Limitations of the study This study has several limitations.First,the deviation resulting from the selection of allocation concealment and randomization was comparatively high,since no placebo was set in the most covered trials.It is especially important when the sample is limited to the Chinese population with unique views on acupuncture therapy.Therefore,differences in inpatient treatment expectations should be accounted for during the interpretation of the study results.Second,most of the samples included in the trial had a small size,with no more than 40 participants in each group,which might reduce the sensitivity and accuracy of the analysis.Third,the specific demographic information was not provided in most of the covered trials,such as the patient's course of the disease and medication history.It hindered the further study of the relationship between treatment effects and demographic factors.Fourth,no covered trials assessed the follow-up results to determine the long-term efficacy of external interventions such as acupuncture and moxibustion.Further research is still needed to determine whether acupuncture is effective for long-term maintenance and treatment of hyperthyroidism and to study related eye diseases.Finally,though seven variables of hyperthyroidism and related complications were included for analysis,the quality of the original RCT may be poor,reducing the efficacy and guiding meanings of the current meta-analysis.Therefore,more high-quality studies are needed.

The above meta-analysis results show that ETCM methods such as acupuncture have considerable curative effects compared with monotherapy,especially in improving exophthalmos,reducing the TCM syndrome score,and mitigating the side effects of conventional drugs.Moreover,as an adjuvant therapy,ETCM can produce additional benefits in treating hyperthyroidism and related complications when it is used in early stages.Nonetheless,more high-quality studies are still needed to provide solid evidence for the application of combined ETCM methods.