Guideline for the diagnosis and treatment of rheumatoid arthritis with integrated traditional Chinese medicine and Western medicine to increase efficiency and reduce toxicity

Zhi-Jun Xie,Wei Cao,Lin Huang,Yang-Qin Xun,Nan Yang,Ping Wang,Qiao Wang,Meng-Juan Ren,Hai-Chang Li,Yun-Lan Liu,Yu-Jun Tang,Yue Hu,Hui Zheng,Juan-Juan Zhang,Hui Lan,Shou-Yuan Wu,Qiang-Qiang Guo,Ya-Jia Sun,Xian-Zhuo Zhang,Xiao-Hui Wang,Xu-Ping Song,Yan-Fang Ma,Yao-Long Chen8,9,0*,Cheng-Ping Wen*

1Basic Medical School,Zhejiang Chinese Medical University,Hangzhou 310053,China.2Department of Rheumatology,Guang’anmen Hospital,China Academy of Chinese Medical Sciences,Beijing 100053,China.3Center for Evidence-Based Medicine,School of Basic Medicine,Lanzhou University,Lanzhou 730000,China.4School of Public Health,Lanzhou University,Lanzhou 730000,China.5The Institutes of Biology and Medical Sciences,Soochow University,Suzhou 215123,China.6The First Clinical Medical College,Lanzhou University,Lanzhou 730000,China.7Hong Kong Chinese Medicine Clinical Study Center,School of Chinese Medicine,Hong Kong Baptist University,Hong Kong SAR,China.8Institute of Health Data Science,Lanzhou University,Lanzhou 730000,China.9Research Unit of Evidence-Based Evaluation and Guidelines(2021RU017),Chinese Academy of Medical Sciences,School of Basic Medical Sciences,Lanzhou University,Lanzhou 730000,China.10WHO Collaborating Centre for Guideline Implementation and Knowledge Translation,Lanzhou 730000,China.

Abstract Rheumatoid arthritis imposes a huge disease burden.Existing practice guidelines do not meet the needs of integrated traditional Chinese medicine and Western medicine in the treatment of rheumatoid arthritis.We established a guideline working group consists of a steering committee,a secretary group,an evidence evaluation group,a consensus group and a review group and developed a guideline following the guidance of the World Health Organization Handbook and the Chinese Medical Association.The guideline includes 35 recommendations which reached consensus by the two rounds Delphi surveys.These recommendations were formulated to address the following themes of most concern to clinician: diagnostic imaging,disease staging,traditional Chinese medicine syndromes,effectiveness and toxicity of integrated traditional Chinese medicine and Western medicine.

Keywords: rheumatoid arthritis;guideline;traditional Chinese medicine;toxicity

Background

Rheumatoid arthritis (RA) is an autoimmune disease with erosive arthritis as the main clinical manifestation,which can occur at any age[1,2].The pathogenesis of RA is still unclear,and the basic pathology is characterized by synovitis,formation of vascular opacities,and progressive destruction of articular cartilage and bone,eventually leading to joint deformity and loss of function [3,4],and can be complicated by pulmonary disease,cardiovascular disease,malignancy,and depression [4-10].Epidemiological surveys show that the global prevalence of RA is 0.5%-1% [1],and the prevalence in China is 0.42%,with a total affected population of about 5 million[11]and a male to female ratio of about 1:4[12,13].The incidence of disability among RA patients in China is 18.6%,43.5%,48.1%,and 61.3% for the disease duration of 1-5 years,5-10 years,10-15 years,and ≥15 years,respectively,and the incidence of disability and functional limitation increases with the prolongation of the disease duration [12],which not only causes a decrease in physical function,quality of life,and social participation of patients,but also brings a huge RA not only causes a decrease in patients’physical function,quality of life and social participation,but also imposes a huge economic burden on patients’families and society[11,14,15].

The currently developed modern medical RA treatment guidelines play a very important role in guiding modern medical RA,but they do not involve any content about traditional Chinese medicine (TCM) or rarely involve the use of TCM;and the TCM treatment guidelines are not oriented to clinical questions,the quality of evidence-based is not available,and no recommendations are given formost of the nearly 100 recommended TCMs,and for the few that have evidence quality and recommendation strength Therefore,the existing TCM guidelines in the field of RA neither reflect the characteristics of TCM nor are they followed the Grading of Recommendations Assessment,Development,and Evaluation (GRADE) system,which makes the use of TCM in clinical practice more difficult.The use of TCM in clinical practice is difficult,complicated and limited.To address the above problems,the group intends to optimize the TCM staging plan for RA based on the TCM treatment protocols for pre-RA and active RA developed in the previous study,based on the GRADE system and Reporting Items for Practice Guidelines in Healthcare (RIGHT),and optimize the TCM staging plan for RA.Based on the internationally recognized GRADE and RIGHT frameworks,we will develop evidence-based guidelines for the treatment of RA TCM that meet international standards and accurately guide clinical practice.

Guideline development process

This guideline is part of the National Key Research and Development Program “Optimization and Evidence-Based Evaluation of Rheumatoid Arthritis Prevention and Treatment Protocols in Traditional Chinese Medicine” undertaken by Zhejiang Chinese Medical University,and was developed by the Guidelines and Standards Research Center of the Institute of Health Data Science of Lanzhou University,the Guidelines and Standards Research Center of the Journal of the Chinese Medical Association,the GRADE Center of Lanzhou University,and the Center for Evidence-Based Medicine of Lanzhou University.GRADE Center,Lanzhou University,and Lanzhou University Evidence-Based Medicine Center are responsible for the development.The guideline was launched on December 2018 and finalized on January 31,2022.The methodology and process for the development of this guideline is mainly based on the “Who Handbook for Guideline Development”published by the World Health Organization in 2014 [16] and the“Basic Methods and Procedures for Developing/Revising of Clinical Guidelines” published by the Chinese Medical Association in 2016[17].And based on the guideline research and evaluation tool(Appraisal of Guidelines Research and Evaluation,AGREE Ⅱ)[18]and RIGHT.The specific requirements of RIGHT[19]were used to develop and report the full guidelines.

Formation of the guideline development working group

This guideline development working group consists of a steering committee,a secretary group,an evidence evaluation group,a consensus group,and a review group.

Steering committee.It is composed of 2 senior clinical experts and methodologists.The main responsibilities are: (1) to establish other working groups for guideline development;(2) to approve the guideline proposal;(3) to supervise the guideline development process;(4) to finalize the full text of the guideline;and (5) to provide necessary consultation and guidance for guideline development.

Secretary group.It consists of 5 members,whose main responsibilities are: (1) to draft the guideline proposal;(2)to conduct research on clinical questions;(3) to organize consensus meetings on recommendations;(4) recording the entire process of guideline development in detail;(5) to write the first draft of the guideline;(6)to submit the guideline;(7) to coordinate the work of other working groups.

Evidence evaluation group.It is composed of 12 members with experience in development of guidelines and systematic reviews.The main responsibilities are: (1) to assist in defining the scope of the guideline and priority clinical questions;(2) to search,evaluate,synthesize and grade the evidence for the clinical questions to be addressed in this guideline;(3) to produce evidence summary tables and preliminary recommendations;(4) to write the first draft of the guideline in collaboration with the secretary group;(5) to provide other methodological support as necessary.

Consensus group.It consists of 24 multidisciplinary experts in rheumatology,TCM,imaging,pharmacology,etc.The main responsibilities are: (1) to determine the scope of the guidelines and priority clinical issues;(2) to vote and reach consensus on the recommendations by Delphi method;(3) to finalize the first and final drafts of the full guidelines.

Review group.It consists of 3 experts from related disciplines and its responsibility is to read and give feedback on the first draft of the guidelines.

Guideline planner and registration

This guideline is registered on the International Practice Guidelines Registry Platform,http://www.guidelines-registry.org (registration number IPGRP-2020CN125).The plan can be obtained by contacting the platform.

Conflict of interest declaration and management

All members of the guideline working group will fill out a declaration of interest form during the clinical problem research,evidence evaluation and grading,consensus on recommendation and guideline external review stages to declare financial and academic conflicts of interest in the past 3 years.If the declared interests of the expert members constitute a conflict of interest for the content of the guidelines,they will be managed according to their severity.

Guideline users and target population

This guideline is intended for use by professionals related to TCM,rheumatology,and pharmacology in medical institutions at all levels.The target population for the guideline is patients with RA.

Scope of the guideline and identification of priority clinical questions

The Evidence Evaluation Group first conducted a systematic search of existing RA clinical practice guidelines,conducted a comparative analysis of the recommendations included in the guidelines,identified a preliminary list of clinical questions,and then de-emphasized the clinical questions.After discussion with the steering committee,16 clinical questions to be addressed in this guideline were finally selected,mainly related to the diagnostic assessment of RA and the effectiveness and safety of combined Chinese and Western medicine treatment.

Evidence search and screening

The evidence evaluation group deconstructed the clinical questions according to the principles of intervention,control,and outcome(population,intervention,comparison,outcome,PICO) to conduct a systematic search: (1) search MEDLINE,the Cochrane Library,Epistemonikos,China Biomedical Literature Service,Wanfang Knowledge Data Service Platform,and China Knowledge Network Database,mainly incorporating systematic reviews,meta-analyses,reticulated meta-analyses,randomized controlled trials(RCTs),cohort studies,case-control studies,and other types of evidence;(2)searching the UK National Institute for Health and Clinical Excellence,Scottish Intercollegiate Guidelines Network,American College of Rheumatology (ACR),European League Against Rheumatism(EULAR),and Asia Pacific League of Rheumatology Societies,and other international academic organizations in the field of rheumatology,mainly to search for RA-related guidelines;(3)supplemented by searching the official websites of Google Scholar,UpToDate,DynaMed and other websites,while retrospectively incorporating the reference list of the literature.The search terms include: Chinese traditional,drugs,Chinese herbal,acupuncture therapy,plants medicinal,Chinese medicine,acupuncture,TCM,RA,etc.All types of literature were searched from the date of library construction to December 31,2019,and the language of publication was limited to English and Chinese.

Literature screening

After completing the evidence search,each clinical question was independently screened for literature by two members of the evidence evaluation team in the order of title,abstract,and full text on a step-by-step basis to determine the literature to be included that met the specific clinical question.The literature inclusion criteria：patients diagnosis RA with the 1987 ACR and 2010 ACR/EULAR classification criteria,with no restriction on the type of study design.Exclusion criteria included both interventions and controls were TCM therapies.After completing the screening two people checked,and if there was disagreement,it was determined by joint discussion or consultation with a third party.

Grading the quality of evidence

The evidence evaluation group used the GRADE method to grade the quality of the body of evidence for each clinical question and strength of recommendation [20-24] The GRADE system was used to evaluate the evidence quality and recommendations(Table 1).

Formation of recommendations

Based on the evidence summary table provided by the evidence group,78 recommendations were initially formulated after considering Chinese patients’ preferences and values,costs and pros and cons of the interventions.After one round of Delphi research and expert feedback,18 recommendations reached consensus (consensus rate＞70%),14 recommendations with consensus rate ≤50% and 24 recommendations were considered for deletion due to lack of evidence,and the remaining 22 recommendations and the 2 added recommendations were subjected to a second round of Delphi research,17 recommendations reached consensus (consensus rate＞70%),5 recommendations with consensus rate ≤50%.A total of 35 recommendations reached consensus in the two rounds.

Guideline writing and external review

After consensus was reached on the recommendations,the guideline development working group completed the first draft of the guideline with reference to the international guideline reporting specifications RIGHT [19],and submitted it to the external review group for expert review,and revised the first draft according to their feedback to finally form the final draft of the guideline.

Promotion and implementation of the guidelines

After the release of the guidelines,the guideline sponsors jointly promote and implement the guidelines through the following ways:(1) introducing and interpreting the guidelines in combination with online and offline academic conferences;(2)systematically organizing nationwide medical workers in TCM,rheumatology,pharmacology and other related fields to study the relevant contents of the guidelines and the step-by-step methods of correct use;(3) disseminating the simplified version of the guidelines through WeChat or other.The simplified version of the guideline will be disseminated through WeChat or other channels.

Update of the guideline

It is planned to be updated in the next 3-5 years based on emerging evidence and feedback from members of the guideline working group and users,following the international guideline update methodology and process[25].

Recommdations

Clinical question 1:What is the value of imaging for the diagnosis of RA?

Imaging techniques such as X-ray,ultrasound,CT and MRI are recommended based on the signs and symptoms of RA patients,as well as cost and facility conditions,and patient wishes.(1B)

Summary of evidence

The current studies mainly investigated the diagnostic value of X-ray,ultrasound,CT and MRI for RA patients [26-30].2018 Chinese Rheumatoid Arthritis Treatment Guidelines[31] summarized the applicability and advantages and disadvantages of various imaging techniques including X-ray,ultrasound,CT and MRI for the diagnosis of RA,which could be used as a reference basis for the selection of RA imaging diagnosis.The EULAR published a guideline for RA imaging in 2013,which included recommendations on how to select imaging techniques for RA progression monitoring,prognosis and activity assessment in addition to the diagnosis of RA[32].However,it should be noted that there are great differences in imaging equipment settings,diagnostic skills of imaging physicians,and health insurance coverage in different regions of China.What’s more,patients have different preferences for the choice of imaging techniques [33,34],clinicians should appropriately select imaging techniques to assist in confirming the diagnosis according to the actual situation of patients and hospitals,and in conjunction with patient’s preference and value.

Table 1 Evidence quality grades and strength of recommendations (GRADE)

Summary of the clinical question and recommendations

Clinical question 1: What is the value of imaging for the diagnosis of RA?

Imaging techniques such as X-ray,ultrasound,CT and MRI are recommended based on the signs and symptoms of RA patients,as well as cost and facility conditions,and patient’s preference and value.(1B)

Clinical question 2: What is the optimal assessment tool for RA disease activity? How is disease staging performed in RA?

Disease Activity Score (DAS28),Simplified Disease Activity Index (SDAI) or Clinical Disease Activity Index (CDAI) were recommend as the disease activity assessment tool after comprehensive consideration.(2B)

RA symptoms was recommended to classify as mild,moderate or severe with reference to the “Guidelines for Clinical Research on New Chinese Medicines(Trial)”,or to classify RA disease activity as no activity,mild activity,moderate activity and severe activity with reference to the Chinese Rheumatoid Arthritis Patient Reported Disease Activity Index Scale (RA-PRO).(2C)

RA was recommended to classify into active and remission phases according to disease activity.(1B)

Clinical question 3: How to make the diagnosis of TCM symptoms of RA?

Recommend refer to the“Diagnostic Efficacy Criteria for Internal Medicine Evidence”or“Guidelines for Clinical Research on New Drugs in Traditional Chinese Medicine(for Trial Implementation)” for the diagnosis of TCM evidence of RA.(2C)

Clinical question 4: What is the effectiveness and safety of methotrexate combined with TCM in the treatment of RA?

Methotrexate may cause side effectsadverse reactions such as gastrointestinal reactionproblems,abnormal liver function,stomatitis,hair loss,skin rash,and infection due to decreased white blood cells when treating RA.(B)

For patients who are menopausal and have no reproductive requirements,the combination of methotrexate withRadix Polygonimulti-glucoside tablets for the treatment of RA is recommended to improve the efficacy of methotrexate.The reproductive toxicity ofRadix Polygonimulti-glucoside tablets should be taken seriously and avoided for use in patients of childbearing age who have a requirement for conception.(1B)

When there is are no contraindications to the use of methotrexate in the treatment of RA,the combination of total peony glycosides is recommended to improve the efficacy.(1C)

When there is are no contraindications to the use of methotrexate in the treatment of RA,consider the combination of Zhengqing Fengxin to improve the efficacy.(2C)

For patients who are menopausal and have no reproductive requirements,when there is no contraindication to the use of methotrexate for the treatment of RA,the combination of Kunxian capsules is recommended to improve the efficacy.The reproductive toxicity of Kunxian capsules should be taken into account and its use in those of childbearing age with the need to conceive should be avoided.(1C)

When there is are no contraindications to the use of methotrexate in the treatment of RA,consider the combination of paralysis capsules to improve the efficacy.(2C)

When there is are no contraindications to the use of methotrexate in the treatment of RA,consider the combination of Wangbi tablets to improve the efficacy.(2C)

Clinical question 5: What is the effectiveness and safety of leflunomide combined with TCM in the treatment of RA?

Leflunomide may cause adverse effects of elevated liver enzymes,diarrhea,respiratory tract infection,nausea,rash,dyspepsia,headache,alopecia,hypertension and weight loss in the treatment of RA.(C)

For patients who are menopausal and have no fertility requirements:based on the use of leflunomide in the treatment of RA,the combination of tripterygium glycosides tablets is recommended to improve the efficacy without increasing the incidence of adverse effects,depending on the specific condition of patient.(1B)

Based on the treatment of RA with leflunomide,the combination of total glucoside of peony is recommended to improve the efficacy and reduce the incidence of adverse effects according to the specific condition of patient.(1B)

Based on the use of leflunomide in combination with methotrexate for the treatment of RA,consider the combination of Juanbi decoction to improve the efficacy according to the specific condition of patient.(2C)

Clinical question 6: What is the efficacy and safety of glucocorticoids combined with TCM in the treatment of RA?

In the treatment of RA with glucocorticoids,the incidence of adverse reactions is related to its dose.In the short term,it may cause digestion,headache,anxiety,hypertension,hyperglycemia,skin disease and other adverse reactions;in the medium and long term,it may cause osteoporosis,cardiovascular disease,acute myocardial infarction,stroke,heart failure and other adverse reactions.There is a lack of high-quality evidence to support glucocorticoid combined with TCM treatment to increase the effectiveness and safety.(A)

In the treatment of RA with glucocorticoids,the incidence of adverse reactions is related to its dose.In the short term,it may cause digestion,headache,anxiety,hypertension,hyperglycemia,skin disease and other adverse reactions;in the medium and long term,it may cause osteoporosis,cardiovascular disease,acute myocardial infarction,stroke,heart failure and other adverse reactions.There is a lack of high-quality evidence to support the increased efficacy and safety of glucocorticoid combined with TCM for RA.(A)

Clinical question 7: How effectiveness and safety is sulfasalazine combined with TCM in the treatment of RA?

Adverse reactions of sulfasalazine include: allergic reaction,involving the blood system,digestive system,central nervous system,thyroid,damage to liver and kidney function,hemolytic anemia and hemoglobinuria,hyperbilirubinemia and neonatal nuclear jaundice,rare pancreatitis,male spermatopenia or infertility.At present,there were lack of high-quality evidence to support sulfasalazine combined with TCM to increase the effectiveness and safety.(B)

Clinical question 8: What is the efficacy and safety of iguratimod combined with TCM for RA?

The common adverse effect of elamod is abnormal liver function.Other adverse effects mainly involve the hematologic,digestive,psychoneurologic,and urinary systems,and some patients may experience allergic symptoms and metabolic disorders.There is a lack of high-quality evidence to support the effectiveness and safety of combining elamod with TCM treatment to increase effectiveness and safety.(C)

The common adverse reaction of iguratimod is abnormal liver function.Other adverse reactions mainly involve the hematologic,digestive,psychoneurologic,and urinary systems,and some patients may occureallergic symptoms and metabolic disorders.There is a lack of high-quality evidence to support the increased efficacy and safety of iguratimod combination with TCM for RA.(C)

Clinical question 9: how effectiveness and safety is non-steroidal anti-inflammatory drugs (NSAIDs) combined with TCM in the treatment of RA?

NSAIDs in the treatment of RA may cause adverse reactions in the digestive system,skin surface and accessories,cardiovascular system,nervous system,liver and kidney system,blood system,respiratory system,hearing or vision.(B)

Clinical question 10:What is the effectiveness and safety of biologics combined with TCM in the treatment of RA?

Biologics may cause adverse effects of infection,complete blood cytopenia,elevated transaminases,congestive heart failure and demyelinating diseases in the treatment of RA.(B)

For patients who are menopausal and without fertility requirements: Use tolimumab in the treatment of RA,an IL-6 receptor antagonist,in combination with tripterygium glycosides tablets to improve the efficacy,depending on the specific condition of patient.(2C)

Clinical question 11:What is the effectiveness and safety of tripterygium glycosides in combination with western drugs for RA?

Leigendan tripterygium glycosides tpolysaccharide tablets may cause liver injury,so and patients with liver injury are advised to use this drug with caution and to monitor liver function during the course of administration.(1B)

Consider the combination of tripterygium glycosidesRadix Polygonimulti-glucoside tablets with NSAIDs(e.g.,celecoxib,etc.) for the treatment of RA to improve efficacy without increasing the incidence of adverse reactionevents.(2C)

Clinical question 12:What is the safety and efficacy of the combination of total peony glycosides with western drugs in the treatment of RA?

Based on the use of methotrexate for RA,it is recommended to combine with peony glycosides to improve the efficacy and reduce the incidence of adverse reactions.(1A)

Based on the use of leflunomide in the treatment of RA,it is recommended to combine with peony glycosides to improve the efficacy and reduce the incidence of liver function damage.(1A)

Based on the combination of methotrexate with leflunomide in the treatment of RA,it is recommended to combine with peony glycosides to improve the efficacy and reduce the incidence of liver function damage.(1B)

Clinical question 13: What is the safety and efficacy of the combination of Kunxian capsules with western drugs in the treatment of RA?

Among RA patients without reproductive requirements and menopause,based on the use of methotrexate,it is recommended to use Kunxian capsules on a dialectical basis to improve the efficacy and reduce the incidence of liver function damage in RA patients.(2B)

Clinical question 14:What is the efficacy and safety of Zhengqing Fengtong Ning combined with Western medicine in the treatment of RA?

Recommendations did not reach consensus.

Clinical question 15:What is the efficacy and safety of herbal tonics combined with western drugs in the treatment of RA?

For patients with RA who take conventional Western medicine,the combination of Guizhi Shaoyao Zhimu decoction (1A),Duhuo Jisheng decoction (1A),Huangqi Guizhi Wuwu decoction (1A),Xuanbi decoction (1B),Juanbi decoction (1B) were recommended to improve the efficacy and reduce the incidence of adverse effects.(1A)

Clinical question 16:What is the efficacy of pills/powder combined with the Western medicine in the treatment of RA?

Yishen Juanbi pill was recommended to use in combination with leflunomide and/ormethotrexate to improve the effect without increasing the incidence of adverse reactions (2B).

Clinical question 2: What is the optimal assessment tool for RA disease activity? How is disease staging performed in RA?

Recommend DAS28,SDAI or CDAI be selected as the disease activity assessment tool after comprehensive consideration.(2B)

Recommend classify RA symptoms as mild,moderate or severe with reference to the “Guidelines for Clinical Research on New Chinese Medicines(Trial)”,or to classify RA disease activity as no activity,mild activity,moderate activity and severe activity with reference to the RA-PRO.(2C)

Recommend classify RA into active and remission phases according to disease activity.(1B)

Summary of evidence

The EULAR [35] and the Asia Pacific League of Associations for Rheumatology [36] list guidelines disease activity in their guidelines.The ACR conducted a systematic search of existing RA disease activity assessment tools and included 63 assessment tools [37],of which six were selected by an expert advisory group for listing in their guidelines [38].These include the DAS28,SDAI,CDAI,Patient Activity Score (PAS),PASII,and Routine Assessment of Patient Data Indicators 3 (RAPID-3).These six assessment tools include patient functional scores,number of tender joints,number of swollen joints,overall patient assessment of disease,overall physician assessment of disease,and laboratory indicators such as C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR) (Table 2).The reliability,validity,and responsiveness of these six assessment tools were measured by the American College of Rheumatology Expert Advisory Group,which showed that DAS28 was superior in all three aspects[37].DAS28 is divided into two types,using CRP and ESR as laboratory indicators.Sensitivity and less susceptible to age,gender,anemia and rheumatoid factor (RF) [39],but the serum CRP test is more expensive and DAS28-ESR can be a low-cost option.SDAI and CDAI do not require complicated steps and the formulas are easy to remember and are superior to DAS28 in terms of ease of calculation.Therefore,it is recommended to consider various factors and choose DAS28,the SDAI or CDAI as the RA disease activity assessment tool.Since there are limitations in assessing disease activity based on disease activity assessment tools alone,it is necessary to combine the physician global assessment (PGA) with the clinical manifestations and other manifestations of RA patients to improve the accuracy of the assessment.

In 2002,theGuidelines for Clinical Research on New Chinese Medicines(for Trial Implementation) [40] classified the symptoms of RA into mild,moderate,and severe quantification tables,and TCM physicians can refer to this table to have symptoms graded in the ratio of mild,moderate,and severe with evidence covering 1/3 of the total score.

In 2018,the Chinese Rheumatology Association of Chinese Medicine proposed clinical outcome scale for patients with RA in China.The scale classified RA disease activity into no activity(RA-PRO ＜3.61),mild activity (3.61 ≤RA-PRO ≤5.54),moderate activity (5.54 ≤RA-PRO ≤7.79),and severe activity (RA-PRO ＞7.79) [41].

The treatment goal of RA is to achieve disease remission [31,35-37],and the classification of RA into remission and active phases facilitates guidance of RA management.According to the disease activity assessment tool,clinical remission is defined as DAS28 ≤2.6,CDAI ≤2.8,or SDAI ≤3.3.In 2011,the ACR and EULAR introduced the following remission criteria: number of tender joints,number of swollen joints,CRP level,and overall patient assessment of disease ≤1[42],which is difficult to achieve in Chinese clinical practice due to its high specificity and can be used as a reference [43].

Clinical question 3:How to make the diagnosis of TCM symptoms of RA?

Recommend refer to the “Diagnostic Efficacy Criteria for Internal Medicine Evidence” or “Guidelines for Clinical Research on New Drugs in Traditional Chinese Medicine(for Trial Implementation)” for the diagnosis of TCM evidence of RA.(2C)

Table 2 Summary of RA disease activity measures

Summary of evidence

The current relatively authoritative diagnostic criteria for RA evidence are proposed by theDiagnostic Efficacy Criteria for Internal Medicine Disease Symptoms in Traditional Chinese Medicineand theGuidelines for Clinical Research on New Drugs in Traditional Chinese Medicine(for Trial Implementation),respectively.

TheGuidelines for Clinical Research on New Drugs in Traditional Chinese Medicine(for Trial Implementation) divided RA [40] into five types of symptoms.(1) Arthralgia symptom with warm-heat blocking collaterals(Xie Qi with warm-heat blocking the meridians and causing arthralgia syndromes):primary symptoms-swollen and painful joints with heat,fever,unfavorable joint flexion,morning stiffness,joint deformity;secondary symptoms -thirst,sweating,yellow urine,dry stool;tongue and pulse -red tongue,yellow thick,greasy coating,slippery or smooth pulse.(2) Arthralgia symptom with cold-damp blocking collaterals(cold-damp Qi blocking the meridians and causing arthralgia syndromes): primary symptoms -cold and swollen joints,increasing pain with cold,decreasing pain with heat,unfavorable joint flexion,morning stiffness,deformity of the joints;secondary symptoms-pale mouth without thirst,evil wind and cold,aggravated by cloudy and rainy days,heavy limbs;tongue and pulse:pale tongue,white fur,tight pulse.(3) Cold syndrome with kidney Qi deficiency(symptom of wind invasion of the body caused by Kidney qi insufficiency): primary symptoms -cold and painful swollen joints,cold and unheated limbs,unfavorable joint flexion and extension,morning stiffness,deformed joints;secondary symptoms -white face,mental fatigue,sore and weak waist and knees;tongue and pulse:pale tongue,white fur,sunken and weak pulse.(4) Symptom of Yin deficiency of liver and kidney(symptom caused by yin insufficiency of liver and kidney): primary symptoms -painful swelling or soreness of joints,unfavorable flexion and extension of joints,morning stiffness,deformity of joints;secondary symptoms -soreness and weakness of waist and knees,dizziness and dizziness,irritability of the five hearts,dry throat,hot flashes;tongue and pulse-red tongue,little coating,sunken and thin pulse.(5) Arthralgia symptom with wind-damp blood stasis (arthralgia symptom caused by blood stagnation and obstruction): primary symptoms -swollen and stinging joints,or pain at night,unfavorable joint flexion and extension,morning stiffness,deformity of joints;secondary symptoms -subcutaneous hard nodes,local dull complexion of joints,dry and lusterless skin,or wrong skin nail,low menstrual flow or amenorrhea in women;tongue and pulsepurple and dark tongue,with petechiae or petechiae,sunken and thin pulse.

The Chinese Society of Traditional Chinese Medicine Rheumatology Branch “Rheumatoid Arthritis Disease Evidence Combined Treatment Guide” [44] divides RA into eight types of evidence.(1) Arthralgia symptom with wind-damp blocking collaterals(as wind-damp invades the skin and migrates around the body,blocking the meridians and causing arthralgia syndromes: main symptoms): primary symptoms -joint pain,swelling,wandering;joint pain,swelling,with intermittent onset and cessation.Secondary symptoms: bad wind,or sweating;headache;heavy limbs.Tongue and pulse:light red tongue,thin white coating,smooth or floating pulse.(2) Arthralgia symptom with cold-damp blocking collaterals : main symptoms: cold and painful joints,not warm to touch,skin not red;pain aggravated by cold,reduced by heat.Secondary symptoms: joint constriction,unfavorable flexion and extension;cold extremities,or fear of cold and prefer warmth;light mouth without thirst.Tongue and pulse: fat tongue,pale tongue,white or greasy coating,string or tight pulse.(3)Arthralgia symptom with warm-heat blocking collaterals (warm-heat Qi blocking the meridians and causing arthralgia syndromes): main:primary symptom -painful swelling and heat in the joints;heat sensation when the joints are touched or self-conscious heat sensation.Secondary symptoms -local reddening of the skin of the joint;fever;disturbed heart;thirst or thirst without desire to drink;yellow urine.Tongue and pulse: red tongue,yellowish greasy or yellowish thick coating,smooth or slippery pulse.(4) Arthralgia syndrome of phlegmdampness blocking collaterals (phlegmdampness invades the body,blockes the meridians,causing arthralgia syndrome): primary symptoms -joint swelling and pain that does not subside over a long period of time;local darkness of the joints,or subcutaneous nodules.Secondary symptoms -joint muscle tingling;joint stiffness and deformation;dull and sallow complexion;dark lips.Tongue and pulse:purple and dark tongue or petechiae,greasy moss,sunken and astringent or sunken and slippery pulse.(5) Arthralgia symptom with wind-damp blood stasis: primary symptom -tingling pain in the joints,the painful area is fixed and does not move;the pain is worse at night.Secondary symptoms-numbness of the limbs;local darkness of the joints;nail fault or dryness of the skin without luster.Tongue and pulse: purple and dark tongue with petechiae or petechial spots,thin white coating,sunken and thin pulse.(6) Symptom with Qi and blood deficiency (symptom caused by Qi and blood insufficiency): primary symptoms -joint pain or vague pain,accompanied by tiredness and fatigue;unpleasant complexion.Secondary symptoms -palpitation and shortness of breath;dizziness;pale claws and nails;poor appetite.Tongue and pulse: light tongue,thin coating,weak or sunken pulse.(7) Symptom of Yin deficiency of liver and kidney: primary symptoms-joint pain,enlargement or stiffness and deformation;soreness and weakness of the waist and knees or soreness of the lower back.Secondary symptoms-heel pain;dizziness and tinnitus;hot flashes and night sweats;frequent urination and nocturia.Tongue and pulse: red tongue with white or less coating and fine pulse.(8) Symptom of yin deficiency of liver and kidney(symptom caused by yin insufficiency of liver and kidney): primary symptoms -joint enlargement with shortness of breath and weakness;muscle pain,dry mouth and eyes.Secondary symptoms -spontaneous sweating or night sweating;heat in the heart of the hands and feet;thinness and weakness of the body,lack of luster in the skin;false irritability and dreaminess.Tongue and pulse:red or cracked tongue,little or no moss,sunken and feeble pulse or fine and feeble pulse.

In addition to the above criteria,other individuals have proposed different evidence types based on patients with RA in different regions.Jiang Xiaofan et al.surveyed 226 modern literature on RA[45] showing the existence of a total of 105 TCM symptoms types.New evidential survey studies have also been published in the last 5 years [46-51],but there are some differences with the above diagnostic criteria.In response to the current inconsistent diagnostic criteria for RA evidence,clinicians can refer to theDiagnostic Efficacy Criteria for Internal Medicine Evidence in Chinese Medicineor theGuidelines for Clinical Research on New Drugs in Traditional Chinese Medicine(for Trial Implementation) for the diagnosis of RA TCM symptoms.

Clinical question 4: What is the effectiveness and safety of methotrexate combined with TCM in the treatment of RA?

Methotrexate may cause side effects such as gastrointestinal problems,abnormal liver function,stomatitis,hair loss,skin rash,and infection due to decreased white blood cells when treating RA.(B)

For patients who are menopausal and have no reproductive requirements,the combination of methotrexate withRadix Polygonimulti-glucoside tablets for the treatment of RA is recommended to improve the efficacy of methotrexate.The reproductive toxicity ofRadix Polygonimulti-glucoside tablets should be taken seriously and avoided for use in patients of childbearing age who have a requirement for conception.(1B)

When there are no contraindications to the use of methotrexate in the treatment of RA,the combination of total peony glycosides is recommended to improve the efficacy.(1C)

When there are no contraindications to the use of methotrexate in the treatment of RA,consider the combination of Zhengqing Fengxin to improve the efficacy.(2C)

For patients who are menopausal and have no reproductive requirements,when there is no contraindication to the use of methotrexate for the treatment of RA,the combination of Kunxian capsules is recommended to improve the efficacy.The reproductive toxicity of Kunxian capsules should be taken into account and its use in those of childbearing age with the need to conceive should be avoided.(1C)

When there are no contraindications to the use of methotrexate in the treatment of RA,consider the combination of paralysis capsules to improve the efficacy.(2C)

When there are no contraindications to the use of methotrexate in the treatment of RA,consider the combination of Wangbi tablets to improve the efficacy.(2C)

Summary of evidence

Methotrexate used for the treatment of RA is associated with the following adverse effects: (1) gastrointestinal reactions (e.g.,diarrhea[52],nausea [52,53],vomiting [53],decreased appetite [52],etc.);(2) abnormal liver function [54,55];(3) stomatitis [54,55];(4)alopecia [54];(5) rash [54];(6) decrease in white blood cells due to infections,etc.[52,56].

A systematic review (including 10 RCTs) [57] compared the use of tripterygium glycosides tablets in combination with methotrexate regimen vs.Methotrexate alone in the ACR.The results showed that the efficacy of TGT in combination with methotrexate in achieving the ACR 20,ACR 50,and ACR 70 targets.The results showed that the TGT combined with methotrexate group showed superior efficacy compared to the methotrexate group in terms of ACR 20 attainment(RR=1.19,95% CI (1.10,1.28)),ACR 50 attainment (RR=1.41,95% CI(1.24,1.61)),and no statistically significant difference in ACR 70 attainment.An RCT (n=108) [58],which analyzed the clinical efficacy of methotrexate vs.methotrexate in combination with methotrexate,indicated that the combination group had better results than the methotrexate group in terms of time to morning stiffness,number of swollen joints,and number of joint induration.The patients also had lower ESR,RF,high mobility group protein 1,and amyloid A levels than the methotrexate group after treatment.Therefore,for patients who do not require reproduction,short-term monitoring of menstruation is required to protect ovarian function;formenopausal women,a combination of regimen polyglucoside tablets may be considered.

A systematic review (8 RCTs) [59] showed that total glucoside of peony combined with methotrexate vs.methotrexate alone was more effective in the treatment of RA (OR=3.70,95% CI (1.51,9.04)).In addition,total glucoside of peony combined with methotrexate resulted in a decrease in ESR(MD=-5.85,95%CI(-8.67,-3.02))and swollen joint count (MD=-1.64,95% CI (-2.27,-1.00)).In 2020,an RCT (n=64) [56] compared the therapeutic effects of peony in combination with methotrexate vs.methotrexate and showed that after treatment in both groups,IL-17,IL-23,IL-6,TNF-α,RF,CRP,ESR and cyclic citrulline peptide protein,number of tender joints,number of swollen joints,and duration of morning stiffness decreased significantly in both groups compared with the pre-treatment period,another RCT (n=72) [52] also showed that patients with RA treated with methotrexate in combination with total glucoside of peony were more effective and had more significant improvements in joint function and inflammatory parameters than those treated with methotrexate alone.

A systematic review (including 12 RCTs) [60] showed that the overall treatment rate was higher for Zhengqing Fengxin combined with methotrexate vs.methotrexate.In addition,the combination of orthoquinone with methotrexate was more effective in terms of grip strength,sedimentation,CRP,and DAS 28 (Disease activity score for RA in 28 joints).A systematic review (11 RCTs) [61] similarly indicated higher efficacy in the combination group than in the methotrexate group (RR=1.08,95% CI (1.01,1.16)).An RCT (n=80) [62] investigated the effectiveness of Zhengqing Fengxin extended-release tablets in combination with methotrexate vs.methotrexate in combination with the nonsteroidal analgesic diclofenac sodium extended-release tablets in the treatment of RA and found that the two groups were more effective in terms of the number of swollen joints,joint pain,joint tenderness,time to morning stiffness and blood sedimentation.The results showed that there were significant differences between the two groups in terms of the number of swollen joints,the number of painful joints,the number of painful joints,the number of joint pressure,the time of morning stiffness of joints and the blood sedimentation and CRP tests.The treatment effect(effective rate) between the two groups was 100% vs.80%respectively.In conclusion for the treatment of RA with Zhengqing Fengxin extended-release tablets combined with methotrexate increased the therapeutic effect.

A systematic review (including 7 RCTs) [63] compared the effectiveness and adverse effects of methotrexate alone vs.Kunxian capsules combined with methotrexate in the treatment of RA.Compared with methotrexate,patients with RA treated with Kunxian capsules in combination with methotrexate were more effective (OR=2.99,95% CI (1.57,5.69)),reduced the number of swollen joints(OR=-1.95,95% CI(-3.13,-0.77)),and had a shorter duration of morning stiffness(OR=-15.14,95%CI(-22.53,-7.75)).In 2018,a network meta-analysis (including 18 RCTs) [64] showed better ACR20 (American College of Rheumatology Rheumatoid Arthritis Panel: ≥20% improvement in number of joint compressions and swellings)for Kunxian capsule combined with methotrexate treatment vs.methotrexate alone for RA (OR=3.15,95% CI (1.07,9.07)).Direct comparison Meta-analysis showed that ACR50 (≥50%improvement in the number of joint pains and swellings) was better for Kunxian capsule combined with methotrexate for RA compared to methotrexate alone(OR=2.05,95%CI(1.19,3.54)),as was ACR70(≥70% improvement in the number of joint pains and swellings) (OR=3.82,95%CI(1.15,12.71)).In 2020,an RCT(n=60)[65]showed that the Kunxian capsule combined with methotrexate treatment group was more effective than the methotrexate treatment group(93.33% vs.86.67%).Therefore,short-term observation of menstruation is required for patients without fertility requirements to protect ovarian function;formenopausal women,the combination of Kunxian capsules may be considered.

Formethotrexate in combination with paralytic capsules: a systematic review in 2018 (including 3 RCTs) [66] compared the effect of paralytic capsules in combination with methotrexate vs.methotrexate for RA and showed a significant difference in the number of patients effectively treated in the combination group (RR=1.17,95% CI (1.06,1.28));RF (SMD=-12.54.95% CI (-16.87,-8.20));number of joint induration(SMD=-2.16,95%CI(-2.86,-1.47));number of joint swelling (SMD=-1.50,95% CI (-1.99,-1.01));joint induration score (SMD=-4.69,95% CI (-5.92,-3.47)).Joint swelling score (SMD=-2.07,95% CI (-2.76,-1.38)).In conclusion,treatment with paralysis capsules in combination with methotrexate appears to be more beneficial in patients with RA than methotrexate alone.In 2020,an RCT (n=70)[67] comparing paralysis capsules in combination with methotrexate vs.leflunomide in combination with methotrexate found that paralysis capsules in combination with methotrexate had comparable efficacy versus methotrexate in combination with leflunomide in the treatment of RA,with a significantly better safety profile.The results showed that the combination of methotrexate and paralytic capsules had comparable efficacy and significantly improved safety in the treatment of RA.In the treatment of RA,the combination of methotrexate and methotrexate in combination with leflunomide was found to be similar to methotrexate,with a significantly improved safety profile.

Formethotrexate in combination with Wangbi tablets,an RCT (n=48)[68] compared the effectiveness of Wangbi tablets in combination with methotrexate tablets vs.methotrexate tablets and Wangbi tablets mimetics in the treatment of RA and showed that Wangbi tablets in combination with methotrexate tablets significantly reduced CRP,RF,and Dickkopf-1 protein in RA patients.In addition,in 2019,an RCT(n=94) [69] on the treatment of RA with Wangbi tablets combined with methotrexate tablets vs.the same dose of methotrexate tablets found that the total effective rate of treatment in the Wangbi tablets combined with methotrexate group was 82.98% compared with 63.83%in the methotrexate alone group,and the comparison between the two groups was statistically significant.

Clinical question 5: What is the effectiveness and safety of leflunomide combined with TCM in the treatment of RA?Leflunomide may cause adverse effects of elevated liver enzymes,diarrhea,respiratory tract infection,nausea,rash,dyspepsia,headache,alopecia,hypertension and weight loss in the treatment of RA.(C)

For patients who are menopausal and have no fertility requirements: Based on the use of leflunomide in the treatment of RA,the combination of tripterygium glycosides tablets is recommended to improve the efficacy without increasing the incidence of adverse effects,depending on the specific condition of patient.(1B)

Based on the treatment of RA with leflunomide,the combination of total glucoside of peony is recommended to improve the efficacy and reduce the incidence of adverse effects according to the specific condition of patient.(1B)

Based on the use of leflunomide in combination with methotrexate for the treatment of RA,consider the combination of Juanbi decoction to improve the efficacy according to the specific condition of patient.(2C)

Summary of evidence

Leflunomide is widely used in the clinical treatment of RA and is often used in combination with methotrexate;in the combination of Chinese and Western medicine treatment,it is often used in combination with tripterygium glycosides,total glucoside of peony,Zhengqing Fengxian Ning,Yi Kidney Remission pill,Yinling Anti-swelling pill,Guizhi Shaoyao Zhimu decoction,and Juanbi decoction to improve the efficacy.

A retrospective study on the combination of leflunomide monotherapy with conventional synthetic disease-modifying antirheumatic drugs for the treatment of RA [70] and a study on the risk analysis of adverse effects of leflunomide [71] mentioned that common adverse effects of leflunomide in clinical application include elevated liver enzymes,diarrhea,respiratory infections,nausea,rash,dyspepsia,headache,alopecia,hypertension and weight loss.

A systematic review (13 RCTs,n=1004) [72] showed that: the overall clinical effectiveness of tripterygium glycosides in combination with leflunomide vs.leflunomide (OR=4.12,95% CI (2.74,6.18)),morning stiffness time (SMD=-1.55,95% CI (-1.87,-1.23)),(SMD=-2.29,95% CI (-3.46,-1.12)),number of joint pains(SMD=-0.94,95% CI (-1.40,-0.49)),number of swollen joints(SMD=-0.78,95% CI (-1.52,-0.04)),ESR (SMD=-1.75,95%CI (-2.38,-1.13)),CRP (SMD=-2.23,95% CI (-2.96,-1.51)),RF (SMD=-2.97,95% CI (-4.22,-1.72)),immunoglobulin G(SMD=-0.58,95% CI (-1.10,-0.06)),IL-1 (SMD=-0.84,95%CI (-1.20,-0.49)),IL-6 (SMD=-4.08,95% CI (-4.86,-3.30)),TNF-α (SMD=-3.24,95% CI (-3.92,-2.56)),(SMD=-0.94,95% CI (-1.30,-0.57)) and soluble intercellular adhesion molecule-1 (SMD=-0.53,95% CI (-0.96,-0.10)),were significantly lower in the combination group than in the monotherapy group.The difference in the incidence of adverse effects between the combination group and the monotherapy group was not statistically significant.For patients without fertility requirements,short-term observation of menstruation and protection of ovarian function were required;formenopausal women,the combination of tripterygium glycosides tablets and leflunomide may be considered.

A systematic review (21 RCTs,n=1662) [73] showed that: total glucoside of peony combined with leflunomide vs.leflunomide efficiency (RR=1.18,95% CI (1.13,1.24)),improvement rate of laboratory tests index CRP (SMD=0.40,95% CI (0.26,0.54)),ESR improvement rate (SMD=0.25,95% CI (0.13,0.36)) were better in the combination group;the overall incidence of adverse effects was lower in the combination group (RR=0.48,95% CI(0.38,0.60)).

An RCT (n=120) [74] showed that the combination of remitting paralysis soup plus orminus with methotrexate and leflunomide(experimental group) vs.methotrexate and leflunomide (control group) was effective (96.67% vs.83.33%);patients’ scores of all indicators of TCM symptoms were significantly lower in the experimental group than in the control group after 12 weeks of treatment;after treatment in the experimental group,ESR,RF,CRP,serum and joint fluid levels of matrix metalloproteinase-3 were significantly lower than those of the control group,while the levels of tissue inhibitor of metalloproteinases-1 were significantly higher than those of the control group after treatment in the test group,but the safety of the test group has yet to be confirmed.An RCT (n=102)[75] showed that the combination of methotrexate and leflunomide(experimental group) and methotrexate and leflunomide (control group) was effective (94.12% vs.78.43%),and the visual analog scores (VAS) score and morning stiffness score of the experimental group were lower than those of the control group after treatment,and the results were statistically significant (P＜0.05).

Clinical question 6: What is the efficacy and safety of glucocorticoids combined with TCM in the treatment of RA?

In the treatment of RA with glucocorticoids,the incidence of adverse reactions is related to its dose.In the short term,it may cause digestion,headache,anxiety,hypertension,hyperglycemia,skin disease and other adverse reactions;in the medium and long term,it may cause osteoporosis,cardiovascular disease,acute myocardial infarction,stroke,heart failure and other adverse reactions.There is a lack of high-quality evidence to support the increased efficacy and safety of glucocorticoid combined with TCM for RA.(A)

Summary of evidence

A systematic review (47 RCTs,n=3112) [76] showed that the incidence of adverse reactions to glucocorticoid therapy for RA was related to its dose.Adverse reactions caused in the short term include digestion (nausea,vomiting,dyspepsia,gastritis,etc.),headache,anxiety,high blood pressure,hyperglycemia,and skin disorders.Medium-long term use decreases bone density in the lumbar spine and hip,and vertebral fractures can occur with long-term use of low-dose(＜10-15 mg/day) glucocorticoids.In addition,medium-long term glucocorticoid use may increase the risk of cardiovascular events (RR=1.47,95% CI (1.34,1.60),P＜0.01),and also of adverse events such as acute myocardial infarction,stroke,and heart failure.

Clinical question 7: How effectiveness and safety is sulfasalazine combined with TCM in the treatment of RA?

Adverse reactions of sulfasalazine include: allergic reaction,involving the blood system,digestive system,central nervous system,thyroid,damage to liver and kidney function,hemolytic anemia and hemoglobinuria,hyperbilirubinemia and neonatal nuclear jaundice,rare pancreatitis,male spermatopenia or infertility.At present,there were lack of high-quality evidence to support sulfasalazine combined with TCM to increase the effectiveness and safety.(B)

Summary of evidence

A cross-sectional study (n=160) [77] in 2012 found that there were 67 patients stopped taking the drug due to gastrointestinal reactions(14 cases,8.8%),rash (6 cases,3.8%) and abnormal liver function (5 cases,3.1%) among 160 patients who used sulfasalazine.The second batch of chemical drug instructions issued by the China Food and Drug Administration in 2001 [78] stated that the adverse drug reactions of sulfasalazine include allergic reaction,neutropenia or deficiency,thrombocytopenia and aplastic anemia,hemolytic anemia and hemoglobinuria,hyperbilirubinemia and neonatal nuclear jaundice,liver damage,kidney damage,nausea,vomiting,hypogastric appetite,diarrhea,headache,fatigue,etc.Goiter,hypothyroidism and toxic reactions of the central nervous system can occur occasionally.Pancreatitis,male spermatopenia or infertility are rare.

Clinical question 8: What is the efficacy and safety of iguratimod combined with TCM for RA?

The common adverse reaction of iguratimod is abnormal liver function.Other adverse reactions mainly involve the hematologic,digestive,psychoneurologic,and urinary systems,and some patients may occureallergic symptoms and metabolic disorders.There is a lack of high-quality evidence to support the increased efficacy and safety of iguratimodcombination with TCM for RA.(C)

Summary of evidence

Approved formarketing in 2016,the drug insert for iguratimod [79]indicates that symptoms such as elevated total bile acids and elevated bilirubin in the blood may occur in the liver;leukopenia and thrombocytopenia in the blood;gastritis,dyspepsia,and nausea in the digestive organs;and elevated creatinine in the blood and frequent urination in the kidneys.In addition,taking iguratimod may also cause symptoms such as rash,eczema,decreased blood iron,headache,insomnia,and increased blood pressure.

Clinical question 9: How effectiveness and safety is NSAIDs combined with TCM in the treatment of RA?

NSAIDs in the treatment of RA may cause adverse reactions in the digestive system,skin surface and accessories,cardiovascular system,nervous system,liver and kidney system,blood system,respiratory system,hearing or vision.(B)

Summary of evidence

An RCT [80] in 2019 showed that 258 patients with RA were treated with NSAIDs,and 79 patients had adverse reactions,with an adverse reaction rate of 30.62%.The main parts of adverse reactions were digestive system,skin surface and accessories,cardiovascular system,nervous system,liver and kidney system,blood system,respiratory system,hearing or vision.Three retrospective studies in 2020 and 2018 [81-83] showed that the clinical application of NSAIDs was prone to adverse reactions,including adverse reactions to cardiovascular system,blood system,digestive system,liver and kidney function,skin,hearing and organs.

Clinical question 10: What is the effectiveness and safety of biologics combined with TCM in the treatment of RA?

Biologics may cause adverse effects of infection,complete blood cytopenia,elevated transaminases,congestive heart failure and demyelinating diseases in the treatment of RA.(B)

For patients who are menopausal and without fertility requirements: use tolimumab in the treatment of RA,an IL-6 receptor antagonist,in combination with tripterygium glycosides tablets to improve the efficacy,depending on the specific condition of patient.(2C)

Summary of evidence

The current RA biologics is a new type of drugs for controlling RA with good anti-inflammatory and stopping disease progression,which mainly includes TNF inhibitors,IL-1 receptor antagonists,IL-6 receptor antagonists,etc.Janus kinase inhibitors including tofacitinib,baricitinib,and upadacitinib are highly used in clinical practice [84].The updated recommendations of the Thai Rheumatism Association for the use of biologics in patients with RA in 2017 [85] stated that patients with active infection,malignancy,or pregnancy should not use biologics for treatment.When applying biologics for the treatment of RA,in addition to the risk of infection,should be concern for pancytopenia,elevated transaminases,congestive heart failure and demyelinating diseases.

An RCT (n=50) [86] showed that morning stiffness time,tender joint count and swollen joint count were less or lower in the combination group than in the monotherapy group when combining tolimumab with tripterygium glycosides tablets vs.tolimumab;12 months after treatment in the combination group,the NKT was higher than it in the monotherapy group.A controlled trial (n=65) [87]showed that the RF,IL-8,TNF-α,CRP,and ESR in the combination group were higher than those in the monotherapy group at 12 months after treatment.A controlled trial(n=80)[88]showed that ESR,RF,CRP,IL-8 and TNF-α levels were significantly lower in the combination group compared with the monotherapy group.Patients in the combination group had essentially normal major joint functional activities,disappearance of major clinical symptoms and signs,and were able to take care of themselves and restore their labor and work abilities to some extent after treatment,but safety had yet to be confirmed.For patients without fertility requirements,short-term observation of menstruation and protection of ovarian function were required;formenopausal women,the combination of tolimumab with tripterygium glycosides tablets may be considered.

Clinical question 11: What is the effectiveness and safety of tripterygium glycosides in combination with western drugs for RA?

For people without reproductive requirements and in menopause.Tripterygium glycosides tablets may cause liver injury,so patients with liver injury are advised to use this drug with caution and to monitor liver function during the course of administration.(1B)

Consider the combination of tripterygium glycosides tablets with NSAIDs (e.g.,celecoxib,etc.) for the treatment of RA to improve efficacy without increasing the incidence of adverse events.(2C)

Summary of evidence

A systematic review (10 RCTs,n=792) [89] showed that tripterygium glycosides combined with methotrexate vs.methotrexate alone was effective in improving the overall clinical effectiveness of patients with RA (RR=1.23,95% CI (1.13,1.35)) and reducing the time to morning stiffness (SMD=-1.51,95% CI (-2.31,-0.71)),joint pain (SMD=-1.50,95% CI (-2.66,0.35)),joint tenderness(SMD=-1.28,95%CI(-1.98,-0.57)),and joint swelling(SMD=-1.46,95%CI(-2.48,-0.44)),and reduced patient ESR,CRP levels and RF levels,and reduced the incidence of adverse events in patients(RR=0.67,95% CI (0.48,0.93)).In 2019,an RCT (n=118) [90]showed that tripterygium glycosides tablets combined with methotrexate and basal therapy vs.methotrexate and basal therapy alone significantly reduced the time to morning stiffness,number of joint indications,number of joint swellings and joint pain scores,and significantly reduced the levels of inflammatory indicators such as ESR,CRP and RF in patients with RA.

A systematic review(including 12 RCTs,n=834)[91]showed that tripterygium glycosides combined with leflunomide vs.leflunomide or other anti-RA drugs improved the overall clinical effectiveness of treatment in RA patients (RR=1.20,95% CI (1.13,1.28)) and effectively decreased the time to morning stiffness (MD=-0.29,95% CI (-0.45,-0.12)),number of joint compressions (MD=-1.51,95% CI (-2.20,-0.83)),number of joint swellings (MD=-1.24,95% CI (-1.59,-0.88)),and ESR,CRP,RF,IL-1,and TNF-α levels but did not increase the incidence of adverse events (16.7% vs.20.1%,RR=0.83,95% CI (0.61,1.13)).In 2020,an RCT (n=78)[92] showed that tripterygium glycosides in combination with leflunomide vs.leflunomide alone improveed RA patients’ overall clinical effectiveness(100%vs.87.18%),and decreased the number of joint compressions and joint swellings,and reduced the RF,ESR and CRP levels.In 2019,an RCT (n=50) [93] showed that tripterygium glycosides tablets in combination with leflunomide vs.leflunomide alone effectively improved the overall clinical treatment efficiency of RA patients (97.5% vs.76.0%) and reduced the overall incidence of adverse events (including gastrointestinal upset,rash,abnormal liver function and leukopenia)(12.0% vs.28.0%,P＜0.05).

An RCT (n=108) [94] showed that tripterygium glycosides tablets combined with celecoxib capsules and conventional therapy vs.celecoxib capsules and conventional therapy were effective in improving the overall treatment effectiveness of RA patients (92.59%vs.79.63%,P=0.008) and the evaluation of RA patients’ condition(DAS28 score) ((1.54 ± 0.34) vs.(2.69 ± 0.56),P＜0.01) and VAS((2.43 ± 0.54) vs.(4.76 ± 0.87),P＜0.01),reduced CRP,IL-6,ESR,RF,IL-37,and soluble programmed death receptor 1 levels and did not increase the incidence of adverse events (14.81% vs.16.67%,P＞0.05).In 2018,an RCT (n=60) [95] showed that tripterygium glycosides combined with celecoxib and conventional therapy vs.celecoxib and conventional therapy was effective in improving the overall clinical effectiveness (93.33% vs.73.33%,P＜0.05),reduced CRP,RF,ESR,IL-6,TNF-α,and IL-23 levels,and did not increase the incidence of adverse events(16.67% vs.20.00%,P＞0.05).

Some studies [96,97] have shown that tripterygium glycosides and its preparations have clear reproductive toxicity,with varying degrees of adverse effects on the reproductive system in both men and women,and need to be used with caution in people with fertility requirements.The use of tripterygium glycosides may also cause menstrual irregularities,and short-term observation of menstruation is required during use.It has also been shown [98] that the use of tripterygium glycosides tablets can cause varying degrees of liver damage,and patients with liver damage need to use this drug with caution and need to have their liver function monitored during use.

Clinical question 12: What is the safety and efficacy of total peony glycosides in combination with western drugs in the treatment of RA?

Based on the use of methotrexate for RA,it is recommended to combine with peony glycosides to improve the efficacy and reduce the incidence of adverse reactions.(1A)

Based on the use of leflunomide in the treatment of RA,it is recommended to combine with peony glycosides to improve the efficacy and reduce the incidence of liver function damage.(1A)

Based on the combination of methotrexate with leflunomide in the treatment of RA,it is recommended to combine with peony glycosides to improve the efficacy and reduce the incidence of liver function damage.(1B)

Summary of evidence

A systematic review (8 RCTs,n=522) [59] showed that leupeptin with methotrexate vs.methotrexate was more helpful in reducing the ESR (MD=-5.85,95% CI (-8.67,-3.02)) and reducing the number of swollen joints more (MD=-1.64,95% CI (-2.27,-1.00)) and a lower incidence of adverse reactions (OR=0.34,95%CI (0.18,0.64)).A RCT (n=80) [99] showed that total peony glycosides with methotrexate vs.methotrexate was more effective(75% vs.95%,χ2=6.275) and did not increase the incidence of adverse reactions (22.5% vs.11.5%,χ2=1.385,P=0.19).

A systematic review (8 RCTs,n=643) [100] showed that leflunomide in combination with total peony glycosides was more effective in treatment (OR=4.31,95% CI (2.02,9.16)),had a lower incidence of hepatic impairment (OR=0.32,95% CI (0.12,0.84)),did not increase the incidence of gastrointestinal discomfort incidence(OR=1.59,95% CI(0.81,3.09)).

A systematic review (including 12 RCTs,n=928) [101] showed that total peony glycosides in combination with methotrexate in combination with leflunomide vs.methotrexate in combination with leflunomide treatment was more efficient (RR=1.10,95% CI (1.04,1.16)) and reduced ESR better (MD=-2.80,95% CI (-5.08,-0.52)),better reduction of CRP (MD=-4.17,95% CI (-7.84,-0.51)),better reduction of RF (MD=-12.09,95% CI (-14.05,-10.14)),and lower incidence of side effects (OR=0.55,95% CI(0.38,0.80));lower incidence of hepatic impairment (OR=0.35,95% CI (0.24,0.52));and no increased incidence of leukopenia,nausea and vomiting,gastrointestinal symptoms,diarrhea,etc.An RCT (n=76) [102] showed that total paeoniflorin in combination with methotrexate in combination with leflunomide vs.methotrexate in combination with leflunomide Better improvement in first-second exertional expiratory volume,exertional spirometry and first-second exertional expiratory volume/exertional spirometry (P≤0.05) and better efficiency (94.74% vs.71.05%) before and after treatment with methotrexate in patients with RA.

Clinical question 13: What is the safety and efficacy of Kunxian capsules in combination with western drugs for the treatment of RA?

Among RA patients without reproductive requirements and menopause,based on the use of methotrexate,it is recommended to use Kunxian capsules on a dialectical basis to improve the efficacy and reduce the incidence of liver function damage in RA patients.(2B)

Summary of evidence

A systematic review [63] (7 RCTs) showed that Kunxian capsules in combination with methotrexate vs.methotrexate were more effective(OR=2.99,95% CI (1.57,5.69)),reduced the number of swollen joints better (OR=-1.95,95% CI (-3.13,-0.77)),reduced morning stiffness better (OR=-15.14,95% CI (-22.53,-7.75)),better reduction of blood sedimentation (MD=-7.55,95% CI(-10.68,-4.41)),better reduction of CRP (MD=-4.60,95% CI(-9.28,0.08)),better reduction of RF (MD=-27.9).In 2020,an RCT[65](n=60)showed that Kunxian capsules in combination with methotrexate vs.methotrexate were more effective in the treatment group (93.99% vs.86.67%,χ2=4.167.The “Guidelines of diagnosis treatment of rheumatoid arthritis disease and syndrome combination”[103]and the“Guidelines for the Diagnosis and Treatment of Rheumatoid Arthritis base on TCM Syndromes” .The “2017 Combined Guidelines for the Treatment of Rheumatoid Arthritis Evidence” [103] and the “2018 Combined Guidelines for the Treatment of Rheumatoid Arthritis Evidence”[104] developed by the Rheumatology Branch of the Chinese Society of Traditional Chinese Medicine both state that patients with fertility needs Kunxian capsules are contraindicated for patients with RA.The drug instructions for Kunxian capsules clearly state that they are contraindicated in patients with reproductive needs [105].The use of Kunxian capsules may also cause menstrual irregularities,and short-term observation of menstruation is required at the time of use.

Clinical question 14:What is the efficacy and safety of Zhengqing Fengtong Ning combined with Western medicine?Summary of evidence

A systematic review [106] (including 8 RCTs,n=708) showed that the combination of Zhengqing Fengtong Ning,methotrexate,leflunomide,lorazepam and NSAIDs has significant overall efficiency(Z=3.64,P=0.003),the time to morning stiffness (MD=-13.29,95% CI (-24.66,-1.92) and joint pressure pain index (MD=-0.94,95% CI (-1.82,-0.07)) were also respectively superior to using these drugs alone.Besides,the combination could reduce the incidence of adverse effects as well (χ2=4.80,P＜0.01).The consensus group did not reach a consensus on the recommendations based on the evidence including the systematic review and one RCT[107].

Clinical question 15: What is the efficacy and safety of herbal tonics combined with western drugs in the treatment of RA?

For patients with RA who take conventional Western medicine,the combination of Guizhi Shaoyao Zhimu decoction(1A),Duhuo Jisheng decoction (1A),Huangqi Guizhi Wuwu decoction (1A),Xuanbi decoction (1B),Juanbi decoction (1B) were recommended to improve the efficacy and reduce the incidence of adverse effects.(1A)

Summary of evidence

Guizhi Shaoyao Zhimu decoction combined with Western medicine in the treatment of RA could improve the effect and reduce the incidence of adverse reactions.A systematic review (including 12 RCTs)published in 2018 [108] showed that combining Guizhi Shaoyao Zhimu decoction with conventional Western medicine for RA vs.Western medicine alone improved the overall effectiveness of treatment(RR=1.24,95%CI(1.16,1.32)),shortened the duration of morning stiffness,reduced joint pain and tenderness,improved joint swelling,and reduced RF,ESR,CRP and reduced the incidence of adverse reactions (4.34% vs.12.58%).A RCT (n=110) [109]published in 2019 showed that combining Guizhi Shaoyao Zhimu decoction with conventional Western medicine treatment for RA vs.conventional Western medicine treatment improved the overall effective rate (92.73% vs.78.18%),reduced the number of joint swelling and joint pain,shortened the time to morning stiffness and 20m walking time,reduced ESR,mean platelet volume,platelet distribution width,CPR and RF,and reduced incidence of adverse events (0.00% vs.10.91%,P＜0.05).

Duhuo Jisheng decoction combined with Western medicine in the treatment of RA could improve the effect and reduce the incidence of adverse reactions.A systematic review (22 RCTs,n=2142) [110]published in 2019 showed that the combination of Duhuo Jisheng decoction with Western medicine for RA vs.Western medicine alone improved the overall efficiency (OR=4.03;95% CI (3.06,5.32)),shortened the duration of morning stiffness,reduced joint pain and swelling,decreased RF,ESR and CRP without increasing the incidence of adverse events (2.82% vs.6.44%).A RCT (n=112) [111]published in 2019 showed that methotrexate combined with Duhuo Jisheng decoction for RA vs.methotrexate alone improved the overall effective rate (94.65% vs.85.71%),reduced the number of joint swelling and tenderness,shortened the duration of morning stiffness,decreased pain score VAS,decreased TNF-a,CRP and IL-6,and decreased the incidence of adverse events (0.00% vs.12.50%,P＜0.05).

Huangqi Guizhi Wuwu decoction combined with Western medicine in the treatment of RA could improve the effect and reduce the incidence of adverse reactions.A systematic review (11 RCTs,n=935) published in 2019 showed [112] that Huangqi Guizhi Wuwu decoction combined with conventional Western medicine for RA vs.Western medicine alone improved the overall efficiency of patients(RR=1.30,95% CI=(1.22,1.39)),shortened the duration of morning stiffness,reduced ESR and RF,and did not increase the adverse reaction.A RCT (n=176) [113] published in 2020 showed that conventional Western medicine combined with Huangqi Guizhi Wuwu decoction vs.conventional medicine improved the overall effective rate (92.0% vs.80.7%),reduced the number reduced joint pain and tenderness,and decreased ESR scores and VAS scores.

In addition,several RCTs have shown that the combination of TCM decoction,such as Xuanbi decoction [114] and Juanbi decoction[115],with western drugs for RA can increase the efficacy of western drugs without increasing or even decreasing the incidence of adverse effects.

Clinical question 16: What is the efficacy of pills/powder combined with the Western medicine in the treatment of RA?

Yishen Juanbi pill was recommended to use in combination with leflunomide and/ormethotrexate to improve the effect without increasing the incidence of adverse reactions(2B).

Summary of evidence

In 2019,a systematic review (including 9 RCTs,n=824) [116]showed that Yishen Juanbi pill combined with Western medicine,compared with Western medicine alone for RA,was more effective in overall effectiveness (RR=1.20,95% CI (1.13,1.27)).The improvement in the number of swollen joints in patients with RA(SMD=-1.03,95% CI (-1.51,-0.54)),number of pressure pain(SMD=-1.36,95% CI (-1.92,-0.79)),time to morning stiffness(SWD=-1.07,95% CI(-1.44,-0.70)),ESR (SMD=-0.73,95%CI (-1.02,-0.44)),CRP (SMD=-0.72,95% CI (-0.98,-0.45))and RF(SMD=-0.99,95%CI(-1.70,-0.29))were superior to the use of western drugs alone as well,without increasing the incidence of adverse drug reactions (RR=0.71,95% CI (0.45,1.14)).In 2018,a meta-analysis (8 RCTs included,n=719) [117] showed that,compared with the control group,the combination of Yishen Juanbi pill had better performance in overall effective rate (RR=1.18,95%CI (1.11,1.25)),significant efficiency (RR=1.33,95% CI (1.13,1.55)),reduction of morning stiffness time (SMD=-0.97,95% CI(-1.37,-0.57)),reduction of joint pressure pain (MD=-2.35,95% CI(-3.29,-1.42)),number of swelling (MD=-1.57,95% CI(-2.28,-0.86)),reduction in RF (MD=-20.61,95% CI (-30.09,-11.13)),ESR (MD=-10.98,95% CI (-14.23,-7.74)),CRP (MD=-9.91,95% CI (-15.00,-4.82)) levels,and its incidence of adverse reactions such as gastrointestinal reactions,skin pruritus,erythema,and elevated transaminases were lower than the control group.

In 2018,an RCT (n=110) [118] showed that the combination of methotrexate and leflunomide with gout-riddled capsules combined with Yihen Juanbi pill versus methotrexate and leflunomide in the treatment of active RA was significantly better in terms of total effective rate,time to morning stiffness,rest pain,number of swollen joints,joint pressure pain index,handgrip strength,disease activity standard score (DAS28),ESR,CRP,RF,matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 level.Tissue inhibitor of metalloproteinases-1 level was superior the control group (P＜0.05)and did not increase the incidence of adverse effects such as nausea,diarrhea abdominal pain and pruritus (P＞0.05).An RCT (n=80)[119] published in 2016 showed that the combination of leflunomide tablets with Yishen Juanbi pill versus leflunomide tablets was more effective in swelling,pain relief onset time,efficiency,joint pain index,joint pressure pain index,joint swelling index,time to morning stiffness,15-meter-walking time,grip strength,RF,ESR,and CRP compared to the leflunomide group alone,in addition,it reduced the incidence of adverse effects as well (12.5% vs.27.5%,P＜0.05).

Developing group

Steering committee.Chengping Wen (Zhejiang University of Traditional Chinese Medicine);Yaolong Chen (Guidelines and Standards Research Center,Institute of Health Data Science,Lanzhou University;Research Unit of Evidence-Based Evaluation and Guidelines,Chinese Academy of Medical Sciences (2021RU017)).

Review group.Wei Cao (Department of Rheumatology and Immunology,Guang’anmen Hospital,Chinese Academy of Traditional Chinese Medicine);Hui Zheng (Institute of Biomedical Research,Soochow University);Yanfang Ma (Hong Kong Chinese Medicine Clinical Study Center,School of Chinese Medicine,Hong Kong Baptist University).

Secretary group.Zhijun Xie,Lin Huang,Qiao Wang (Zhejiang University of Traditional Chinese Medicine);Xiaohui Wang,Xuping Song (School of Public Health,Lanzhou University).

Consensus group (in pinyin order of last name).Mingli Gao(Department of Rheumatology and Immunology,Affiliated Hospital of Liaoning University of Chinese Medicine),Zhaofu Li (Yunnan University of Chinese Medicine),Chunying Liu (Department of Nephrology,Affiliated Hospital of Shaanxi University of Chinese Medicine),Wei Liu (Department of Rheumatology and Immunology,First Affiliated Hospital of Tianjin University of Chinese Medicine),Wukai Ma (Department of Rheumatology and Immunology,Second Affiliated Hospital of Guiyang College of Traditional Chinese Medicine);Xuefeng Pang (Department of Rheumatology and Immunology,Ruikang Hospital,Guangxi University of Traditional Chinese Medicine),Jiangyun Peng (Department of Rheumatology,Provincial Hospital of Traditional Chinese Medicine),Huanru Qu(Department of Rheumatology,Longhua Hospital,Shanghai University of Traditional Chinese Medicine),Xiaofeng Rong(Department of Integrative Medicine,First Affiliated Hospital of Chongqing Medical University),Li Su (Department of Rheumatology,Longhua Hospital,Shanghai University of Traditional Chinese Medicine),Jingyang Tang (Department of Rheumatology,Xiyuan Hospital,Chinese Academy of Traditional Chinese Medicine),and Tao Qingwen (Department of Rheumatology,Department of Traditional Chinese Medicine,Sino-Japanese Hospital),Tu Shenghao(Department of Rheumatology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology),Chengwu Wang (Department of Rheumatology,Affiliated Hospital of Changchun University of Traditional Chinese Medicine (Jilin Provincial Hospital of Traditional Chinese Medicine),Hailong Wang (Department of Rheumatology,Dongzhimen Hospital,Beijing University of Traditional Chinese Medicine),Guolin Wu (Department of Traditional Chinese Medicine,The First Hospital of Zhejiang University School of Medicine),Guangyu Wu (Department of Rheumatology and Endocrinology,The Second People′s Hospital of Fujian Province),Weidong Xu(Department of Rheumatology,Jiangxi Department of Rheumatology,Oriental Hospital of Beijing University of Traditional Chinese Medicine).

Evidence evaluation group.Yangqin Xun,Nan Yang,Ping Wang(Center for Evidence-Based Medicine,School of Basic Medical Sciences,Lanzhou University);Mengjuan Ren,Yunlan Liu,Yue Hu,Juanjuan Zhang,Hui Lan,Shouyuan Wu,Qiangqiang Guo,Yajia Sun(School of Public Health,Lanzhou University),Xianzhuo Zhang (First Clinical Medical College,Lanzhou University);Haichang Li,Yujun Tang(Zhejiang University of Traditional Chinese Medicine).