Acupuncture Study on Rheumatoid Arthritis, Monitoring Microbiome and Blood

Study Overview
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Brief Summary
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Acupuncture is used and recommended by the WHO for the treatment of Rheumatoid Arthritis. The molecular bases of this recommendation are not known, the investigators want to compare with the usage of high-throughput molecular technologies the variations occurring in patients treated with acupuncture and conventional treatment with the ones treated with conventional treatment only. The investigators observe the variations in blood and in the gut microbiome.

Official Title
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Non Inferiority Trial for the Study of Acupuncture on Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: methotrexate
* Drug: non-steroidal anti-inflammatory drug (NSAID)
* Drug: leflunomide
* Drug: methotrexate
* Drug: non-steroidal anti-inflammatory drug (NSAID)
* Drug: leflunomide
* Procedure: Acupuncture


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient should be diagnosed as the first or second stage of rheumatoid Arthritis (RA) and checked with X ray for additional diagnose. diagnosed for RA according to ACR(1987) the patient should be in the active stage of the disease, defined as： swollen joints >3 tender joints > 5 any one of the following： (c1.) morning stiffness lasting more than 45 minutes (c2.) Erythrocyte Sedimentation Rate (ESR) >= 28mm/h (c3.) C-reactive protein (CRP)>= 12mg/L Should not be resistant to MTX nor leflunomide Blood test should satisfy: Hemoglobin (Hb)>=85g/L White cell >=3.5 10+9/L Platelets >= 100 10+9/L Liver function: serum alanine aminotransaminase (ALT), aspartate transaminase (AST) and total bilirubin (TBil) should be less than 1.5 times the upper limit of normal (ULN) Kidney function: Serum creatinine (Cr) level should be less than ULN. Pregnancy test should be negative should be positive for anti-cyclic citrullinated protein antibodies (anti-CCP). should agree to sign the informed consent Exclusion Criteria: Serious diseases affecting liver, kidney, heart and lung, or diseases related to hematologic，endocrine and nervous systems. . Be treated by MTX or Leflunomide in the last 3 months. Be treated with cortical hormone （could be intramuscular injection, intravenous injection or injection to articular cavity） in the last 4 weeks. Be treated with biological agents, such as antagonist of TNF-alpha,IL-6, and CD20 mono antibody in the last 3 months. Be treated by chronic medicine, such as immunosuppressive agent, Penicillamine, chloroquine and gold based Disease-modifying antirheumatic drugs (DMARDs) in the last 3 months. Pregnant and breast-feeding woman Having history of serious drug allergy In the acute or chronic phase of infection (such as lung diseases) Easy bleeding patients or patients with local skin infection (only for acupuncture) The patients cannot accept acupuncture (only for acupuncture) Be treated with acupuncture in the past 3 months（only for acupuncture）. No pregnant and breast-feeding woman. No history of serious drug allergy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acupuncture<br>Acupuncture plus conventional treatment (methotrexate+leflunomide+non-steroid anti-inflammatory drugs) | Drug: methotrexate<br>* methotrexate: 7.5mg/week to 15mg/week for 3 months<br>Drug: non-steroidal anti-inflammatory drug (NSAID)<br>* NSAID: 100mg twice a day for 3 months<br>Drug: leflunomide<br>* leflunomide: 20mg/day for 3 months<br>Procedure: Acupuncture<br>* 30 minutes acupuncture every other day for 3 months. Basic acupoints: Zusanli, st36; Taixi，KI3）; Shenxu, BL23 Additional acupoints due to personal condition: Waiguan，SJ5; Baxie，Ex-UE9;Yinlingquan，(SP9）; Quchi，LI11; Yanglingquan，GB34; Xuehai，SP10; Dazhu，BL11; Dazhui，DU14; Pixu，BL20.<br>|
| Active Comparator: Control<br>Conventional treatment (methotrexate+leflunomide+non-steroid anti-inflammatory drugs) | Drug: methotrexate<br>* methotrexate: 7.5mg/week to 15mg/week for 3 months<br>Drug: non-steroidal anti-inflammatory drug (NSAID)<br>* NSAID: 100mg twice a day for 3 months<br>Drug: leflunomide<br>* leflunomide: 20mg/day for 3 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR20 Response Rate at 3 Weeks | ACR criteria stands for: American College of Rheumatology Criteria. ACR criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate) patient assessment physician assessment pain scale disability/functional questionnaire The number indicates the percentage of improvement in tender or swollen joint counts as well percentage improvement in three of the other five criteria (patient's assessment of pain, a physician's global assessment of disease, a patient's global assessment of disease, physical function as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the level of acute-phase reactant) | From baseline to 3 weeks | 
| ACR20 Response Rate at 3 Months | ACR criteria stands for: American College of Rheumatology Criteria. ACR criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate) patient assessment physician assessment pain scale disability/functional questionnaire The number indicates the percentage of improvement in tender or swollen joint counts as well percentage improvement in three of the other five criteria (patient's assessment of pain, a physician's global assessment of disease, a patient's global assessment of disease, physical function as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the level of acute-phase reactant) | From baseline to three months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR50 Response Rate at 3 Weeks | ACR criteria stands for: American College of Rheumatology Criteria. ACR criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate) patient assessment physician assessment pain scale disability/functional questionnaire The number indicates the percentage of improvement in tender or swollen joint counts as well percentage improvement in three of the other five criteria (patient's assessment of pain, a physician's global assessment of disease, a patient's global assessment of disease, physical function as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the level of acute-phase reactant) | From baseline to 3 weeks | 
| ACR50 Response Rate at 3 Months | ACR criteria stands for: American College of Rheumatology Criteria. ACR criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate) patient assessment physician assessment pain scale disability/functional questionnaire The number indicates the percentage of improvement in tender or swollen joint counts as well percentage improvement in three of the other five criteria (patient's assessment of pain, a physician's global assessment of disease, a patient's global assessment of disease, physical function as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the level of acute-phase reactant) | From baseline to three months | 
| ACR70 Response Rate at 3 Weeks | ACR criteria stands for: American College of Rheumatology Criteria. ACR criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate) patient assessment physician assessment pain scale disability/functional questionnaire The number indicates the percentage of improvement in tender or swollen joint counts as well percentage improvement in three of the other five criteria (patient's assessment of pain, a physician's global assessment of disease, a patient's global assessment of disease, physical function as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the level of acute-phase reactant) | From baseline to 3 weeks | 
| ACR70 Response Rate at 3 Months | ACR criteria stands for: American College of Rheumatology Criteria. ACR criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate) patient assessment physician assessment pain scale disability/functional questionnaire The number indicates the percentage of improvement in tender or swollen joint counts as well percentage improvement in three of the other five criteria (patient's assessment of pain, a physician's global assessment of disease, a patient's global assessment of disease, physical function as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the level of acute-phase reactant) | From baseline to three months | 
| DAS28 at Baseline | The DAS28 (disease activity score) considers 28 tender and swollen joint counts, general health (GH; patient assessment of disease activity using a 100 mm visual analogue scale (VAS) with 0 = best, 100 = worst), plus levels of an acute phase reactant (either the level of erythrocyte sedimentation rate ESR (mm/h) or C-reactive protein CRP (mg/litre)). DAS28 values were calculated as follows: DAS28 (CRP) = 0.56*√(TJC28) +0.28*√(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96; DAS28 (ESR) = 0.56*√(TJC28)+0.28*√(SJC28)+0.014*GH+0.70*ln(ESR), where TJC = tender joint count and SJC = swollen joint count. The scale does not have bounds. DAS28 total score < 2,6 means remission DAS28 total score ranged between 2.6-3.2 means inactive disease; DAS28 total score ranged between 3.3-5.1 means moderate disease activity; DAS28 total score >5.1 means very active disease | At baseline | 
| DAS28 at 3 Weeks | The DAS28 (disease activity score) considers 28 tender and swollen joint counts, general health (GH; patient assessment of disease activity using a 100 mm visual analogue scale (VAS) with 0 = best, 100 = worst), plus levels of an acute phase reactant (either the level of erythrocyte sedimentation rate ESR (mm/h) or C-reactive protein CRP (mg/litre)). DAS28 values were calculated as follows: DAS28 (CRP) = 0.56*√(TJC28) +0.28*√(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96; DAS28 (ESR) = 0.56*√(TJC28)+0.28*√(SJC28)+0.014*GH+0.70*ln(ESR), where TJC = tender joint count and SJC = swollen joint count. The scale does not have bounds. DAS28 total score < 2,6 means remission DAS28 total score ranged between 0-3.2 means inactive disease; DAS28 total score ranged between 3.3-5.1 means moderate disease activity; DAS28 total score >5.1 means very active disease | At 3 weeks | 
| DAS28 at 3 Months | The DAS28 (disease activity score) considers 28 tender and swollen joint counts, general health (GH; patient assessment of disease activity using a 100 mm visual analogue scale (VAS) with 0 = best, 100 = worst), plus levels of an acute phase reactant (either the level of erythrocyte sedimentation rate ESR (mm/h) or C-reactive protein CRP (mg/litre)). DAS28 values were calculated as follows: DAS28 (CRP) = 0.56*√(TJC28) +0.28*√(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96; DAS28 (ESR) = 0.56*√(TJC28)+0.28*√(SJC28)+0.014*GH+0.70*ln(ESR), where TJC = tender joint count and SJC = swollen joint count. The scale does not have bounds. DAS28 total score < 2,6 means remission DAS28 total score ranged between 0-3.2 means inactive disease; DAS28 total score ranged between 3.3-5.1 means moderate disease activity; DAS28 total score >5.1 means very active disease | At 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, blood, gut intestinal microbiome