Efficacy of JAK STAT Pathways Inhibitors in Treatment of Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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There is no treatment that could utterly cure Rheumatoid arthritis (RA), but the disease is mainly improved by conventional disease-modifying anti rheumatic drugs. Methotrexate and biological DMARDs as JAK-STAT inhibitors may be used to control and delay the progression of the disease and improve the quality of lives of patients. However, DMARDs have deleterious effects on human health. Several natural components have JAK-STAT inhibitory effect such as Boswellic acid (Boswellia serrata extract), Glycyrrhizin (Glycyrrhiza glabra extr.) and Apigenin (Chamomile extr)

Detailed Description
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Rheumatoid arthritis (RA) is a systemic chronic, progressive, autoimmune disease characterized by inflammatory cell infiltration and synovial proliferation, accompanied by injury to articular cartilage and subchondral bone The prevalence of RA in women is 3.6% and 1.7% for men . There is no treatment that could utterly cure RA, but the disease is mainly improved by conventional disease-modifying antirheumatic drugs. Methotrexate and biological DMARDs as JAK-STAT inhibitors may be used to control and delay the progression of the disease and improve the quality of lives of patients. However, DMARDs have deleterious effects on human health. Chronic use of these agents by pregnant patients may induce teratogenic effects . Many studies showed that some natural plant extracts or mixed herbal compounds effectively regulate the immune system and possess in vitro and/or in vivo inhibitory effects against STAT to alleviate RA by inhibiting pro-inflammatory cytokines. Several natural components have JAK-STAT inhibitory effect such as Boswellic acid (Boswellia serrata extract), Glycyrrhizin (Glycyrrhiza glabra extr.) and Apigenin (Chamomile extr.). Boswellic acid and its derivative acetyl-11- keto boswellic acid, are reported to be the most potent inhibitors in the synthesis of 5-LOX. Since 5-LOX is an important enzyme involved in the biosynthesis of leukotrienes and is significantly expressed in RA. B. serrata extract, when administered orally, inhibits IL-6, IL-1 , IFN- TNF- and PGE2 in complete Freund's adjuvant-induced arthritis in rats. Glycyrrhizin reduced the activity of JAK/STAT signaling pathway, which is the upstream regulator of HMGB1. These natural products have inhibitory effect for the STAT3 signaling pathway that have anti-inflammatory and anti-rheumatoid as well as anticancer effects. These inhibitors have been found to inhibit the STAT3 signaling pathway by reducing IL-6 production . Apigenin is a plant-derived flavonoid that is abundant in celery, Chamomile, plantain seed, and is effective in the prevention and treatment of inflammatory diseases, prostate cancer, and in inhibiting tumorigenesis and angiogenesis in melanoma, breast, skin, and colon cancers. Apigenin reduced p-JAK1/2 and p-STAT3 in breast cancer (BT-474) cells, and demonstrated antirheumatic and anticancer activity by inhibiting JAK-STAT . our aim To assess the efficacy of some natural JAK-STAT inhibitors as complementary medicine in the treatment of rheumatoid arthritis and attenuation of the side effects of regular methotrexate our Research outcome measures: Primary (main): The change in DAS28 based on C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) Rate of achieving 20%, 50% and 70% improvement in the American College Rheumatology criteria (ACR20, ACR50, ACR70). Secondary (subsidiary): Change in visual analogue scale (VAS). Determination of effusion synovitis volume on musculoskeletal ultrasound(MSUS) Determination of Inflammatory cytokines levels: (Tumour necrosis factor α and Interleukin 6). Safety and Tolerability Measures: adverse events including nausea, vomiting, dizziness and abdominal pain, CBC and urine analysis as well as kidney and liver function tests will be performed before enrolment.

Official Title
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Evaluation of the Efficacy of Natural JAK_ STAT Pathways Inhibitors in Treatment of Patients With Rheumatoid Arthritis as a Complementary Medicine

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Dietary Supplement: apigenin and glycyrrhizin
* Dietary Supplement: glycyrrhizin and boswellic acid
* Dietary Supplement: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female,ages18-60. Patients who met criteria for the diagnosis of RA Patients who were signed the informed consent form. Exclusion Criteria: Patients with Malignant tumours, Patients with Infectious diseases, Patients with Hematologic diseases. Patients with other rheumatic diseases. Women who are pregnant or breastfeeding. Hypersensitivity to dietary supplement used in this study. Hypertensive patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: apigenin and glycyrrhizin<br>Patients will receive one capsule contains 10 mg of apigenin (Matricaria chamomilla L extract) and one capsule contains glycyrrhizin 50(licorice extract) twice daily for 6 months | Dietary Supplement: apigenin and glycyrrhizin<br>* apigenin will be administered as capsule (10mg,eq 200mg Matricaria chamomilla L extract) two times daily. Also, glycyrrhizin  will be administered as capsule(50 mg eq 250 mg licorice extract) two times daily. The two types of capsules administration will be continue for 6 months<br>|
| Active Comparator: boswellic acid and glycyrrhizin<br>Patients will receive one capsule contains 200 mg boswellic acid (Boswellia serrata extract) and one capsule contains glycyrrhizin 50(licorice extract) twice daily for 6 months | Dietary Supplement: glycyrrhizin and boswellic acid<br>* boswellic acid will be administered as capsule (200mg,eq 250mg Boswellia serrata extract) two times daily. Also, glycyrrhizin  will be administered as capsule(50 mg eq 250 mg licorice extract) two times daily. The two types of capsules administration will be continue for 6 months<br>|
| Placebo Comparator: placebo<br>Patients will receive daily two capsules contain placebo for 6 months | Dietary Supplement: placebo<br>* Placebo capsule will be administered two times daily for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in DAS28 based on C-reactive protein (DAS28-CRP) | DAS-28 score: a DAS-28 score > 5.1 indicating high disease activity; 3.2< DAS-28 score≤5.1 indicates moderate disease activity; 2.6< DAS-28 score≤3.2 indicates low disease activity; DAS-28 score≤2.6 indicates basic disease remission | Before the intervention, 3 months after the intervention, and 6 months after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in visual analogue scale (VAS | each patient will be asked to indicate his or her current level of pain on 100mm scale.0scale indicate no pain and 100mm indicate worst pain imaginable | Before the intervention, 3 months after the intervention, and 6 months after the intervention | 
| Determination of effusion synovitis volume on musculoskeletal ultrasound(MSUS) | Determination of effusion synovitis volume on musculoskeletal ultrasound | Before the intervention, 3 months after the intervention, and 6 months after the intervention | 
| Determination of Inflammatory cytokines levels: (Tumour necrosis factor α and Interleukin 6). | laboratory test | Before the intervention, 3 months after the intervention, and 6 months after the intervention |