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

Rheumatoid Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05788705
• Other study ID #: Natural JAK STAT Inhibitors
• Status: Not yet recruiting
• Phase: N/A
• Start date: July 2023
• Est. completion date: December 2025

Study information

• Verified date: March 2023
• Source: Assiut University
• Contact: Adel A Gomaa, ph.D
• Phone: 01009534841
• Email: a.gomaa[@]aun.edu.eg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Description:

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:

1. Primary (main):

1. The change in DAS28 based on C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI)

2. Rate of achieving 20%, 50% and 70% improvement in the American College Rheumatology criteria (ACR20, ACR50, ACR70).

2. Secondary (subsidiary):

1. Change in visual analogue scale (VAS).

2. Determination of effusion synovitis volume on musculoskeletal ultrasound(MSUS)

3. Determination of Inflammatory cytokines levels: (Tumour necrosis factor α and Interleukin 6).

4. 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 75
• Est. completion date: December 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Dietary Supplement:
• "apigenin" and "glycyrrhizin"
"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
• "glycyrrhizin" and "boswellic acid"
"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
• "placebo"
"Placebo "capsule will be administered two times daily for 6 months

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Adel A.Gomaa

References & Publications (11)

Abid R, Ghazanfar S, Farid A, Sulaman SM, Idrees M, Amen RA, Muzammal M, Shahzad MK, Mohamed MO, Khaled AA, Safir W, Ghori I, Elasbali AM, Alharbi B. Pharmacological Properties of 4', 5, 7-Trihydroxyflavone (Apigenin) and Its Impact on Cell Signaling Pathways. Molecules. 2022 Jul 4;27(13):4304. doi: 10.3390/molecules27134304. — View Citation

Dudics S, Langan D, Meka RR, Venkatesha SH, Berman BM, Che CT, Moudgil KD. Natural Products for the Treatment of Autoimmune Arthritis: Their Mechanisms of Action, Targeted Delivery, and Interplay with the Host Microbiome. Int J Mol Sci. 2018 Aug 24;19(9):2508. doi: 10.3390/ijms19092508. — View Citation

Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018 Apr 27;6:15. doi: 10.1038/s41413-018-0016-9. eCollection 2018. — View Citation

Hoisnard L, Pina Vegas L, Dray-Spira R, Weill A, Zureik M, Sbidian E. Risk of major adverse cardiovascular and venous thromboembolism events in patients with rheumatoid arthritis exposed to JAK inhibitors versus adalimumab: a nationwide cohort study. Ann Rheum Dis. 2023 Feb;82(2):182-188. doi: 10.1136/ard-2022-222824. Epub 2022 Oct 5. — View Citation

Kumar R, Singh S, Saksena AK, Pal R, Jaiswal R, Kumar R. Effect of Boswellia Serrata Extract on Acute Inflammatory Parameters and Tumor Necrosis Factor-alpha in Complete Freund's Adjuvant-Induced Animal Model of Rheumatoid Arthritis. Int J Appl Basic Med Res. 2019 Apr-Jun;9(2):100-106. doi: 10.4103/ijabmr.IJABMR_248_18. — View Citation

Oton T, Carmona L. The epidemiology of established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019 Oct;33(5):101477. doi: 10.1016/j.berh.2019.101477. Epub 2020 Jan 25. — View Citation

Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016 Oct 22;388(10055):2023-2038. doi: 10.1016/S0140-6736(16)30173-8. Epub 2016 May 3. Erratum In: Lancet. 2016 Oct 22;388(10055):1984. — View Citation

Wu X, Wang W, Chen Y, Liu X, Wang J, Qin X, Yuan D, Yu T, Chen G, Mi Y, Mou J, Cui J, Hu A, E Y, Pei D. Glycyrrhizin Suppresses the Growth of Human NSCLC Cell Line HCC827 by Downregulating HMGB1 Level. Biomed Res Int. 2018 Jan 15;2018:6916797. doi: 10.1155/2018/6916797. eCollection 2018. — View Citation

Wu Y, Wang Z, Du Q, Zhu Z, Chen T, Xue Y, Wang Y, Zeng Q, Shen C, Jiang C, Liu L, Zhu H, Liu Q. Pharmacological Effects and Underlying Mechanisms of Licorice-Derived Flavonoids. Evid Based Complement Alternat Med. 2022 Jan 17;2022:9523071. doi: 10.1155/2022/9523071. eCollection 2022. — View Citation

Yang J, Wang L, Guan X, Qin JJ. Inhibiting STAT3 signaling pathway by natural products for cancer prevention and therapy: In vitro and in vivo activity and mechanisms of action. Pharmacol Res. 2022 Aug;182:106357. doi: 10.1016/j.phrs.2022.106357. Epub 2022 Jul 19. — View Citation

Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, Germino R, Menon S, Sun Y, Wang C, Shapiro AB, Kanik KS, Connell CA; ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022 Jan 27;386(4):316-326. doi: 10.1056/NEJMoa2109927. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Determination of Inflammatory cytokines levels: (Tumour necrosis factor a and Interleukin 6).	laboratory test	Before the intervention, 3 months after the intervention, and 6 months after the intervention