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This study aims at evaluating the therapeutic effects of Cilostazol as adjuvant therapies to low dose of Methotrexate in patients with Rheumatoid Arthritis and to evaluate their impact on Cyclic adenosine monophosphate(CAMP), Heme Oxygenase-1(HO-1).
Rheumatoid arthritis (RA) is characterized by the presence of hyperplastic synovium in association with immune-mediated inflammatory synovitis associated with chronic production of proinflammatory cytokines, which lead to cartilage and bone degradation .This study is a randomized, controlled double blind placebo-controlled ,prospective study to evaluate the potential therapeutic effects of Cilostazol on synovial inflammation when administered as add-on treatments to the low dose of Methotrexate.
A total of 70 RA patients with active disease will be recruited from Outpatient Clinic of Physical Medicine, Rheumatology and Rehabilitation at Mansoura University hospitals, Mansoura, Egypt will be included in the study. They will be diagnosed with RA according to the American College of Rheumatology/European League Against Rheumatism criteria 2010 (the ACR/EULAR 2010 criteria).
RA Patients who will meet the inclusion criteria will be enrolled in the study.
They will be classified into two groups:
Group 1: 35 RA patients who will receive Methotrexate and placebo for 12 weeks and serve as the control group.
Group 2: 35 RA patients who will receive Methotrexate and Cilostazol 50 mg twice daily for 12 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cilostazol and Methotrexate | Active Comparator | Participants in this arm will receive Cilostazol 50 mg twice daily with Methotrexate for rheumatoid arthritis for 12 weeks. |
|
| Placebo and Methotrexate | Placebo Comparator | Participants in this arm will receive Placebo with Methotrexate for rheumatoid arthritis for 12 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cilostazol | Drug | Cilostazol 50 MG |
| |
| Methotrexate |
| Measure | Description | Time Frame |
|---|---|---|
| change in DAS-28 CRP score | Clinical assessment by calculating of 28-joint count Disease Activity score (DAS-28) using C-reactive protein according to calculating formula(DAS28 (CRP) = 0.56*√(Tender joint count28) +0.28*√(Sowallen joint count28)+0.36*ln (CRP+1)*1.10+1.15 will done where high disease activity ≥ 5.1, low disease activity ≤ 3.2, and remission < 2.6. | Baseline,12 weeks |
| Change in Multi Dimensional Health Assessment score | Functional assessment will be assessed through Multi Dimensional Health Assessment score that include 14 items Health Assessment Questionaire .The score of the HAQ Questionnaire is calculated from the mean of the sum of the responses of the items where each item is scored from 0-3, where 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do. in addition, MDHAQ includes the assessment of morning stiffness (MS) duration in minutes. | Baseline,12weeks |
| Change in Visual analog scale for pain | Visual analog scales which ranges from 0 to 10,it is a psychometric scale that is generally used in hospitals and clinics by doctors to conduct pain scale surveys to understand varying degrees of pain or discomfort experienced by a patient. | Baseline,12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the serum level of the assessed biological marker C-reactive protein | C-reactive protein :CRP value (normal range <1.0 mg/dl). If the value is increased, the disease activity worsened. If the value is reduced the disease activity is improved. | Baseline,12weeks |
| Change in the serum level of the assessed biological marker Nuclear factor kabba-B p65 |
| Measure | Description | Time Frame |
|---|---|---|
| Numbers of participants with treatment-related adverse events | The adverse events in each group will be observed and documented during the whole procedure to show the safety of the treatment. | Baseline,12weeks |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Samar Mahmoud Eldadamouny, Pharmacist | Contact | +201008456735 | samer.abdelfattah99@gmail.com | |
| Tarek Mohamed Mostafa, Professor | Contact | +201154594035 | tarek.mostafa@pharm.tanta.edu.eg |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Faculty of medicine | Recruiting | Al Mansurah | Egypt |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22820172 | Background | Kim HY, Lee SW, Park SY, Baek SH, Lee CW, Hong KW, Kim CD. Efficacy of concurrent administration of cilostazol and methotrexate in rheumatoid arthritis: pharmacologic and clinical significance. Life Sci. 2012 Sep 17;91(7-8):250-7. doi: 10.1016/j.lfs.2012.07.003. Epub 2012 Jul 20. | |
| 26170060 | Background | Park SY, Lee SW, Kim HY, Lee SY, Lee WS, Hong KW, Kim CD. Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition. Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2137-44. doi: 10.1016/j.bbadis.2015.07.007. Epub 2015 Jul 11. |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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Not provided
| ID | Term |
|---|---|
| D000077407 | Cilostazol |
| D008727 | Methotrexate |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Drug |
Methotrexate (MTX) is the first-line therapy for treatment of RA patients. MTX suppresses proliferation of synovial fibroblasts, modulates cytokine synthesis and superoxide anion production, and inhibits neutrophil chemotaxis. |
|
| Placebo | Drug | Placebo |
|
Transcriptional factor involved intracellular responses to stimuli and stress .So If the value is increased, the disease activity worsened. If the value is reduced the disease activity is improved. |
| Baseline,12weeks |
| Change in the serum level of the assessed biological marker Hemeoxygenase-1 | Hemeoxygenase-1 . | Baseline,12weeks |
| Change in the serum level of the assessed biological marker Cyclic adenosine monophosphate | Cyclic adenosine monophosphate level. | Baseline,12weeks |
| 17265482 | Background | Kirino Y, Takeno M, Murakami S, Kobayashi M, Kobayashi H, Miura K, Ideguchi H, Ohno S, Ueda A, Ishigatsubo Y. Tumor necrosis factor alpha acceleration of inflammatory responses by down-regulating heme oxygenase 1 in human peripheral monocytes. Arthritis Rheum. 2007 Feb;56(2):464-75. doi: 10.1002/art.22370. |
| 20131233 | Background | Park SY, Lee SW, Shin HK, Chung WT, Lee WS, Rhim BY, Hong KW, Kim CD. Cilostazol enhances apoptosis of synovial cells from rheumatoid arthritis patients with inhibition of cytokine formation via Nrf2-linked heme oxygenase 1 induction. Arthritis Rheum. 2010 Mar;62(3):732-41. doi: 10.1002/art.27291. |
| 40380042 | Derived | Eldadamony SM, El-Haggar SM, Ali AMA, Mostafa TM. Clinical study evaluating the efficacy and safety of Cilostazol as an adjuvant therapy to methotrexate on patients with rheumatoid arthritis. Inflammopharmacology. 2025 Jun;33(6):3499-3508. doi: 10.1007/s10787-025-01782-2. Epub 2025 May 16. |
| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D011804 |
| Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |