Histopathological evaluation of docetaxel effects in treatment of rheumatoid arthritis induced in rat model


  • Omar Mustafa Alghulami Pharmacology and Toxicology Department, College of Pharmacy, Mustansiriyah University
  • Ghaith A. Jasim Pharmacology and Toxicology Department, College of Pharmacy, Mustansiriyah University
  • Suzan Yousif Jasim** Dept. of Clinical Laboratory Sciences, Collage of Pharmacy, Mustansiriyah University




Rheumatoid arthritis, docetaxel, Histopathology, Arthritis index


Rheumatoid arthritis is an immune-mediated condition that affects synovial joints. Synovial tissue, cartilage, bone, and less frequently extra-articular structures which in turn experience

inflammatory changes. Paclitaxel's semi-synthetic equivalent, docetaxel, is an anti-neoplastic drug. Methotrexate is a treatment for early RA and may have a mildly negative impact on peptidyl arginine deiminase type 4 fluorescence test. However, 30% of patients fail to complete treatment within the first year due to resistance or side effects. The synovial membrane of Rheumatoid arthritis patient infiltrated with macrophages and neutrophils that express peptidyl arginine deiminase type 4 which their effect in rheumatoid arthritis pathogenesis lies in the generation of citrullinated neoepitopes that are Anti cyclic citrullinated peptide antibodies-targeted.

The purpose of this study: was to assess the anti-inflammatory effects of docetaxel and methotrexate on the joint structure.

Methods: Five groups of eight rats were formed from the 40 male Wister rats. Complete Freund’s adjuvant was injected subcutaneously into rats to induce the disease. The first group is control group which was the only group consists of (healthy untreated) rats. Second group was received complete Freund’s adjuvant. 0.5ml of ordinary saline was intraperitoneally administered to both the control and induction groups. Based on a preliminary experiment, the third group was given intraperitoneally 1 mg/kg/on alternative day docetaxel. The fourth group was given intraperitoneally 1 mg/kg/week of Methotrexate. Fifth group was given a half dose of both Methotrexate and docetaxel concurrently. Arthritis index was measured and Knee joint was histopathological examined.

Results: significant Arthritis Index decrease in docetaxel group (p≤0.05). Significant lowering Histometric scoring (p≤0.05) in docetaxel, and Methotrexate group (cellular hyperplasia, formation of granulation tissue, infiltration of leukocytes, destroying of cartilage and intensity of erosion & Articular cartilage thickness) level in rats induced arthritis. Conclusion:  This study showed that docetaxel may have anti-arthritic effects through their significant lowering Histometric scoring(p≤0.05).


-Van Delft MAM, Huizinga TWJ. An overview of autoantibodies in rheumatoid arthritis. J Autoimmun 2020;110.102392:1-11. DOI: https://doi.org/10.1016/j.jaut.2019.102392

- Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J Autoimmun2020;110.102392:1-15. DOI: https://doi.org/10.1016/j.jaut.2019.102400

- Philippou E, Petersson SD, Rodomar C, Nikiphorou E. Rheumatoid arthritis and dietary interventions: Systematic review of clinical trials. Nutr Rev 2021;79(4):410–28. DOI: https://doi.org/10.1093/nutrit/nuaa033

- Prasad P, Verma S, Surbhi, Ganguly NK, Chaturvedi V, Mittal SA. Rheumatoid arthritis: advances in treatment strategies. Mol Cell Biochem 2022:1–20. DOI: https://doi.org/10.1007/s11010-022-04492-3

- Farooq AO, Mohammed NH. Effect of Captopril on Toll Like Receptor Expression in Adjuvant Induced Arthritis. Al Mustansiriyah Journal of Pharmaceutical Sciences 2022;22 (1):1–7. DOI: https://doi.org/10.32947/ajps.v22i1.825

- Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 2018;6(1):1-14. DOI: https://doi.org/10.1038/s41413-018-0016-9

- Darrah E, Andrade F. Rheumatoid arthritis and citrullination. Curr Opin Rheumatol2018;30(1):72–8. DOI: https://doi.org/10.1097/BOR.0000000000000452

- Zamanpoor M. The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis. Clin Genet 2019;95(5):547–57. DOI: https://doi.org/10.1111/cge.13498

- Elshabrawy HA, Chen Z, Volin M v., Ravella S, Virupannavar S, Shahrara S. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 2015 18:4 2015;18(4):433–48. DOI: https://doi.org/10.1007/s10456-015-9477-2

- Tardito S, Martinelli G, Soldano S, Paolino S, Pacini G, Patane M, et al. Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review. Autoimmun Rev 2019;18(11): 102397:1-21. DOI: https://doi.org/10.1016/j.autrev.2019.102397

- Carmona-Rivera C, Carlucci PM, Goel RR, James E, Brooks SR, et al. Neutrophil extracellular traps mediate articular cartilage damage and enhance cartilage component immunogenicity in rheumatoid arthritis. JCI Insight 2020;5(13) e139388:1-14. DOI: https://doi.org/10.1172/jci.insight.139388

- Vossenaar ER, Nijenhuis S, Helsen MMA, van der Heijden A, Senshu T, van den Berg WB, et al. Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 2003;48(9):2489–500. DOI: https://doi.org/10.1002/art.11229

- Cecchi I, Arias de la Rosa I, Menegatti E, Roccatello D, Collantes-Estevez E, Lopez-Pedrera C, et al. Neutrophils: Novel key players in Rheumatoid Arthritis. Current and future therapeutic targets. Autoimmun Rev 2018;17(11):1138–49. DOI: https://doi.org/10.1016/j.autrev.2018.06.006

- majeed yousuf gays, al-abbassi mustafa ghazi, al-zubaidy ghaith ali jasim. Histopathological Study on The Effect of Neuregulin-1 Against Cardiotoxicity Induced by Trastuzumab in Adult Mice. Al Mustansiriyah Journal of Pharma-ceutical Sciences 2018;18 (2):63–77. DOI: https://doi.org/10.32947/ajps.v18i2.477

- Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nature Immunology 2019 20:7 2019;20(7):928–42. DOI: https://doi.org/10.1038/s41590-019-0378-1

- Imran M, Saleem S, Chaudhuri A, Ali J, Baboota S. Docetaxel: An update on its molecular mechanisms, therapeutic trajectory and nanotechnology in the treatment of breast, lung and prostate cancer. J Drug Deliv Sci Technol 2020; 60:101959:1-18. DOI: https://doi.org/10.1016/j.jddst.2020.101959

- Vacca A, Ribatti D, Iurlaro M, Merchionne F, Nico B, Ria R, et al. Docetaxel Versus Paclitaxel for Antiangiogenesis. https://home .liebertpub.com/scd 2004;11(1):103–18. DOI: https://doi.org/10.1089/152581602753448577

- Zhao Y, Chang ZF, Li R, Li ZG, Li XX, Li L. Original Article Paclitaxel suppresses collagen-induced arthritis: a reevaluation. Am J Transl Res 2016;8(11):5044–51.

- Bicker KL, Thompson PR. The protein arginine deiminases: Structure, function, inhibition, and disease. Biopolymers2013;99(2):155–63. DOI: https://doi.org/10.1002/bip.22127

- Callender MA, Antonarakis ES. Rheumatoid arthritis masked by docetaxel chemotherapy in a patient with ovarian carcinoma. Journal of Clinical Rheumatology 2008;14 (2):121. DOI: https://doi.org/10.1097/RHU.0b013e31816b8728

- S.O. Choi. A case of patient with coincident lung cancer and rheumatoid arthritis treated with docetaxel-cisplatin chemotherapy. J Korean Rheum 2006; 13:166–70.

- Drosos AA, Pelechas E, Voulgari P v. Treatment strategies are more important than drugs in the management of rheumatoid arthritis. Clin Rheumatol 2020;39(4):1363–8. DOI: https://doi.org/10.1007/s10067-020-05001-x

- Harrington R, al Nokhatha SA, Conway R. JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical Data. J Inflamm Res 2020; 13:519-531. DOI: https://doi.org/10.2147/JIR.S219586

- Knuckley B, Luo Y, Thompson PR. Profiling Protein Arginine Deiminase 4 (PAD4): A novel screen to identify PAD4 inhibitors. Bioorg Med Chem 2008;16(2):739–45. DOI: https://doi.org/10.1016/j.bmc.2007.10.021

- Poulsen TBG, Damgaard D, Jørgensen MM, Senolt L, Blackburn, et al. Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis using citrulline-specific protein arrays. Scientific Reports 2021 11:1 2021;11(1):1–14. DOI: https://doi.org/10.1038/s41598-021-96675-z

- Pearson CM. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med 1956;91(1):95–101. DOI: https://doi.org/10.3181/00379727-91-22179

- Roy T, Ghosh S. Animal models of rheumatoid arthritis: correlation and usefulness with human rheumatoid arthritis. Indo American Journal of Pharmaceutical Research 2013;3 (8)6131-6142.

- Hong M, Fan X, Liang S, Xiang W, Chen L, Yang Y, et al. Total Flavonoids of Bidens pilosa Ameliorates Bone Destruction in Collagen-Induced Arthritis. Planta Med 2021;87(7):550–559. DOI: https://doi.org/10.1055/a-1352-5124

- Kumar A, Dhaliwal N, Dhaliwal J, Dharavath RN, Chopra K. Astaxanthin attenuates oxidative stress and inflammatory responses in complete Freund-adjuvant-induced arthritis in rats. Pharmacological Reports 2019 72:1 2019;72(1):104–114. DOI: https://doi.org/10.1007/s43440-019-00022-z

- Epa U, Response Team E. Tissue Homogenization Procedure. [cited 2022 Jun 11]; Available from: https://clu-in.org/download /ert/1820.R00.pdf

- Maynard RL, Downes N. Introduction to the Skeleton. In: Anatomy and Histology of the Laboratory Rat in Toxicology and Biomedical Research. Elsevier. 2019. page 11–22. DOI: https://doi.org/10.1016/B978-0-12-811837-5.00003-4

- Nikkari ST, O’Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, et al. Interstitial Collagenase (MMP-1) Expression in Human Carotid Atherosclerosis. Circulation 1995;92 (6):1393–8. DOI: https://doi.org/10.1161/01.CIR.92.6.1393

- Wang M, Sampson ER, Jin H, Li J, Ke QH, Im HJ, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 2013;15(1):1–11. DOI: https://doi.org/10.1186/ar4133

- Lim MA, Louie B, Ford D, Heath K, Cha P, Betts-Lacroix J, et al. Development of the Digital Arthritis Index, a novel metric to measure disease parameters in a rat model of rheumatoid arthritis. Front Pharmacol. 2017;14; 8:818:1-18. DOI: https://doi.org/10.3389/fphar.2017.00818

- Bolon B, Stolina M, King C, Middleton S, Gasser J, Zack D, et al. Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy. J Biomed Biotechnol. 2011; 2011:569068:1-21. DOI: https://doi.org/10.1155/2011/569068

- Qasim LB, Jasim GA, Rabeea IS. Histopathological study of diclofenac induced acute renal failure under lipoic acid and bosentan therapy in male albino rats. Al Mustansiriyah Journal of Pharmaceutical Sciences 2022;22(1):49–58. DOI: https://doi.org/10.32947/ajps.v22i1.829

- Liu YL, Lin HM, Zou R, Wu JC, Han R, Raymond LN, et al. Suppression of complete Freund’s adjuvant-induced adjuvant arthritis by cobratoxin. Acta Pharmacologica Sinica 2009 30:2 2009;30(2):219–27. DOI: https://doi.org/10.1038/aps.2008.20

- Akhter S, Irfan HM, Alamgeer, Jahan S, Shahzad M, Latif MB. Nerolidol: a potential approach in rheumatoid arthritis through reduction of TNF-α, IL-1β, IL-6, NF-kB, COX-2 and antioxidant effect in CFA-induced arthritic model. Inflammo-pharmacology 2022 30:2 2022;30 (2):537–48. DOI: https://doi.org/10.1007/s10787-022-00930-2

- Ahmed N, Siddiqui AH, Anwar A, Shad MN, Karim A. Therapeutic Effect of Berberine Versus Methotrexate on Histopathology in a Rat Model of Pristane-Induced Arthritis. Proc West Mark Ed Assoc Conf 2022;36(1):49–55. DOI: https://doi.org/10.47489/PSZMC-825361-49-55

- Anchi P, Panda B, Mahajan RB, Godugu C. Co-treatment of Nimbolide augmented the anti-arthritic effects of methotrexate while protecting against organ toxicities. Life Sci 2022; 295:120372:1-11. DOI: https://doi.org/10.1016/j.lfs.2022.120372

- Sheng Z, Zeng J, Huang W, Li L, Li B, Lv C, et al. Comparison of therapeutic efficacy and mechanism of paclitaxel alone or in combination with methotrexate in a collagen-induced arthritis rat model. Z Rheumatol 2022;81(2):164–73. DOI: https://doi.org/10.1007/s00393-020-00940-x




How to Cite

Omar Mustafa Alghulami, Ghaith A. Jasim, & Suzan Yousif Jasim**. (2023). Histopathological evaluation of docetaxel effects in treatment of rheumatoid arthritis induced in rat model. Al Mustansiriyah Journal of Pharmaceutical Sciences, 23(2), 168–179. https://doi.org/10.32947/ajps.v23i2.1018