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Protective effect of filgotinib in rat endotoxin-induced uveitis model

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Abstract

Purpose

To investigate the protective effect of filgotinib in endotoxin-induced uveitis model in rats.

Materials and method

This study used 24 Wistar Albino rats. Group I (control group) included the healthy controls; in Group II (sham group), only 300 µg/kg intraperitoneal (ip) lipopolysaccharide (LPS) was administered; and in Group III (treatment group), 3 mg/kg/day filgotinib was administered orally for 10 days followed by 300 µg/kg ip LPS. In all groups, clinical activity scores were evaluated after 24 h. Moreover, histopathological and immunological examinations were performed.

Results

In Groups I, II, and III, the mean clinical activity and histopathological examination scores were 0.00, 3.25 ± 0.70, and 1.89 ± 0.60 and 0.00, 2.88 ± 1.12, and 1.44 ± 0.52, respectively. The clinical activity and histopathological examination scores were significantly increased in the sham group compared to the control group (p < 0.05); these findings were significantly reduced in the treatment group (p < 0.05). The mean TNF-α and IL-6 ELISA levels in all groups were 50.20 ± 3.24, 59.87 ± 2.98, and 54.34 ± 4.62 and 30.88 ± 1.79, 36.77 ± 1.21, and 33.66 ± 1.86, respectively. The TNF-α and IL-6 ELISA levels were significantly decreased in the treatment group compared to the sham group (p < 0.05); there was no significant difference between the treatment group and the control group (p = 0.105, p = 0.067, respectively)

Conclusion

Filgotinib may be an alternative treatment option in preventing the development of noninfectious uveitis.

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References

  1. Tomkins-Netzer O, Talat L, Bar A et al (2014) Long-term clinical outcome and causes of vision loss in patients with uveitis. Ophthalmology 121:2387–2392. https://doi.org/10.1016/j.ophtha.2014.07.007

    Article  PubMed  Google Scholar 

  2. Jabs DA (2016) Prevalence of the uveitides in the United States. JAMA Ophthalmol 134:1245–1246. https://doi.org/10.1001/jamaophthalmol.2016.3289

    Article  PubMed  Google Scholar 

  3. Yadav UCS, Ramana KV (2019) Endotoxin-induced uveitis in rodents. In: Allen IC (ed) Mouse models of innate immunity. Humana Press, New York, pp 227–36

  4. Franks WA, Limb GA, Standford MR et al (1992) Cytokines in human intraocular inflammation. Curr Eye Res 11:187–191. https://doi.org/10.3109/02713689208999531

    Article  PubMed  Google Scholar 

  5. Mok CC (2019) The Jakinibs in systemic lupus erythematosus: progress and prospects. Expert Opin Investig Drugs 28(1):85–92. https://doi.org/10.1080/13543784.2019.1551358

    Article  CAS  PubMed  Google Scholar 

  6. Gadina M, Le MT, Schwartz DM, Silvennoinen O et al (2019) Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatol (United Kingdom) 58:4–16. https://doi.org/10.1093/rheumatology/key432

    Article  CAS  Google Scholar 

  7. Guo D, Dunbar JD, Yang CH et al (1998) Induction of Jak/STAT signaling by activation of the type 1 TNF receptor. J Immunol 160:2742–2750

    CAS  PubMed  Google Scholar 

  8. Ahmad SF, Ansari MA, Zoheir KMA et al (2015) Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation. Immunobiology 220(7):889–898. https://doi.org/10.1016/j.imbio.2015.01.008

    Article  CAS  PubMed  Google Scholar 

  9. Hoekzema R, Murray PI, Kijlstra A et al (1990) Cytokines and intraocular inflammation. Curr Eye Res 9(sup1):201–207. https://doi.org/10.3109/02713689008999443

    Article  Google Scholar 

  10. Vos AFD, Hoekzema R, Kijlstra A et al (1992) Cytokines and uveitis, a review. Curr Eye Res 11(6):581–597. https://doi.org/10.3109/02713689209001814

    Article  PubMed  Google Scholar 

  11. Hoekzema R, Murray PI, van Haren MA et al (1991) Analysis of interleukin-6 in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 32(1):88–95

    CAS  PubMed  Google Scholar 

  12. Babon JJ, Varghese LN, Nicola NA et al (2014) Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 26(1):13–19. https://doi.org/10.1016/j.smim.2013.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Van Rompaey L, Galien R, van der Aar EM et al (2013) Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol 191(7):3568–3577. https://doi.org/10.4049/jimmunol.1201348

    Article  CAS  PubMed  Google Scholar 

  14. Caspi RR, Silver PB, Luger D et al (2008) Mouse models of experimental autoimmune uveitis. Ophthalmic Res 40(3–4):169–174. https://doi.org/10.1159/000119871

    Article  CAS  PubMed  Google Scholar 

  15. Rosenbaum JT, McDevitt HO, Guss RB et al (1980) Endotoxin-induced uveitis in rats as a model for human disease. Nature 286(5773):611–613. https://doi.org/10.1038/286611a0

    Article  CAS  PubMed  Google Scholar 

  16. Behar-Cohen FF, Savoldelli M, Parel JM et al (1998) Reduction of corneal edema in endotoxin-induced uveitis after application of L-NAME as nitric oxide synthase inhibitor in rats by iontophoresis. Invest Ophthalmol Vis Sci 39(6):897–904

    CAS  PubMed  Google Scholar 

  17. Tilton RG, Chang K, Corbett JA et al (1994) Endotoxin-induced uveitis in the rat is attenuated by inhibition of nitric oxide production. Invest Ophthalmol Vis Sci 35(8):3278–3288

    CAS  PubMed  Google Scholar 

  18. Lowry OH, Rosenbrough NJ, Farr AL et al (1951) Protein measurements with the folin fenol reagent. J Biol Chem 193(1):265–275

    Article  CAS  Google Scholar 

  19. Ghoreschi K, Jesson MI, Li X et al (2011) Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol 186(7):4234–4243. https://doi.org/10.4049/jimmunol.1003668

    Article  CAS  PubMed  Google Scholar 

  20. Clark JD, Flanagan ME, Telliez JB (2014) Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 57(12):5023–5038. https://doi.org/10.1021/jm401490p

    Article  CAS  PubMed  Google Scholar 

  21. Meyer D, Jesson M, Li X et al (2010) Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm 7(1):1–2. https://doi.org/10.1186/1476-9255-7-41

    Article  CAS  Google Scholar 

  22. Lundquist LM, Cole SW, Martha LS (2014) Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop 5:504–511. https://doi.org/10.5312/wjo.v5.i4.504

    Article  PubMed  PubMed Central  Google Scholar 

  23. Panes J, Su C, Bushmakin AG et al (2015) Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes. BMC Gastroenterol 15(1):14. https://doi.org/10.1186/s12876-015-0239-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang JF, Yafawi R, Zhang M et al (2012) Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease. Ophthalmology 119(7):e43-50. https://doi.org/10.1016/j.ophtha.2012.03.017

    Article  PubMed  Google Scholar 

  25. Paley MA, Karacal H, Kumar Rao P et al (2019) Tofacitinib for refractory uveitis and scleritis. Am J Ophthalmol Case Reports 13:53–55. https://doi.org/10.1016/j.ajoc.2018.12.001

    Article  Google Scholar 

  26. Miserocchi E, Giuffrè C, Cornalba M et al (2020) JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol. https://doi.org/10.1007/s10067-019-04875-w

    Article  PubMed  Google Scholar 

  27. Westhovens R, Taylor PC, Alten R et al (2017) Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis 76(6):998–1008. https://doi.org/10.1136/annrheumdis-2016-210104

    Article  CAS  PubMed  Google Scholar 

  28. Kavanaugh A, Kremer J, Ponce L et al (2017) Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis 76(6):1009–1019. https://doi.org/10.1136/annrheumdis-2016-210105

    Article  CAS  PubMed  Google Scholar 

  29. Genovese M, Westhovens R, Meuleners L et al (2018) Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: patient-reported outcomes. Arthritis Res Ther 20:57. https://doi.org/10.1186/s13075-018-1541-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vermeire S, Schreiber S, Petryka R et al (2017) Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 389:26. https://doi.org/10.1016/S0140-6736(16)32537-5

    Article  CAS  Google Scholar 

  31. Mease P, Coates LC, Helliwell PS et al (2018) Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo- controlled, phase 2 trial. Lancet 392(10162):2367–2377. https://doi.org/10.1016/S0140-6736(18)32483-8

    Article  CAS  PubMed  Google Scholar 

  32. Genovese MC, Smolen JS, Weinblatt ME et al (2016) Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol 68(12):2857–2866. https://doi.org/10.1002/art.39808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang Y, Wu TR, Cai S et al (2000) Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappa B activation. Mol Cell Biol 20(13):4505–4512. https://doi.org/10.1128/mcb.20.13.4505-4512.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063. https://doi.org/10.1074/jbc.R700016200

    Article  CAS  PubMed  Google Scholar 

  35. Ivashkiv LB, Donlin LT (2014) Regulation of type I interferon responses. Nat Rev Immunol 14(1):36–49. https://doi.org/10.1038/nri3581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fleischmann R (2012) Novel small-molecular therapeutics for rheumatoid arthritis. Curr Opin Rheumatol 24:335–341. https://doi.org/10.1097/BOR.0b013e32835190ef

    Article  CAS  PubMed  Google Scholar 

  37. Winthrop KL, Yamanaka H, Valdez H et al (2014) Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol 66(10):2675–2684. https://doi.org/10.1002/art.38745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Reddy V, Cohen S (2020) JAK Inhibitors: What is new? Curr Rheumatol Rep 22(9):1–10. https://doi.org/10.1007/s11926-020-00931-6

    Article  CAS  Google Scholar 

  39. Galien R, Brys R, Van der Aa A et al (2015) Absence of effects of filgotinib on erythrocytes, CD8+ and NK cells in rheumatoid ar- thritis patients brings further evidence for the JAK1 selectivity of filgotinib. ACR meeting Abstract 2781. XXX

  40. Levy-Clarke G, Jabs DA, Read RW et al (2014) Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 121(3):785–796. https://doi.org/10.1016/j.ophtha.2013.09.048

    Article  PubMed  Google Scholar 

  41. Genovese MC, Kalunian K, Gottenberg JE et al (2019) Effect of filgotinib vs placebo on clinical response in patients with moderate to severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug therapy the FINCH 2 randomized clinical trial. JAMA 322(4):315–325. https://doi.org/10.1001/jama.2019.9055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Combe B, Kivitz A, Tanaka Y et al (2019) Efficacy and safety of filgotinib for patients with rheumatoid arthritis with inadequate response to methotrexate: FINCH 1 primary outcome results. https://doi.org/10.1136/annrheumdis-2019-eular.8676

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Funding

Financial support was received from Fırat University Scientific Research Project Center (FÜBAP) for this submission (Project No: TF: 2019/197).

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Authors

Contributions

ME contributed to concept, design, intellectuel content and drafting article. MB contributed to design, concept and statistical analysis. Nİ contributed to biochemical analysis and interpretation of data. İÇ contributed to histopathological analysis, acquisition of data, interpretation of data. FU contributed to drafting article, statistical analysis and interpretation of data. YE contributed to histological analysis, data analysis, intellectual content. HY contributed to data analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Murat Erdağ.

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Human and animal rights

This study was carried out in accordance with the ARVO Statement of Ophthalmic and Vision Research on Animal Use. The Fırat University Experimental Animal Studies Ethics Committee approved the study protocols (2019/197).

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Erdağ, M., Balbaba, M., İlhan, N. et al. Protective effect of filgotinib in rat endotoxin-induced uveitis model. Int Ophthalmol 41, 2905–2912 (2021). https://doi.org/10.1007/s10792-021-01851-9

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