The efficacy and mechanism for action of iguratimod in primary Sjögren’s syndrome patients

Abstract

Purpose

Primary Sjögren’s syndrome (pSS) has been proven as a systemic autoimmune disorder (such as Sjogren’s syndrome dry eye). This research aimed to evaluate potential treating effects of Iguratimod on pSS.

Methods

Fifty pSS patients were enrolled and randomly divided into Conventional group and Iguratimod group. Improvement in pSS was evaluated every 4 weeks. pSS disease activity was evaluated with European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI). Symptoms were evaluated by determining EULAR Sjögren’s syndrome patient-reported index (ESSPRI), platelet (PLT), IgG and Schirmer I test. Peripheral blood B cell molecules (CD135, IgD, CD38, CD20) and human B cell-activating factor-receptor (BAFF-R) were analyzed with flow cytometry.

Results

After treating for 12-weeks, pSS patients in Iguratimod and Conventional group showed a significant decrease in disease activity (ESSPRI, ESSDAI, PLT, IgG and Schirmer I test) comparing with baselines. Patients’ ESSPRI (2.92 ± 0.19) and disease activity of ESSDAI (4.32 ± 0.29), PLT (95.64 ± 1.86), IgG (13.0 ± 0.45) and Schirmer I test (4.67 ± 0.31) in Iguratimod group were significantly lower compared to Conventional group (4.64 ± 0.15, 5.8 ± 2.08, 77.44 ± 1.41, 16.5 ± 0.44 and 2.25 ± 0.11) (p < 0.0001). Changes of ESSPRI, ESSDAI, PLT, IgG and Schirmer I test were remarkable observed between two groups (p < 0.001). Iguratimod and Conventional treatment demonstrated a significant reduction in total B cells in pSS patients compared with pre-treatment. The pSS patients from Iguratimod and Conventional group showed a significant decreased BAFF-R (61.82 ± 1.52, 74.07 ± 1.11) and CD38+IgD+ (48.08 ± 0.92, 62.66 ± 1.12) on B cells after treatment compared with baseline (92.26 ± 0.32, 91.53 ± 0.45, 84.39 ± 0.59, 85.04 ± 0.46) (p < 0.001). After treating 12 weeks, BAFF-R, CD38+IgD+ expression in Iguratimod group decreased significantly compared to Conventional group (p < 0.001).

Conclusions

Iguratimod alleviated symptoms and mediated adaptive-immunity balance by suppressing BAFF-R positive B cell in pSS patients.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Ioannidis JP, Vassiliou VA, Moutsopoulos HM (2002) Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjogren’s syndrome. Arthritis Rheum 46:741–747

    Article  Google Scholar 

  2. 2.

    Groom J, Kalled SL, Cutler AH et al (2002) Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest 109:59–68

    CAS  Article  Google Scholar 

  3. 3.

    Ishiguro N, Yamamoto K, Katayama K et al (2013) Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial. Mod Rheumatol 23:430–439

    CAS  Article  Google Scholar 

  4. 4.

    Lu LJ, Teng JL, Bao CD et al (2008) Safety and efficacy of T-614 in the treatment of patients with active rheumatoid arthritis: a double blind, randomized, placebo-controlled and multicenter trial. Chin Med J (Engl) 121:615–619

    CAS  Article  Google Scholar 

  5. 5.

    Hara M, Abe T, Sugawara S et al (2007) Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter, double-blind, parallel-group study. Mod Rheumatol 17:1–9

    Article  Google Scholar 

  6. 6.

    Kim CK, Sakudo A, Taniuchi Y et al (2007) Late-onset olfactory deficits and mitral cell loss in mice lacking prion protein with ectopic expression of Doppel. Int J Mol Med 20:169–176

    CAS  PubMed  Google Scholar 

  7. 7.

    Lu LJ, Bao CD, Dai M et al (2009) Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate. Arthritis Rheum 61:979–987

    CAS  Article  Google Scholar 

  8. 8.

    Aikawa Y, Tanuma N, Shin T et al (1998) A new anti-rheumatic drug, T-614, effectively suppresses the development of autoimmune encephalomyelitis. J Neuroimmunol 89:35–42

    CAS  Article  Google Scholar 

  9. 9.

    Tanaka K, Aikawa Y, Kawasaki H et al (1992) Pharmacological studies on 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (T-614), a novel antiinflammatory agent. 4th communication: inhibitory effect on the production of interleukin-1 and interleukin-6. J Pharmacobiodyn 15:649–655

    CAS  Article  Google Scholar 

  10. 10.

    Xu Y, Zhu Q, Song J et al (2015) Regulatory effect of Iguratimod on the balance of Th subsets and inhibition of inflammatory cytokines in patients with rheumatoid arthritis. Mediat Inflamm 2015:356040

    Google Scholar 

  11. 11.

    Tanaka K, Yamamoto T, Aikawa Y et al (2003) Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology (Oxford) 42:1365–1371

    CAS  Article  Google Scholar 

  12. 12.

    Yan Q, Du F, Huang X et al (2014) Prevention of immune nephritis by the small molecular weight immunomodulator iguratimod in MRL/lpr mice. PLoS ONE 9:e108273

    Article  Google Scholar 

  13. 13.

    Vitali C, Bombardieri S, Jonsson R et al (2002) Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558

    CAS  Article  Google Scholar 

  14. 14.

    Kang YS, Lee HS, Li Y et al (2018) Manifestation of meibomian gland dysfunction in patients with Sjogren’s syndrome, non-Sjogen’s dry eye, and non-dry eye controls. Int Ophthalmol 38:161–1167

    Article  Google Scholar 

  15. 15.

    Yoshioka Y, Takahashi N, Kaneko A et al (2016) Disease activity early in treatment as a predictor of future low disease activity in RA patients treated with iguratimod. Mod Rheumatol 26:169–174

    CAS  Article  Google Scholar 

  16. 16.

    Duan XW, Zhang XL, Mao SY et al (2015) Efficacy and safety evaluation of a combination of iguratimod and methotrexate therapy for active rheumatoid arthritis patients: a randomized controlled trial. Clin Rheumatol 34:1513–1519

    Article  Google Scholar 

  17. 17.

    Nagashima T, Ishihara M, Shibuya E et al (2017) Three cases of tubulointerstitial nephritis and uveitis syndrome with different clinical manifestation. Int Ophthalmol 37:753–759

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by Sichuan Science and Technology Plan Project Application Basic Research (2019–2021) (Grant No. 2019YJ0139).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yi Liu.

Ethics declarations

Conflict of interest

All authors declare that no competing conflict of interests and non-financial conflict of interests or non-commercial interests in this manuscript.

Ethical approval

This research has been approved by the Ethic Committee of The West China Hospital, Sichuan University.

Informed consent

Written informed consent was obtained from all patients before they participate in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jiang, W., Zhang, L., Zhao, Y. et al. The efficacy and mechanism for action of iguratimod in primary Sjögren’s syndrome patients. Int Ophthalmol 40, 3059–3065 (2020). https://doi.org/10.1007/s10792-020-01490-6

Download citation

Keywords

  • Iguratimod
  • B cell
  • Arthritis
  • Primary Sjögren’s syndrome