Skip to main content

Advertisement

SpringerLink
Log in

Comparison of combination therapy of prednisolone and cyclosporine with corticosteroid pulse therapy in Vogt–Koyanagi–Harada disease

  • Clinical Investigation
  • Published:
Japanese Journal of Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To compare the efficacy and safety of a combination therapy of prednisolone and cyclosporine and corticosteroid pulse therapy in Vogt–Koyanagi–Harada (VKH) disease.

Study design

A prospective, multicenter, randomized, non-inferiority trial.

Methods

Patients of new-onset acute VKH disease at 11 centers in Japan between 2014 and 2018 were randomized to a combination (oral prednisolone 60 mg daily with gradual taper-off to 35 mg/day and cyclosporine 3 mg/kg/day) and corticosteroid (methylprednisolone 1000 mg for 3 days followed by oral prednisolone) groups, and were followed for 1 year.

Results

Thirty-four were assigned to the combination and thirty-six patients to the corticosteroid group. Recurrence/worsening risk was 0.15 (95% confidence-interval [CI] 0.03–0.27) in the combination group and 0.25 (95% CI 0.11–0.39) in the corticosteroid group, with a risk difference of − 0.10 (90% CI − 0.27 to 0.06), demonstrating non-inferiority of the combination group with a non-inferiority margin of 0.20 (P = 0.0013). Serious adverse events occurred in three patients (two with hyponatremia and one with severe headaches) in the combination group and none in the corticosteroid group. Sunset glow fundus grades and cataract rates at 1 year were 0.57 (95% CI 0.42–71) and 4.3% in the combination group and 0.91 (95% CI 0.78–1.04) and 34.0% in the corticosteroid group, respectively.

Conclusions

Combination therapy was noninferior to corticosteroid therapy with respect to recurrence/worsening risk. Notably, the recurrence/worsening risk, sunset glow fundus grade, and cataract rate were lower in the combination group than in the corticosteroid group.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sugiura S. Some observations on uveitis in Japan, with special reference to Vogt–Koyanagi–Harada and Behcet diseases. Nippon Ganka Gakkai Zasshi. 1976;80:1285–326 ((In Japanese)).

    CAS  PubMed  Google Scholar 

  2. Moorthy RS, Inomata H, Rao NA. Vogt–Koyanagi–Harada syndrome. Surv Ophthalmol. 1995;39:265–92.

    Article  CAS  Google Scholar 

  3. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, Arellanes-Garcia L, et al. Revised diagnostic criteria for Vogt–Koyanagi–Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. 2001;131:647–52.

    Article  CAS  Google Scholar 

  4. Yamaki K, Gocho K, Hayakawa K, Kondo I, Sakuragi S. Tyrosinase family proteins are antigens specific to Vogt–Koyanagi–Harada disease. J Immunol. 2000;165:7323–9.

    Article  CAS  Google Scholar 

  5. Sugita S, Sagawa K, Mochizuki M, Shichijo S, Itoh K. Melanocyte lysis by cytotoxic T lymphocytes recognizing the MART-1 melanoma antigen in HLA-A2 patients with Vogt–Koyanagi–Harada disease. Int Immunol. 1996;8:799–803.

    Article  CAS  Google Scholar 

  6. Sugita S, Takase H, Taguchi C, Imai Y, Kamoi K, Kawaguchi T, et al. Ocular infiltrating CD4+ T cells from patients with Vogt–Koyanagi–Harada disease recognize human melanocyte antigens. Investig Ophthalmol Vis Sci. 2006;47:2547–54.

    Article  Google Scholar 

  7. Lambe T, Leung JC, Bouriez-Jones T, Bouriez-Jonew T, Silver K, Makinen K, et al. CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions. J Immunol. 2006;177:3055–62.

    Article  CAS  Google Scholar 

  8. Sonoda K-H, Hasegawa E, Namba K, Okada AA, Ohguro N, Goto H, et al. Epidemiology of uveitis in Japan: a 2016 retrospective nationwide survey. Jpn J Ophthalmol. 2021;65:184–90.

    Article  Google Scholar 

  9. Islam SM, Numaga J, Fujino Y, Hirata R, Matsuki K, Maeda H, et al. HLA class II genes in Vogt–Koyanagi–Harada disease. Investig Ophthalmol Vis Sci. 1994;35:3890–6.

    CAS  Google Scholar 

  10. Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1 typing of Vogt–Koyanagi–Harada’s disease by PCR-RFLP and the strong association with DRB1*0405 and DR*0410. Br J Ophthalmol. 1994;78:223–6.

    Article  CAS  Google Scholar 

  11. Damico FM, Kiss S, Young LH. Vogt–Koyanagi–Harada disease. Semin Ophthalmol. 2005;20:183–90.

    Article  Google Scholar 

  12. Inoue R, Taguchi C, Kawahara S, Yamakawa R. A fifteen-year review of Vogt–Koyanagi–Harada disease. Jpn J Clin Ophthalmol. 2011;65:1431–4 (in Japanese).

    Google Scholar 

  13. Iwahashi C, Okuno K, Hashida N, Nakai K, Ohguro N, Nishida K. Incidence and clinical features of recurrent Vogt–Koyanagi–Harada disease in Japanese individuals. Jpn J Ophthalmol. 2015;59:157–63.

    Article  Google Scholar 

  14. Rubsamen PE, Gass JD. Vogt–Koyanagi–Harada syndrome: clinical course, therapy, and longterm visual outcome. Arch Ophthalmol. 1991;109:682–7.

    Article  CAS  Google Scholar 

  15. Al-Kharashi AS, Aldibhi H, Al-Fraykh H, Kangave D, Abu El-Asrar AM. Prognostic factors in Vogt–Koyanagi–Harada disease. Int Ophthalmol. 2007;27:201–10.

    Article  Google Scholar 

  16. Lai TYY, Chan RPS, Chan CKM, Lam DSC. Effects of the duration of initial oral corticosteroid treatment on the recurrence of inflammation in Vogt–Koyanagi–Harada disease. Eye. 2009;23:543–8.

    Article  CAS  Google Scholar 

  17. Kotake S, Ohno S. “Pulse” methylprednisolone therapy in the treatment of Vogt–Koyanagi–Harada disease. Jpn J Clin Ophthalmol. 1984;38:1053–8 (in Japanese).

    Google Scholar 

  18. Yamanaka E, Ohguro N, Yamamoto S, Nakagawa Y, Imoto Y, Tano Y. Evaluation of pulse corticosteroid therapy for Vogt–Koyanagi–Harada disease assessed by optical coherence tomography. Am J Ophthalmol. 2002;134:454–6.

    Article  CAS  Google Scholar 

  19. Hirooka K, Saito W, Namba K, Mizuuchi K, Iwada D, Hashimoto Y, et al. Early post-treatment choroidal thickness to alter sunset glow fundus in patients with Vogt–Koyanagi–Harada disease treated with systemic corticosteroids. PLoS One. 2017;12:e0172612.

    Article  Google Scholar 

  20. Nakayama M, Keino H, Watanabe T, Okada AY. Clinical features and visual outcomes of 111 patients with new-onset acute Vogt–Koyanagi–Harada disease treated with pulse intravenous corticosteroids. Br J Ophthalmol. 2019;103:274–8.

    Article  Google Scholar 

  21. Nussenblatt RB, Palestine AG, Chan CC. Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol. 1983;96:275–82.

    Article  CAS  Google Scholar 

  22. Paredes I, Ahmed M, Foster CS. Immunomodulatory therapy for Vogt–Koyanagi–Harada patients as first-line therapy. Ocul Immunol Inflamm. 2006;14:87–90.

    Article  CAS  Google Scholar 

  23. Urzua CA, Velasquez V, Sabat P, Berger O, Ramirez S, Goecke A, et al. Earlier immunomodulatory treatment is associated with better visual outcomes in a subset of patients with Vogt–Koyanagi–Harada disease. Acta Ophthalmol. 2015;93:e475–80.

    Article  CAS  Google Scholar 

  24. Oo EEL, Chee S-P, Wong KKY, Htoon HM. Vogt–Koyanagi–Harada disease managed with immunomodulatory therapy within 3 months of disease onset. Am J Ophthalmol. 2020;220:37–44.

    Article  Google Scholar 

  25. Keino H, Goto H, Usui M. Sunset glow fundus in Vogt–Koyanagi–Harada disease with or without chronic ocular inflammation. Graefes Arch Clin Exp Ophthalmol. 2002;240:878–82.

    Article  Google Scholar 

  26. Keino H, Goto H, Mori H, Iwasaki T, Usui M. Association between severity of inflammation in CNS and development of sunset glow fundus in Vogt–Koyanagi–Harada disease. Am J Ophthalmol. 2006;141:1140–1.

    Article  Google Scholar 

  27. Chee SP, Jap A, Bacsal K. Spectrum of Vogt–Koyanagi–Harada disease in Singapore. Int Ophthalmol. 2007;27:137–42.

    Article  Google Scholar 

  28. Tugal-Tutkun I, Ozyazgan Y, Akova YA, Sullu Y, Akyol N, Soylu M, et al. The spectrum of Vogt–Koyanagi–Harada disease in Turkey. Int Ophthalmol. 2007;27:117–23.

    Article  Google Scholar 

  29. Sakata VM, da Silva FT, Hirata CE, Marin MLC, Rodrigues H, Kalil J, et al. High rate of clinical recurrence in patients with Vogt–Koyanagi–Harada disease treated with early high-dose corticosteroids. Graefes Arch Clin Exp Ophthalmol. 2015;253:785–90.

    Article  CAS  Google Scholar 

  30. Watanabe N, Sakamoto K, Taniguchi K, Kondoh Y, Kimura T, Kataoka K, et al. Efficacy of combined therapy with cyclosporin and low-dose of prednisolone in interstitial pneumonia associated with connective tissue disease. Clin Investig. 2014;87:467–77.

    Google Scholar 

  31. The Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–16.

  32. Miyanaga M, Kawaguchi T, Shimizu K, Miyata K, Mochizuki M. Influence of early cerebrospinal fluid-guided diagnosis and early high-dose corticosteroid therapy on ocular outcomes of Vogt–Koyanagi–Harada disease. Int Ophthalmol. 2007;27:183–8.

    Article  Google Scholar 

  33. Jaffe GJ, Dick AD, Brezin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375:932–43.

    Article  CAS  Google Scholar 

  34. Nguyen QD, Merrill PT, Jaffe G, Dick AD, Kurup SK, Sheppard J, et al. Adalimumab for prevention of uveitic flare in patients with inactive noninfectious uveitis controlled by corticosteroids (VISUAL II): a multi-center, double-masked, randomized, placebo-controlled phase 3 trial. Lancet. 2016;388:1183–92.

    Article  CAS  Google Scholar 

  35. Suhler EB, Adan A, Brezin A, Fortic E, Goto H, Jaffe G, et al. Safety and efficacy of adalimumab in patients with noninfectious uveitis in an ongoing open-label study: VISUAL III. Ophthalmology. 2018;125:1075–87.

    Article  Google Scholar 

  36. de Kort EA, de Lil HS, Bremmers MEJ, Bremmers ME, van Groningen LFJ, Blijlevens NMA, et al. Cyclosporine A trough concentrations are associated with acute GvHD after non-myeloablative allogeneic hematopoietic cell transplantation. PLoS One. 2019;14:e0213913.

    Article  Google Scholar 

  37. Takubo M, Tanaka S, Kushimoto K, Ikeda J, Ogawa K, Suzuki Y, et al. Hyponatremia associated with prophylactic low-dose trimethoprim during systemic corticosteroid therapy for AQP4-Positive optic neuritis in a diabetic patient. Antibiotics. 2020;9:201.

    Article  Google Scholar 

  38. Abu El-Asrar AM, Dosari M, Hemachandran S, Gikandi PW, Al-Muammar A. Mycophenolate mofetil combined with systemic corticosteroids prevents progression to chronic recurrent inflammation and development of “sunset glow fundus” in initial-onset acute uveitis associated with Vogt–Koyanagi–Harada disease. Acta Ophthalmol. 2017;95:85–90.

    Article  CAS  Google Scholar 

  39. Papasavvas I, Tugal-Tutlun I, Herbort CP. Vogt–Koyanagi–Harada is a curable autoimmune disease: early diagnosis and immediate dual steroidal and non-steroidal immunosuppression are crucial prerequisites. J Curr Ophthalmol. 2020;32:310–4.

    Article  Google Scholar 

Download references

Acknowledgements

A list of Study Group Members and Safety and Efficacy Monitoring Committee Members are Miyata Eye Hospital, Miyakonojo, Japan: Manabu Mochizuki, MD, PhD, Takashi Ono, MD, Takashi Komizo, MD, Kazurori Miyata, MD, PhD; Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan: Hiroshi Goto, MD, PhD, Akihiko Umazume, MD, PhD, Yoshihiko Usui, MD, PhD; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan: Tsutomu Sakai, MD, PhD, Hideo Kohno, MD, Ranko Aoyagi, MD; Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Japan: Fumihiko Nitta, MD, PhD, Kazuichi Maruyama, MD, PhD; Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Japan: Nobuhisa Mizuki, MD, PhD, Etsuko Shibuya, MD, Yasutsugu Ida, MD; Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan: Hiroshi Takase, MD, PhD, Shintaro Horie, MD, PhD, Mitsunao Ide, MD, Yuko Iwasaki, MD, PhD, Koju Kamoi, MD, PhD, Yukiko Terada, MD; Department of Ophthalmology and Visual Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan: Yutaka Kaneko, MD, PhD; Department of Ophthalmology, Nippon Medical School, Tokyo, Japan: Junko Hori, MD, PhD, Tomoko Yui, MD, Ayaka Takeda, MD; Department of Ophthalmology, Oita University, Faculty of Medicine, Oita, Japan: Satoko Nakano, MD, PhD; Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan: Nobuhisa Nao-I, MD, PhD; Department of Ophthalmology, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan: Nobuyuki Ohguro, MD, PhD; School of Data Science, Yokohama City University, Kanagawa, Japan: Makoto Tomita, PhD; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan: Ko-hei Sonoda, MD, PhD; Department of Ophthalmology, Japan Community Health Care Organization Tokyo Shinjuku Medical Center, Tokyo, Japan: Yujiro Fujino, MD, PhD; Biostatistical Research Corporation, Tokyo, Japan: Toshihito Furukawa, PhD; Department of Renal Transplantation, Masuko Memorial Hospital, Nagoya, Japan: Kunio Morozumi, MD, PhD. And also a list of Study Group Members and Safety and Efficacy Monitoring Committee Members is available online.

The authors are grateful for the support of the Safety and Efficacy Monitoring Committee members, including Koh-Hei Sonoda, M.D., PhD. (Kyushu University); Yujiro Fujino, M.D., Ph.D. (Japan Community Health Care Organization Tokyo Shinjuku Medical Center); Toshihito Furukawa, Ph.D. (Biostatistical Research Corporation); and Kunio Morozumi, M.D., Ph.D. (Masuko Memorial Hospital).

Author information

Authors and Affiliations

  1. Miyata Eye Hospital, 6-3 Kurahara, Miyakonojo, Miyazaki, 885-0051, Japan

    Takashi Ono, Kazunori Miyata & Manabu Mochizuki

  2. Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan

    Hiroshi Goto

  3. Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan

    Tsutomu Sakai

  4. Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Japan

    Fumihiko Nitta

  5. Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Japan

    Nobuhisa Mizuki

  6. Department of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Hiroshi Takase & Manabu Mochizuki

  7. Department of Ophthalmology and Visual Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan

    Yutaka Kaneko

  8. Department of Ophthalmology, Nippon Medical School, Tokyo, Japan

    Junko Hori

  9. Department of Ophthalmology, Oita University, Faculty of Medicine, Oita, Japan

    Satoko Nakano

  10. Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Nobuhisa Nao-I

  11. Department of Ophthalmology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan

    Nobuyuki Ohguro

  12. School of Data Science, Yokohama City University, Yokohama, Japan

    Makoto Tomita

Authors
  1. Takashi Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsutomu Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fumihiko Nitta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nobuhisa Mizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Takase
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yutaka Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junko Hori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Satoko Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nobuhisa Nao-I
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nobuyuki Ohguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kazunori Miyata
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Makoto Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Manabu Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

The Japan VKH Disease Treatment Study Group

  • Manabu Mochizuki
  • , Takashi Ono
  • , Takashi Komizo
  • , Kazurori Miyata
  • , Hiroshi Goto
  • , Akihiko Umazume
  • , Yoshihiko Usui
  • , Tsutomu Sakai
  • , Hideo Kohno
  • , Ranko Aoyagi
  • , Fumihiko Nitta
  • , Kazuichi Maruyama
  • , Nobuhisa Mizuki
  • , Etsuko Shibuya
  • , Yasutsugu Ida
  • , Hiroshi Takase
  • , Shintaro Horie
  • , Mitsunao Ide
  • , Yuko Iwasaki
  • , Koju Kamoi
  • , Yukiko Terada
  • , Yutaka Kaneko
  • , Junko Hori
  • , Tomoko Yui
  • , Ayaka Takeda
  • , Satoko Nakano
  • , Nobuhisa Nao-I
  • , Nobuyuki Ohguro
  •  & Makoto Tomita

Corresponding author

Correspondence to Manabu Mochizuki.

Ethics declarations

Conflicts of interest

T. Ono, Lecture fee (Bayer, Santen, AbbVie); H. Goto, None; T. Sakai, None; F. Nitta, None; N. Mizuki, None; H. Takase, Lecture fee (Santen, Novartis, AbbVie, Senju, Eisai, Otsuka); Y. Kaneko, None; J. Hori, None; S. Nakano, Grant (Novartis); N. Nao-I, None; N. Ohguro, None; K. Miyata, Grant, Lecture fee (AMO, Alcon, Senju, Santen), Grant (Kissei, Chugai, Bayer, M's science, Novartis), Lecture fee (Otsuka, Kowa, HOYA, J-TEC, JFC Sales Plan); M. Tomita, None; M. Mochizuki, None.

Additional information

Publisher's Note

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

Corresponding Author: Manabu Mochizuki

A list of Study Group Members and Safety and Efficacy Monitoring Committee Members is available both in Acknowledgements and online.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ono, T., Goto, H., Sakai, T. et al. Comparison of combination therapy of prednisolone and cyclosporine with corticosteroid pulse therapy in Vogt–Koyanagi–Harada disease. Jpn J Ophthalmol 66, 119–129 (2022). https://doi.org/10.1007/s10384-021-00878-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10384-021-00878-w

Keywords

Search

Navigation