Abstract
Objectives
To evaluate the therapeutic efficacy and safety of obinutuzumab in remission induction for IgG4-related ophthalmic disease (IgG4-ROD) patients.
Methods
Eight IgG4-ROD patients were retrospectively enrolled. They were intravenously administered 1000 mg obinutuzumab at baseline and examined for changes in physical signs, orbital structure imaging parameters, IgG4-related disease responder index (IgG4-RD RI), serological index, and adverse events during treatment. The number of treatment sessions was based on treatment response.
Results
The mean IgG4-RD RI scores of all patients at baseline (7.75 ± 2.92) and after treatment (2.00 ± 0.76) were highly significantly different (P < 0.001). Six patients achieved complete remission (CR) (75%) and two patients achieved partial remission (25%). The mean serum IgG4 levels at baseline (9.45 ± 6.95 g/L) and after treatment (1.55 ± 1.09 g/L) showed a mean decrease of 83% (P = 0.0079). The serum IgG4 level correlated well with IgG4-RD RI at baseline and that after each treatment (r = 0.852, P < 0.01; r = 0.78, P < 0.001). In patients with CR, the serum IgG4 levels at baseline correlated positively with dose numbers required for CR (r = 0.86, P < 0.05). Five patients (62.5%) experienced infusion-related reactions (IRRs) during the first obinutuzumab infusion, while only one (12.5%) experienced IRRs during all subsequent eight infusions.
Conclusion
Obinutuzumab is a safe and promising therapeutic option for IgG4-ROD. It rapidly reduces ocular inflammation and serum IgG4 levels to avoid excessive corticosteroid usage and reduce potential risk of adverse events.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 18 print issues and online access
$259.00 per year
only $14.39 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
Data that support the findings of this study are available from the corresponding author on reasonable request.
References
Saitakis G, Chwalisz BK. The neurology of IGG4-related disease. J Neurol Sci. 2021;424:117420. https://doi.org/10.1016/j.jns.2021.117420.
Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51. https://doi.org/10.1056/NEJMra1104650.
Derzko-Dzulynsky L. IgG4-related disease in the eye and ocular adnexa. Curr Opin Ophthalmol. 2017;28:617–22. https://doi.org/10.1097/icu.0000000000000427.
McNab AA, McKelvie P. IgG4-related ophthalmic disease. Part II: clinical aspects. Ophthalmic Plast Reconstr Surg. 2015;31:167–78. https://doi.org/10.1097/iop.0000000000000364.
Wallace ZS, Deshpande V, Stone JH. Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review. Semin Arthritis Rheum. 2014;43:806–17. https://doi.org/10.1016/j.semarthrit.2013.11.008.
Detiger SE, Karim AF, Verdijk RM, van Hagen PM, van Laar JAM, Paridaens D. The treatment outcomes in IgG4-related orbital disease: a systematic review of the literature. Acta Ophthalmol. 2019;97:451–9. https://doi.org/10.1111/aos.14048.
Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International Consensus Guidance Statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol. 2015;67:1688–99. https://doi.org/10.1002/art.39132.
Hong JW, Kang S, Song MK, Ahn CJ, Sa HS. Clinicoserological factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease. Br J Ophthalmol. 2018;102:1591–5. https://doi.org/10.1136/bjophthalmol-2017-311519.
Akiyama M, Takeuchi T. IgG4-related disease: beyond glucocorticoids. Drugs Aging. 2018;35:275–87. https://doi.org/10.1007/s40266-018-0534-6.
Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755–62. https://doi.org/10.1002/art.27435.
Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74:1171–7. https://doi.org/10.1136/annrheumdis-2014-206605.
Wu A, Andrew NH, Tsirbas A, Tan P, Gajdatsy A, Selva D. Rituximab for the treatment of IgG4-related orbital disease: experience from five cases. Eye (Lond). 2015;29:122–8. https://doi.org/10.1038/eye.2014.251.
Ginthör NE, Artinger K, Pollheimer MJ, Stradner MH, Eller K. Membranous nephropathy associated with immunoglobulin G4-related disease successfully treated with obinutuzumab. Clin Kidney J. 2022;15:564–6. https://doi.org/10.1093/ckj/sfab250.
Goto H, Takahira M, Azumi A. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2015;59:1–7. https://doi.org/10.1007/s10384-014-0352-2.
Wallace ZS, Khosroshahi A, Carruthers MD, Perugino CA, Choi H, Campochiaro C, et al. An International Multispecialty Validation Study of the IgG4-Related Disease Responder Index. Arthritis Care Res. 2018;70:1671–8. https://doi.org/10.1002/acr.23543.
Zongfei J, Lijuan Z, Ying S, Dongmei L, Sifan W, Xiufang K, et al. Improved clinical outcomes of tocilizumab versus cyclophosphamide for IgG4-related disease: insights from a prospective IgG4-related disease registry. Ther Adv Chronic Dis. 2021;12:20406223211028776. https://doi.org/10.1177/20406223211028776.
Takahashi Y, Kitamura A, Kakizaki H. Bilateral optic nerve involvement in immunoglobulin G4-related ophthalmic disease. J Neuroophthalmol. 2014;34:16–9. https://doi.org/10.1097/WNO.0b013e3182a304f4.
Zhang W, Luo J, Jiao J. Optic nerve involvement in immunoglobulin G4-related disease: a case report. Exp Ther Med. 2016;12:111–4. https://doi.org/10.3892/etm.2016.3291.
Chen TS, Figueira E, Lau OC, McKelvie PA, Smee RI, Dawes LC, et al. Successful “medical” orbital decompression with adjunctive rituximab for severe visual loss in IgG4-related orbital inflammatory disease with orbital myositis. Ophthalmic Plast Reconstr Surg. 2014;30:e122–5. https://doi.org/10.1097/IOP.0b013e3182a64fa4.
Nagpal SJS, Chari ST. Immunoglobulin G4 Levels. JAMA. 2019;321:202–3. https://doi.org/10.1001/jama.2018.16665.
Zhao Z, Mou D, Wang Z, Zeng Q, Wang Z, Xue J, et al. Clinical features and relapse risks of IgG4-related ophthalmic disease: a single-center experience in China. Arthritis Res Ther. 2021;23:98. https://doi.org/10.1186/s13075-021-02489-9.
Yuan Y, Meng F, Ren H, Yue H, Xue K, Zhang R. Pathological count of IgG4-positive plasmacytes suggests extraophthalmic involvement and relapse in patients with IgG4-related ophthalmic disease: a retrospective study. Arthritis Res Ther. 2022;24:80. https://doi.org/10.1186/s13075-022-02757-2.
Tsang KFP, Oppong WK, Leeds SJ, Bekkali LHN, Nayar KM. Does IgG4 level at the time of diagnosis correlate with disease outcome in IgG4-Related disease? Pancreatology. 2019;19:177–81. https://doi.org/10.1016/j.pan.2018.10.013.
Perugino CA, AlSalem SB, Mattoo H, Della-Torre E, Mahajan V, Ganesh G, et al. Identification of galectin-3 as an autoantigen in patients with IgG(4)-related disease. J Allergy Clin Immunol. 2019;143:736–45.e6. https://doi.org/10.1016/j.jaci.2018.05.011.
Yoon HK, Shim YS, Kim PH, Park SR. The TLR7 agonist imiquimod selectively inhibits IL-4-induced IgE production by suppressing IgG1/IgE class switching and germline ε transcription through the induction of BCL6 expression in B cells. Cell Immunol. 2019;338:1–8. https://doi.org/10.1016/j.cellimm.2019.02.006.
Goede V, Klein C, Stilgenbauer S. Obinutuzumab (GA101) for the treatment of chronic lymphocytic leukemia and other B-cell non-hodgkin’s lymphomas: a glycoengineered type II CD20 antibody. Oncol Res Treat. 2015;38:185–92. https://doi.org/10.1159/000381524.
van Meerten T, Hagenbeek A. CD20-targeted therapy: the next generation of antibodies. Semin Hematol. 2010;47:199–210. https://doi.org/10.1053/j.seminhematol.2010.01.007.
Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum. 2004;50:3580–90. https://doi.org/10.1002/art.20592.
Mattoo H, Stone JH, Pillai S. Clonally expanded cytotoxic CD4(+) T cells and the pathogenesis of IgG4-related disease. Autoimmunity. 2017;50:19–24. https://doi.org/10.1080/08916934.2017.1280029.
Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393–402. https://doi.org/10.1182/blood-2009-06-225979.
Reddy V, Klein C, Isenberg DA, Glennie MJ, Cambridge G, Cragg MS, et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology. 2017;56:1227–37. https://doi.org/10.1093/rheumatology/kex067.
Klomjit N, Fervenza FC, Zand L. Successful treatment of patients with refractory PLA(2)R-associated membranous nephropathy with obinutuzumab: a report of 3 cases. Am J Kidney Dis. 2020;76:883–8. https://doi.org/10.1053/j.ajkd.2020.02.444.
Hart PA, Topazian MD, Witzig TE, Clain JE, Gleeson FC, Klebig RR, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62:1607–15. https://doi.org/10.1136/gutjnl-2012-302886.
Dawson K, Moran M, Guindon K, Wan H. Managing infusion-related reactions for patients with chronic lymphocytic leukemia receiving obinutuzumab. Clin J Oncol Nurs. 2016;20:E41–8. https://doi.org/10.1188/16.Cjon.E41-e48.
Fresa A, Autore F, Innocenti I, Piciocchi A, Tomasso A, Morelli F, et al. Non-overt disseminated intravascular coagulopathy associated with the first obinutuzumab administration in patients with chronic lymphocytic leukemia. Hematol Oncol. 2021;39:423–7. https://doi.org/10.1002/hon.2837.
Shimony S, Bar-Sever E, Berger T, Itchaki G, Gurion R, Yeshurun M, et al. Late onset neutropenia after rituximab and obinutuzumab treatment - characteristics of a class-effect toxicity. Leuk Lymphoma. 2021;62:2921–7. https://doi.org/10.1080/10428194.2021.1948037.
Author information
Authors and Affiliations
Contributions
All authors contributed in data collection and participated in the writing of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Informed consent
Patient consent has been received for the publication of Fig. 1.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Sun, H., Zeng, X., Li, Y. et al. Successful remission induction of IgG4-related ophthalmic disease by obinutuzumab therapy: a retrospective study of 8 patients. Eye 38, 723–729 (2024). https://doi.org/10.1038/s41433-023-02758-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41433-023-02758-8