Additive effect of leflunomide and glucocorticoids compared with glucocorticoids monotherapy in preventing relapse of IgG4-related disease: A randomized clinical trial
Introduction
IgG4-related disease (IgG4-RD) is a recently described fibrotic autoimmune systemic disorder [1], [2], [3]. In the recent guidelines for IgG4-RD, glucocorticoids (GCs) therapy was recommended as the first-line therapy for the remission induction. However, many patients may fail to maintain remission during or after the tapering of GCs [4]. Moreover, recurrent flares lead to irreversible organ damage and higher cumulative GCs doses [5]. In order to address the unmet need of a treatment allowing patients with IgG4-RD to reduce their dependence on GCs, the efficacy of steroid-sparing immunosuppressive agents (IMs), including biological agents or conventional IMs, has been explored by several studies [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Rituximab has been indicated to have a good efficacy according to a prospective, open-label, single-arm trial [6]. however, it is less accessible to individuals of a lower socio-economic status as it is less likely to be covered by medical insurances in many countries. The use of conventional IMs including azathioprine [7], [8], [9], mycophenolate mofetil (MMF) [10,11]. cyclophosphamide [12], leflunomide (LEF) [13], tacrolimus [14], and methotrexate [15] has been reported for treating IgG4-RD. However, their clinical utilization is challenged by the lack of high-quality evidence [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16],17]. So far, most of the reports were observational studies [17], except for one randomized controlled trial (RCT) evaluating the efficacy of MMF in IgG4-RD [10].
Increasing evidences have been emerging to support the pathogenic role of B cell-T cell interaction at the onset of IgG4-RD and the latest studies have highlighted a key role of specific T cell subsets like the CD4+ SLAMF7+ cytotoxic T cells and T follicular helper cells in IgG4-RD [18], [19], [20], [21]. LEF targets at the metabolism of pyrimidines to influence the proliferation of the lymphocytes, especially T cells [22]. LEF has been widely used in treating diseases associated with T-cell disorders such as Takayasu arteritis [23,24] and giant cell arteritis [25]. Considering the associated T-cell disorder in IgG4-RD, LEF may have potential benefits for individuals with this condition. Base on the efficacy of the GCs + LEF combination therapy in IgG4-RD observed in our clinical practice, we reported the preliminary outcomes of the patients received the GCs + LEF combination therapy [13]. The promising preliminary results prompted us to conduct this investigator-initiated, randomized, open-label, controlled clinical trial to quantitatively evaluate the additive effect of LEF compared with GCs monotherapy.
Section snippets
Trial design
This study has been designed as a 12-month, randomized, open-label, controlled clinical trial and was conducted at the Chinese PLA General Hospital. The enrolled patients were assessed at months 0, 1, 3, 6 and 12, or at termination due to relapse. The study was approved by the ethics committee at the Chinese PLA General Hospital and was conducted in compliance with the Helsinki Agreement. Informed consent was obtained from all the enrolled patients.
Patients
The inclusion criteria were patients diagnosed
Patients
A total of 69 patients diagnosed with IgG4-RD were assessed for eligibility between March 2016 and January 2018. After the initial assessment, 3 patients, including 1 who had received GCs in the past 3 months, 1 who had chronic hepatitis B and 1 who declined to participate, were excluded. Finally, 66 patients with active IgG4-RD were enrolled (33 in each group). The treatment assignments and patient withdrawal data are represented in Fig. 1. Eight patients were lost to follow-up in this trial.
Discussion
This is the first RCT to evaluate the efficacy and safety of LEF in treating IgG4-RD. The results of our study suggest that the GCs + LEF combination therapy is significantly superior to the GCs monotherapy.
In our study, the relapse rate (14, 42.4%) of patients with IgG4-RD in the GCs monotherapy group was high, consistent with previous studies [28,[31], [32], [33]]. Disease relapse occurred less frequently in the combination therapy group (18.2%, P = 0.032). The GCs + LEF combination therapy
Availability of data and materials
The dataset analyzed in this paper is available from the corresponding author on reasonable request, and with appropriate additional ethical approvals, where necessary.
Authors’ contributions
Yiwen Wang contributed to the study design, data collection, data analysis and data interpretation. Zhen Zhao contributed to the study concept and the primary outcome judgement. Dai Gao contributed to the study concept, data analysis and data interpretation. Hui Wang and Simin Liao contributed to the data collection. Chongya Dong contributed to the data analysis. Gui Luo contributed to the data collection the study concept. Xiaojian Ji contributed to the data interpretation. Jianglin Zhang
What is already known about this subject?
- •
Glucocorticoids (GCs) was recommended as first-line therapy for the remission induction of IgG4-related disease (IgG4-RD), however, many patients receiving GCs monotherapy may fail to maintain remission during or after the GCs tapering.
- •
Although several steroid-sparing immunosuppressive agents (IMs) had been mentioned in previous publications, opinions were split due to few data overall to support their efficacy in IgG4-RD.
- •
LEF influences the proliferation of lymphocytes, especially T cells, and
CRediT authorship contribution statement
Yiwen Wang: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing - original draft. Zheng Zhao: Methodology, Investigation. Dai Gao: Methodology, Writing - review & editing. Hui Wang: Investigation. Simin Liao: Investigation. Chongya Dong: Methodology, Formal analysis. Gui Luo: Investigation. Xiaojian Ji: Writing - review & editing. Yan Li: Investigation. Xiuru Wang: Investigation. Yurong Zhao: Investigation. Kunpeng Li: Investigation. Jie Zhang: Investigation.
Declaration of competing interest
The authors have declared no conflicts of interest in this work.
Acknowledgements
We are extremely grateful to the participants for their support. We appreciate the contribution of all the staff at our department for their cooperation throughout the course of this clinical trial. We want to acknowledge the colleagues from the departments of hepatobiliary, general surgery, urology surgery, ultrasound and nuclear medicine for their assistance in the patient recruitment. We thank Yu An, Sarah Lawrence College, for helping us refine the manuscript.
Funding
This work was supported by the National Key Basic Research Program of China (973 program) (Grant no. 2014CB541806).
Ethics approval and consent to participate
This trial was approved by the Ethics Committee at Chinese PLA General Hospital (S2015-096-01) and was conducted in compliance with the Helsinki Agreement. All patients signed the informed consent form.
References (46)
- et al.
IgG4-related disease
Lancet
(2015) - et al.
Consensus statement on the pathology of IgG4-related disease
Mod Pathol
(2012) - et al.
The clinical spectrum of IgG4-related disease
Autoimmun Rev
(2014) - et al.
New insights into immune cells cross-talk during IgG4-related disease
Clin Immunol
(2019) - et al.
Leflunomide in Takayasu arteritis - A long term observational study
Rev Bras Reumatol Engl Ed
(2016) - et al.
International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease
Arthritis Rheumatol
(2015) - et al.
Recurrent attacks of autoimmune pancreatitis result in pancreatic stone formation
Am J Gastroenterol
(2004) - et al.
Rituximab for IgG4-related disease: a prospective, open-label trial
Ann Rheum Dis
(2015) - et al.
Azathioprine as successful maintenance therapy in IgG4-related tubulointerstitial nephritis
Clin Kidney J
(2012) - et al.
Hypophysitis due to IgG4-related disease responding to treatment with azathioprine: an alternative to corticosteroid therapy
Pituitary
(2014)
Autoimmune pancreatitis associated with various extrapancreatic lesions during a long-term clinical course successfully treated with azathioprine and corticosteroid maintenance therapy
Intern Med
Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial
Rheumatology (Oxford)
Addition of second-line steroid sparing immunosuppressants like mycophenolate mofetil improves outcome of Immunoglobulin G4-related disease (IgG4-RD): a series from a tertiary care teaching hospital in South India
Rheumatol Int
Efficacy of Cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids
Sci Rep
Combination therapy of leflunomide and glucocorticoids for the maintenance of remission in patients with IgG4-related disease: a retrospective study and literature review
Intern Med J
Tacrolimus as a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis
Z Gastroenterol
Methotrexate for maintenance of remission in IgG4-related disease
Rheumatology (Oxford)
Treatment approaches to IgG4-related systemic disease
Curr Opin Rheumatol
Therapeutic approach to IgG4-related disease: a systematic review
Medicine (Baltimore)
IgG4-related disease
Annu Rev Pathol
Immunology of IgG4-related disease
Clin Exp Immunol
New insights into the pathophysiology of IgG4-related disease and markers of disease activity
Expert Rev Clin Immunol
Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases
Expert Rev Clin Pharmacol
Cited by (23)
IgG4-related cholangitis – a mimicker of fibrosing and malignant cholangiopathies
2023, Journal of HepatologyChiari decompression for syringomyelia in the setting of IgG4-related hypertrophic pachymeningitis: A case-based update
2022, NeurochirurgieCitation Excerpt :In addition, nine clinical trials investingating alternative treatments are ongoing. Four trials are exploring the efficacy of monoclonal antibodies (Elotuzumab, Belimumab, Inebilizumab, and XmAb5871 [11]), two studying tyrosine kinase inhibitors (Rilzabrutinib and Zanubrutinib), and three studying immunomodulators, Abatercept [12], Leflunomide [13] and Lenalidomide. Ultimately, close follow up with a Rheumatologist is essential as recurrence and re-emergence at a different site is possible.
IgG4-related disease
2021, Medicine (Spain)Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review
2021, International ImmunopharmacologyProgresses and hot spots of type 1 autoimmune pancreatitis in the past decade
2024, Chinese Journal of Internal Medicine/Zhonghua Neike Zazhi