Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis

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Abstract

Introduction

Current therapies for autoimmune rheumatic diseases (ARDs) have limited efficacy in certain patients, highlighting the need for the development of novel treatment approaches. This meta-analysis aims to assess the efficacy and safety of low-dose interleukin-2 (LD-IL-2) and evaluate the alterations in lymphocyte subsets in various rheumatic diseases following administration of different dosages of LD-IL-2.

Methods

A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, Embase databases and CNKI to identify relevant studies. A total of 31 trials were included in this meta-analysis. The review protocols were registered on PROSPERO (CRD42022318916), and the study followed the PRISMA guidelines.

Results

Following LD-IL-2 treatment, patients with ARDs exhibited a significant increase in the number of Th17 cells and Tregs compared to their pre-treatment levels [standardized mean difference (SMD) = 0.50, 95% confidence interval (CI) (0.33, 0.67), P < 0.001; SMD = 1.13, 95% CI (0.97, 1.29), P < 0.001]. Moreover, the Th17/Tregs ratio showed a significant decrease [SMD = − 0.54, 95% CI (− 0.64, − 0.45), P < 0.001]. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), LD-IL-2 injection led to a significant increase in Treg numbers, and the Th17/Tregs ratio and disease activity scores, including Disease Activity Score-28 joints (DAS28), Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), were all significantly reduced. No serious adverse events were reported in any of the included studies. Additionally, 54.8% of patients with lupus nephritis achieved distinct clinical remission following LD-IL-2 treatment. Injection site reactions and fever were the most common side effects of LD-IL-2, occurring in 33.1% and 14.4% of patients, respectively.

Conclusion

LD-IL-2 treatment showed promise and was well tolerated in the management of ARDs, as it effectively promoted the proliferation and functional recovery of Tregs.

Trial Registration

Retrospectively registered (CRD42022318916, 21/04/2022).

Supplementary Information

The online version contains supplementary material available at 10.1007/s40744-023-00620-7.

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Most cited references 33

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To provide the level and trends of prevalence, incidence and disability adjusted life years (DALYs) for rheumatoid arthritis (RA) in 195 countries from 1990 to 2017 by age, sex, Socio-demographic Index (SDI; a composite of sociodemographic factors) and Healthcare Access and Quality (an indicator of health system performance) Index. Data from the Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2017 were used. GBD 2017 modelled the burden of RA for 195 countries from 1990 to 2017, through a systematic analysis of mortality and morbidity data to estimate prevalence, incidence and DALYs. All estimates were presented as counts and age-standardised rates per 100 000 population, with uncertainty intervals (UIs). Globally, the age-standardised point prevalence and annual incidence rates of RA were 246.6 (95% UI 222.4 to 270.8) and 14.9 (95% UI 13.3 to 16.4) in 2017, which increased by 7.4% (95% UI 5.3 to 9.4) and 8.2% (95% UI 5.9 to 10.5) from 1990, respectively. However, the age-standardised rate of RA DALYs per 100 000 population was 43.3 (95% UI 33.0 to 54.5) in 2017, which was a 3.6% (95% UI −9.7 to 0.3) decrease from the 1990 rate. The age-standardised prevalence and DALY rates increased with age and were higher in females; the rates peaked at 70–74 and 75–79 age groups for females and males, respectively. A non-linear association was found between age-standardised DALY rate and SDI. The global age-standardised DALY rate decreased from 1990 to 2012 but then increased and reached higher than expected levels in the following 5 years to 2017. The UK had the highest age-standardised prevalence rate (471.8 (95% UI 428.9 to 514.9)) and age-standardised incidence rate (27.5 (95% UI 24.7 to 30.0)) in 2017. Canada, Paraguay and Guatemala showed the largest increases in age-standardised prevalence rates (54.7% (95% UI 49.2 to 59.7), 41.8% (95% UI 35.0 to 48.6) and 37.0% (95% UI 30.9 to 43.9), respectively) and age-standardised incidence rates (48.2% (95% UI 41.5 to 55.1), 43.6% (95% UI 36.6 to 50.7) and 36.8% (95% UI 30.4 to 44.3), respectively) between 1990 and 2017. RA is a major global public health challenge. The age-standardised prevalence and incidence rates are increasing, especially in countries such as Canada, Paraguay and Guatemala. Early identification and treatment of RA is vital especially among females, in order to reduce the ongoing burden of this condition. The quality of health data needs to be improved for better monitoring of disease burden.

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Author and article information

Contributors

Sheng-Xiao Zhang:

ORCID: http://orcid.org/0000-0003-1341-7588

zhangshengxiaol@sxmu.edu.cn

Journal

Journal ID (nlm-ta): Rheumatol Ther

Journal ID (iso-abbrev): Rheumatol Ther

Title: Rheumatology and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2198-6576

ISSN (Electronic): 2198-6584

Publication date (Electronic): 19 November 2023

Publication date PMC-release: 19 November 2023

Publication date Collection: February 2024

Volume: 11

Issue: 1

Pages: 79-96

Affiliations

[1 ]Present Address: Department of Rheumatology, The Second Hospital of Shanxi Medical University, ( https://ror.org/03tn5kh37) 382. Wuyi Road, Taiyuan, Shanxi China

[2 ]Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, The Shanxi Medical University, ( https://ror.org/0265d1010) Taiyuan, Shanxi China

[3 ]Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, ( https://ror.org/03m01yf64) Taiyuan, China

Author information

Sheng-Xiao Zhang http://orcid.org/0000-0003-1341-7588

Article

Publisher ID: 620

DOI: 10.1007/s40744-023-00620-7

PMC ID: 10796881

PubMed ID: 37980696

SO-VID: a4455b31-8082-4184-b404-b801e8dc2e60

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 23 September 2023

Date accepted : 23 October 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: No. 82001740

Award Recipient : Sheng-Xiao Zhang

Funded by: FundRef http://dx.doi.org/10.13039/501100004480, Natural Science Foundation of Shanxi Province;

Award ID: No. 202203021221269

Award Recipient : Sheng-Xiao Zhang

Custom metadata

Keywords: autoimmune rheumatic diseases,tregs,meta-analysis,systematic review,low-dose interleukin-2 (ld-il-2)

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Keywords: autoimmune rheumatic diseases, tregs, meta-analysis, systematic review, low-dose interleukin-2 (ld-il-2)

Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis

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Abstract

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Conclusion

Trial Registration

Supplementary Information

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Most cited references 33

Global, regional and national burden of rheumatoid arthritis 1990–2017: a systematic analysis of the Global Burden of Disease study 2017

Pathogenesis of systemic lupus erythematosus.

Autoimmunity and organ damage in systemic lupus erythematosus

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