Low-dose IL-2 improved clinical symptoms by restoring reduced regulatory T cells in patients with refractory rheumatoid arthritis: A randomized controlled trial

Abstract

BackgroundRegulatory T cells (Tregs) have been found to play crucial roles in immune tolerance. However, the status of Tregs in refractory rheumatoid arthritis (RA) is still unclear. Moreover, low-dose interleukin-2 (IL-2) has been reported to selectively promote the expansion of Tregs. This study investigated the status of CD4+ Tregs and low-dose IL-2 therapy in patients with refractory RA.MethodsThe absolute number of CD4+CD25+FOXP3+ Treg (CD4 Treg), CD4+IL17+ T (Th17), and other subsets in peripheral blood (PB) from 41 patients with refractory RA and 40 healthy donors was characterized by flow cytometry combined with an internal microsphere counting standard. Twenty-six patients with refractory RA were treated with daily subcutaneous injections of 0.5 million IU of human IL-2 for five consecutive days. Then, its effects on CD4 Treg and Th17 cells in PB were analyzed.ResultsA decrease in the absolute number of PB CD4 Tregs rather than the increase in the number of Th17 was found to contribute to an imbalance between Th17 and CD4 Tregs in these patients, suggesting an essential role of CD4 Tregs in sustained high disease activity. Low-dose IL-2 selectively increased the number of CD4 Tregs and rebalanced the ratio of Th17 and CD4 Tregs, leading to increased clinical symptom remission without the observed side effects.ConclusionsAn absolute decrease of PB CD4 Tregs in patients with refractory RA was associated with continuing disease activation but not the increase of Th17 cells. Low-dose IL-2, a potential therapeutic candidate, restored decreased CD4 Tregs and promoted the rapid remission of patients with refractory RA without overtreatment and the observed side effects.Clinical trial registrationhttp://www.chictr.org.cn/showproj.aspx?proj=13909, identifier ChiCTR-INR-16009546.

The efficacy and safety of short-term and low-dose IL-2 combined with tocilizumab to treat rheumatoid arthritis

“…We have previously reported that Tregs are significantly reduced with the aggravation of disease in RA patients, and combined with low-dose IL-2 therapy can maintain or even rebuild autoimmune homeostasis by promoting the proliferation of Treg cells, thus delaying the deterioration of disease ( 22 , 30 ). Great heterogeneity exists in the clinical presentation and immune mechanisms of RA, as a consequence, not all patients respond similarly to the same drug.…”

“…We previously reported that combined with low-dose IL-2[0.5 Million International Units (MIU)/day of IL-2 for five consecutive days] on the basis of previous treatment can promote the proliferation of circulating Tregs in patients with RA, PsA, and pSS, and significantly improve the symptoms of patients ( 22 , 28 , 29 ). Therefore, eligible participants were randomly assigned to three age-sex matched groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9).…”

“…Tregs have emerged as potential therapeutic targets for many autoimmune diseases such as RA ( 20 , 21 ). Initial data indicate that the number of circulating Tregs in RA patients decreases with increasing disease activity, which can be reversed by exogenous supplementation with low doses of IL-2 ( 22 ). IL-2, a cytokine with multiple immunomodulatory functions, has been widely recognized for its ability to selectively expand Tregs and maintain or restore the balance of CD4+T subgroup balance and immune tolerance ( 23 , 24 ).…”

Comparison of Low-Dose Interleukin 2 Therapy in Conjunction With Standard Therapy in Patients With Systemic Lupus Erythematosus vs Rheumatoid Arthritis: A Systematic Review

“…It was also demonstrated that during the course of their study, there was no significant decrease in rheumatoid factor (RF) and anti-cyclic-citrullinated peptide (anti-CCP) [ 19 ]. Wang et al demonstrated that patients who received low-dose IL2 therapy in conjunction with conventional therapy had a greater clinical response with a significant decrease in the DAS28 score, 28 tender count, and swollen joint count as compared with RA patients being treated with only conventional therapy [ 20 ]. The findings in this study consolidated the findings of the study carried out by Zhang et al, which suggested that the significant improvement seen in the low-dose IL2 group is directly correlated with immunomodulation.…”

“…Severe adverse effects in the study were noted to be singular events and no specific association was seen with treatment [ 19 ]. Wang et al also conducted a randomized controlled trial in which they demonstrated that other than mild reactions at the injection sites in some patients treated with low-dose IL2, no other adverse effects were noted [ 20 ]. Similarly, Zhang et al conducted a non-randomized clinical trial where RA patients were given low-dose IL2 therapy in conjunction with conventional therapy and were followed after five days of treatment regimen [ 21 ].…”