Efficacy and Safety of Low-Dose Interleukin 2 for Primary Sjögren Syndrome

Abstract

ImportancePrimary Sjögren syndrome (pSS) is a systemic autoimmune disease associated with dysregulated immune cells, with no efficient therapy. There is a need to study potential therapeutic approaches.ObjectiveTo investigate the efficacy, safety, and immune response of low-dose interleukin 2 (LD-IL-2) in the treatment of pSS.Design, Setting, and ParticipantsA double-blind, placebo-controlled randomized clinical trial was conducted with a 2-group superiority design from June 2015 to August 2017. Sixty patients, aged 18 to 70 years, were recruited from Peking University People’s Hospital. Efficacy analyses were based on the intention-to-treat (ITT) principle. Data were analyzed from December 2018 to March 2020.InterventionsPatients with pSS were treated with LD-IL-2 or placebo for 12 weeks and accompanied by 12 weeks of follow-up.Main Outcomes and MeasuresThe primary end point was defined as a 3-point or greater improvement on the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) by week 24. The secondary end points included other clinical responses, safety, and changes of immune cell subsets at week 12 and 24.ResultsSixty patients with pSS were recruited, with 30 in the LD-IL-2 group (mean [SD] age, 47.6 [12.8] years; 30 [100%] women) and 30 in the placebo group (mean [SD] age, 51.0 [11.9] years; 30 [100%] women), and 57 completed the trial. More patients in the LD-IL-2 group (20 [66.7%]) achieved ESSDAI score reduction of at least 3 points than in the placebo group (8 [26.7%]) at week 24 (P = .004). There were greater resolutions of dryness, pain, and fatigue in the LD-IL-2 group than placebo group at week 12 (dryness: difference, −18.33 points; 95% CI, −28.46 to −8.21 points; P = .001; pain: difference, −10.33 points; 95% CI, −19.38 to −1.29 points; P = .03; fatigue: difference, −11.67 points; 95% CI, −20.65 to −2.68 points; P = .01). No severe adverse events were observed in either group. In addition, the LD-IL-2 group showed a significant decrease in infection compared with the placebo group (1 [3.3%] vs 9 [30.0%]; P = .006). Immunological analysis revealed that LD-IL-2 promoted an expansion of regulatory T cells and regulatory CD24highCD27+ B cells.Conclusions and RelevanceIn this randomized clinical trial, LD-IL-2 was effective and well tolerated in patients with pSS, and it restored immune balance, with enhanced regulatory T cells and CD24highCD27+ B cells.Trial RegistrationClinicalTrials.gov Identifier: NCT02464319

Autoimmune uveitis in Behçet's disease and Vogt‐Koyanagi‐Harada disease differ in tissue immune infiltration and T cell clonality

“…A striking observation was that Treg cells (C2) underwent the least clonal expansion in both VKHD and BD, suggesting that insufficient expansion of Treg cells might posit in the root of losing immune tolerance in autoimmune uveitis. Our previous clinical trials of low-dose IL-2 therapy in systemic lupus erythematosus and Sjogren's syndrome have demonstrated that it could enhance antigenindependent expansions of Treg cells, [36][37][38] thus providing a strategy to improve the poor clonal expansion of Treg cells in autoimmune uveitis. However, IPA analyses also suggest that IL-2 could be involved in the generation of pro-inflammatory CD4 + Tem and CD8 + Tem cells.…”

Regulatory Mechanisms and Reversal of CD8+T Cell Exhaustion: A Literature Review

“…Therefore, IL-2 acts as the double-edged sword, although IL-2 signaling can promote an exhausted phenotype, it is also a feasible pathway to reverse CD8 + T-cell exhaustion. Initially, the earliest therapeutic applications of IL-2 were to improve immune responses in cancer patients [ 128 , 129 ]. In present, combining IL-2 treatment with immune checkpoints inhibitors PD-1 has striking synergistic effects for re-invigorating exhausted CD8 + T cells [ 130 ].…”

Immune-mediated lung diseases: A narrative review

“…Autoreactive effector T-cells originate and reinforce pathogenic B-cell responses. Interleukin 2 (IL-2) is the key stimulator of CD4+ T-cells and controls regulatory T-cells (Tregs) ( 49 ). The function of Treg cells was observed to be disrupted in patients with primary SS ( 50 ).…”

“…Low-dose IL-2 therapy significantly improved disease activity scores and immunological effects in 60 primary SS patients ( 49 ). However, the potential role of this therapy on ILD in SS is not well-defined.…”