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Interleukin-2 (IL-2) is crucial for the growth and survival of regulatory T cells (Treg) and, thus, for the control of autoimmunity.1 ,2 In previous studies, we have proven a causal relationship between an acquired IL-2-deficiency, defects in Treg biology and the development of systemic lupus erythematosus (SLE).3 Accordingly, we showed that compensation of IL-2 deficiency by IL-2 therapy corrects associated Treg defects and ameliorates already established disease in lupus-prone mice.3 In line with this, two independent clinical studies showed recently that low-dose IL-2 induced expansion of the Treg pool and reduced clinical symptoms in two different immunological diseases without known IL-2 deficiency.4 ,5 These promising clinical findings in conjunction with preclinical data3 ,6 ,7 provide strong rationales for an IL-2-based immunotherapy of SLE in order to restore Treg activity and, thus, to re-establish endogenous mechanisms of tolerance that can counteract autoimmunity.
Here we report a rapid and robust reduction of disease activity in parallel with a remarkable expansion of the Treg population by low-dose IL-2 therapy in one patient with a long-term history of SLE and increased disease activity refractory or intolerant to a large variety of approved and experimental therapies, including azathioprine, mycophenolate, rituximab, cyclophosphamide, bortezomib and, lastly, belimumab, in combination with methotrexate.
The therapeutic regimen consisted of four treatment cycles each with daily subcutaneous injections of recombinant human IL-2 (aldesleukin) at single doses of 1.5 or 3.0 million international units (only second cycle) on five consecutive days separated by washout periods of 9–16 days and followed by a 9-week follow-up period (adapted from Saadoun et al4). Treatment with hydroxychloroquine and prednisolone was maintained during the whole study.
This 36-year-old female patient with SLE had a high disease activity at baseline due to active arthritis (tenderness in 14 joints, morning stiffness of 2 h, recurrent swellings), clinical and laboratory signs of myositis, rash, hypocomplementaemia and elevated anti-dsDNA antibodies (SELENA-SLEDAI 14). Already after the first treatment cycle with IL-2, signs of arthritis and 10 days later, just before the second cycle, active skin eruptions and laboratory signs of myositis also disappeared (figure 1A–C). Myalgia also improved 3 weeks later. Additionally, serum levels of anti-dsDNA-antibodies quantified by ELISA decreased and anti-ds-DNA-antibody titres assessed by crithidia luciliae immunofluorescence-test even turned negative (figure 1D). During the following three cycles, organ manifestations remained absent, disease activity remained low (SELENA-SLEDAI 4) (figure 1A–C), antibody levels declined further and antibody titres remained negative (figure 1D). By contrast, only very slight and transient decreases in the levels of total Ig were observed suggesting a specific effect on auto-antibodies. Additionally, the daily dose of glucocorticosteroids could be reduced step by step, from 30 mg/day at baseline to 10 mg/day after the fourth cycle (figure 1E). The clinical response was associated with cyclic and treatment-related increases of the CD25++Foxp3+CD127lo Treg population (figure 1F). Treg from this patient showed an intact suppressive function, as assessed on day 57 and day 83 by in vitro suppression assays (data not shown). Only marginal effects on other cell subsets were observed. In general, the therapy was very well tolerated, and adverse events, which included erythema at the injection site, increased day and night sweats, and one episode of fever, were mild and transient.
Six weeks after the last cycle, the patient presented with a moderate disease flare due to recurrence of skin manifestations and myositis (SELENA-SLEDAI 10) accompanied by rising antibody levels, requiring an increase in glucocorticosteroids and the reinitiation of the previous treatment.
In summary, these data provide the first evidence for the clinical efficacy of a subcutaneous low-dose IL-2 therapy in conjunction with the boosting of Treg activity in SLE and strongly support the rationales of this selective biological treatment strategy.
Funding This study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB650, TP10) and the Charité—University Medicine Berlin.
Contributors Study concept and design: JYH, TA, FH, AR, G-RB, GR. Acquisition of data: JYH, CvS-M, ES. Analysis and interpretation of data: JYH, CvS-M, TA and GR. Drafting of the manuscript: JYH and GR. Study supervision: JYH and GR.
Competing interests None.
Ethics approval This study was announced as ‘off-label’ therapy to the institutional Ethics Committee of the Charité—University Medicine Berlin. Written informed consent was obtained from the patient prior to the initiation of the off-label treatment with aldesleukin according to the Declaration of Helsinki in the revised version of 1996, and the International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP).
Provenance and peer review Not commissioned; externally peer reviewed.
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