The universal effects of low-dose interleukin-2 across 13 autoimmune diseases in a basket clinical trial.

BACKGROUND: A Tregs insufficiency is central to autoimmune and inflammatory diseases pathophysiology and low dose interleukin-2 (IL-2LD) can specifically activate Tregs. OBJECTIVE: To assess IL-2LD therapeutic potential and select diseases for further clinical development, we performed an open-label, phase 2a, disease-finding, "basket trial" involving patients with one of 13 different autoimmune diseases. METHODS: 81 patients treated with IL-2LD (1 million IU/day) for 5 days, followed by fortnightly injections. The first 48 patients received diluted Proleukin®, while the subsequent 33 received ready-to-use ILT-101®. The primary endpoint was the change in Tregs at day-8 compared to baseline. Key secondary endpoints included clinical efficacy assessments using the Clinical Global Impression (CGI) scale, disease-specific scores, and EuroQL-5D-5L. RESULTS: Our study unveiled a universal and significant expansion and activation of Tregs, without concomitant Teffs activation, across all 13 autoimmune diseases. Both Proleukin® and ready-to-use ILT-101® demonstrated identical effects on Tregs. CGI scores reflecting activity, severity, and efficacy were significantly reduced in the overall patient population. Disease-specific clinical scores improved in five of the six disease cohorts with at least six patients, namely ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, Sjögren's syndrome, and systemic sclerosis. Urticaria was the only severe adverse event related to treatment. CONCLUSION: IL-2LD was well-tolerated, exhibiting specific Treg activation and clinical improvements across the 13 autoimmune diseases. CLINICAL IMPLICATION: Tregs stimulation by IL-2LD is a promising therapeutic strategy and IL-2LD holds considerable promise for integration into combinatorial therapeutic approaches.

Effect of Transcutaneous Vagus Nerve Stimulation in Erosive Hand Osteoarthritis: Results from a Pilot Trial.

Beyond its effect on vegetative functions, the activation of the vagus nerve inhibits inflammation and reduces pain signaling. The aim of this open-label pilot study was to determine the efficacy and tolerance of transcutaneous auricular VNS (taVNS) on erosive hand osteoarthritis (EHOA) symptoms. Symptomatic EHOA patients with hand pain VAS ≥ 40/100 mm and ≥1 interphalangeal swollen joint(s) were included. The taVNS was performed for 4 weeks using an auricular electrode applied one hour per day and connected to a TENS device with pre-established settings. Clinical efficacy was evaluated by changes between baseline and at 4 weeks with hand pain VAS and the functional index FIHOA score, using a Wilcoxon t-test. The treatment tolerance was also evaluated. Eighteen patients (median age 69 years old, 83% women) were analyzed. At baseline, hand pain VAS was 60 mm [IQR 50; 78.2] and FIHOA 15 [10.7; 20.2]. After 4 weeks, taVNS significantly reduced hand pain VAS, with a median decrease of 23.5 mm [7.7; 37.2] (p = 0.001), as well as FIHOA, with a median decrease of 2 points [0.75; 5.2] (p = 0.01). No serious adverse events were reported. One patient stopped taVNS because of auricular discomfort. This first proof-of-concept trial indicated that taVNS is feasible and may decrease joint inflammation and clinical symptoms in EHOA, arguing for a randomized controlled study versus sham stimulation.

Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial.

OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.

Quality of life and psychological status in patients with primary Sjögren's syndrome and sicca symptoms without autoimmune features.

OBJECTIVE: To compare pain, fatigue, and sicca symptoms; quality of life; and psychological status between patients with primary Sjögren's syndrome (SS) and those with sicca symptoms but no autoimmune features (sicca asthenia polyalgia syndrome [SAPS]), and to determine whether a psychological pattern can be detected in patients with SAPS, which could suggest psychological distress as the cause. METHODS: This cross-sectional, prospective study included 111 patients with primary SS according to the American-European Consensus Group criteria and 65 SAPS patients with no focus on lip biopsy and no anti-SSA/SSB antibodies. Pain, fatigue, and sicca symptoms were assessed using visual analog scales; quality of life was assessed using the Short Form 36 (SF-36); and psychological distress by the Symptom Checklist-90-Revised (SCL-90-R) questionnaire. RESULTS: No difference was observed between primary SS and SAPS patients for pain, fatigue, sicca symptoms, quality of life, and psychological status. Fatigue and pain, but not dryness, were correlated with both quality of life and psychological distress in both groups. For primary SS patients, physical and mental composite scores on the SF-36 correlated well with global severity index (GSI) scores of the SCL-90-R (r = -0.29, P = 0.006 and r = -0.61, P < 0.0001, respectively). CONCLUSION: Patients with primary SS and SAPS do not differ in quality of life or psychological status. Although both diseases probably have a different origin, they may require the same psychological support or psychiatric care. The strong correlation between the composite physical and mental scores of the SF-36 and the GSI scores of the SCL-90-R in primary SS patients emphasizes the importance of the psychological dimension in results of the SF-36.