Interleukin-1 Inhibition and Fatigue in Primary Sjögren's Syndrome – A Double Blind, Randomised Clinical Trial

Abstract

ObjectivesFatigue is a major cause of disability in primary Sjögren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue.MethodsTwenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4.ResultsThere was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group.ConclusionsThis randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS.Trial registrationClinicalTrials.gov NCT00683345

Inflammation and the Silent Sequelae of Stroke

“…And, as with depression, the administration of proinflammatory cytokines [e.g., interleukin (IL)-6] is associated with the perception of fatigue [49]. Further, treatment with cytokine antagonists is associated with a decrease in fatigue-administration of exogenous IL-1ra (anakinra) decreases fatigue in patients with Sjögren's syndrome [50], and the tumor necrosis factor (TNF)-α receptor antagonist infliximab and the IL-6 receptor antagonist toclizumab reduce fatigue in patients with cancer and autoimmune diseases [51][52][53][54][55].…”

“…The FAS has been validated in healthy cohorts [71]. FAS scores of 10-21 indicate that the patient is "not tired", scores of 22-34 indicate that the patient is "tired", and scores of [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] indicate that the patient is "very tired" [72]. We evaluated the relationship between the biomarkers of inflammation shown in Fig.…”

“…Inhibiting proinflammatory cytokines in these patients appears to lessen fatigue. Treatment with exogenous IL-1ra (anakinra), for instance, decreases fatigue in patients with Sjögren's syndrome [50]. Similarly, the TNF-α receptor antagonist infliximab and the IL-6 receptor antagonist tocilizumab reduce fatigue in patients with cancer [51] and a variety of autoimmune diseases [52][53][54][55].…”

Safety of treatments for primary Sjögren’s syndrome

“…[119] Anakinra indeed reduced fatigue, but the study was underpowered for the primary outcome measurement and treatment duration was only 4 weeks. As expected, anakinra caused injection-site reactions in a large proportion of pSS patients (54%).…”

“…As expected, anakinra caused injection-site reactions in a large proportion of pSS patients (54%). [119,120] Due to the small sample size and short follow-up, no definitive conclusions can be made regarding the efficacy and safety of anakinra in pSS. Further study is needed.…”