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

Objectives: Fatigue 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. Methods: Twenty-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. Results: There 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. Conclusions: This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction i

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome

Flowchart of inclusion in the study.

<p>The pilot-study was conducted in 2008 and the main study in 2010. All patients underwent the same procedures. PSS, primary Sjögren's syndrome; FSS, Fatigue Severity Scale.</p

Fatigue and depression scores at inclusion and during the study.

<p>*Represents median and interquartile range.</p><p>**Represents mean ± SD.</p><p>A, active drug; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; P, placebo; VAS, visual analogue scale.</p

Selected demographic and laboratory variables at inclusion for 26 patients with primary Sjögren's syndrome (pSS).

<p>*Represents median and range.</p><p>**Represents mean ± standard deviation (SD).</p>†<p>BMI, body mass index. Available for the 18 patients in 2010 study only.</p><p>Numbers in parentheses represent percentages.</p><p>CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TSH, thyroid-stimulating hormone.</p

Median fatigue at baseline and during the study.

<p>Brackets represent inter-quartile range. VAS, visual analogue scale.</p

Neurofilament light is a biomarker of brain involvement in lupus and primary Sjögren’s syndrome

Background To test the hypothesis that neurofilament light (NfL) in CSF is a biomarker of CNS involvement in patients with systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS), we measured NfL in CSF from 52 patients with lupus and 54 with pSS and explored associations with clinical, structural, immunological and biochemical abnormalities. Methods In CSF, we measured NfL, anti-P antibodies, protein S100B and TWEAK by ELISA and anti-NR2 antibodies by electrochemiluminescence. Anti-phospholipid antibodies and routine immunological tests were performed in blood. IgG and albumin were measured in CSF and serum for assessment of the blood–brain barrier function (Q-albumin) and intrathecal IgG production (IgG index). Cerebral MRI and neuropsychological testing were performed. Results A multivariable regression model showed that increasing CSF anti-NR2 antibody levels were associated with increasing NfL levels in patients with SLE (B 1.27, 95% CI 0.88–1.65, p < 0.001). Age contributed significantly in the model (B 0.04, 95% CI 0.03–0.05, p < 0.001). Similar findings were observed in the pSS group. Adjusted for age and sex, no associations were found between NfL levels and any MRI data. In SLE patients, higher NfL concentrations were associated with impairments in psychomotor speed and motor function, and in pSS with motor dysfunction. These associations remained in multivariable regression models. Conclusions Increased concentration of NfL in CSF is a marker of cerebral involvement in patients with SLE and pSS, is strongly associated with the presence of anti-NR2 antibodies, and correlates with cognitive impairment in several domains.publishedVersio