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

Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.Research reported in this publication was supported by the National Institutes of Health (NIH): R01AR073855 (C.J.L.), R01AR065953 (C.J.L.), R01AR074310 (A.D.F.), P50AR060804 (K.L.S.), R01AR050782 (K.L.S), R01DE018209 (K.L.S.), R33AR076803 (I.A.), R21AR079089 (I.A.); NIDCR Sjögren’s Syndrome Clinic and Salivary Disorders Unit were supported by NIDCR Division of Intramural Research at the National Institutes of Health funds - Z01-DE000704 (B.W.); Birmingham NIHR Biomedical Research Centre (S.J.B.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (T.W.); Research Council of Norway (Oslo, Norway) – Grant 240421 (TR.R.), 316120 (M.W-H.); Western Norway Regional Health Authority (Helse Vest) – 911807, 912043 (R.O.); Swedish Research Council for Medicine and Health (L.R., G.N., M.W-H.); Swedish Rheumatism Association (L.R., G.N., M.W-H.); King Gustav V’s 80-year Foundation (G.N.); Swedish Society of Medicine (L.R., G.N., M.W-H.); Swedish Cancer Society (E.B.); Sjögren’s Syndrome Foundation (K.L.S.); Phileona Foundation (K.L.S.). The Stockholm County Council (M.W-H.); The Swedish Twin Registry is managed through the Swedish Research Council - Grant 2017-000641. The French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive) was sponsored by Assistance Publique-Hôpitaux de Paris (Ministry of Health, PHRC 2006 P060228) and the French society of Rheumatology (X.M.).publishedVersio

Biological mechanisms for chronic fatigue in primary Sjøgren`s syndrome

Background: Primary Sjøgren`s syndrome (pSS) is a chronic autoimmune disease, characterised by lymphocytic infiltration of exocrine glands and autoantibody production. Fatigue is a frequent phenomenon in pSS, associated with reduced health-related quality of life. Fatigue is influenced by depressed mood, sleep disorder and autonomic dysfunction, but also occurs without these co-factors. Evidence from animal and human studies indicates that immune activation may directly influence fatigue in chronic inflammatory disorders. Sickness behaviour in animals is characterized by decreased activity, social withdrawal and a reduction in the intake of food and water. This behaviour is hypothesized to increase survival by shielding the sick animal from predators, and occurs automatically as a response to infection and inflammation. The proinflammatory cytokine interleukin (IL)-1β is crucial for this behaviour. Fatigue in humans can be considered an element of sickness behaviour, and we hypothesized that inhibition of IL-1 would lead to a reduction in fatigue in pSS. We tested this in a randomized clinical trial by giving anakinra, a recombinant IL-1 receptor antagonist (IL-1Ra) - or placebo - to pSS patients with a high level of fatigue. Inflammation is closely connected with oxidative stress, and generation of reactive oxygen species is an important mechanism for killing of pathogens. Increased oxidative stress has been reported in relation to fatigue in human diseases, but has never been investigated in relation to fatigue in pSS. We hypothesized that pSS patients would have higher levels of oxidative stress than healthy controls, and that oxidative stress would be associated with fatigue. Taking oxidative stress and pro-inflammatory cytokines into consideration, some pSS patients are still more affected by fatigue than otherwise comparable individuals. Part of the explanation for this might be found in the genetic makeup of each individual patient, and several recent studies point to both genetic and epigenetic factors that may be important for fatigue generation. Based on this, we aimed to investigate genetic variation in relation to fatigue in pSS. Main objectives: Write a review article of the current knowledge of biological mechanisms of fatigue in inflammatory and non-inflammatory conditions. Investigate the efficacy and safety of IL-1 inhibition on fatigue in pSS. Investigate the plasma levels of oxidative stress markers in pSS as compared to healthy individuals, and further explore any association of oxidative stress with fatigue in pSS. Investigate genetic variation, i.e., single nucleotide polymorphisms (SNP) in relation to fatigue in pSS. Subjects and methods: All patients included in this dissertation were recruited from the pSS patient pools at Stavanger University Hospital (SUS) and Haukeland University Hospital (HUS). SUS is the only hospital in the southern part of Rogaland County and HUS is the main hospital in Hordaland County, Norway. For the double-blind, randomised treatment trial all pSS patients in the southern part of Rogaland County were identified and invited to the study, and a total of 26 patients were eligible and agreed to participate. The patients were randomly allocated to treatment with either an IL-1Ra or placebo (0.9% NaCl in identical syringes), and self-administered the drug or the placebo by a daily subcutaneous injection. Neither patients nor investigators were aware of the treatment allocation. The study ran over four weeks. Blood was sampled and a visual analogue scale (VAS) and the Fatigue Severity Scale (FSS) were used to asses fatigue at the start of the study (week 0), at week 2, at the end of the study (week 4) and at week 5. The same 26 patients were included for the plasma measures of oxidative stress. Two markers of protein oxidation; advanced oxidation protein products (AOPP) and protein carbonyl (PC), were measured in blood samples collected at week 0, before any interventions took place. For the genetic analysis we used whole blood samples from 207 pSS patients and 376 healthy controls. We investigated the associations of fatigue and minor allele frequencies in 85 SNPs in 12 genes, half of which are related to mitochondrial function. The genes were selected based on previous studies of gene expression in the chronic fatigue syndrome. Results: We found that: IL-1 inhibition influences fatigue in pSS as compared to placebo. We were not able to show this in the primary endpoint, but ad hoc analysis points to a strong positive effect of IL-1 inhibition on fatigue. IL-1 inhibition appears to be safe in pSS. Markers of protein oxidation are increased in pSS as compared to healthy controls. There is no association between fatigue and plasma protein oxidation in pSS. Genetic variation in SLC25A40 and PKN1 show signals of association with fatigue in pSS. Conclusions: This dissertation strengthens the view that at least some part of fatigue has a biological fundament, related to inflammation. The IL-1 system is crucial in the development of fatigue in this setting, and IL-inhibition seems to reduce fatigue generation. There is a trend for association between genetic variation and fatigue in pSS. Fatigue is not associated with the amount of oxidised plasma proteins in pSS

Fatigue in psoriasis: a phenomenon to be explored

Fatigue is a prevalent and substantial phenomenon in many patients with chronic inflammatory diseases, often rated by patients as the most troublesome symptom and aspect of their disease. It frequently interferes with physical and social functions and may lead to social withdrawal, long-standing sick leave and disability. Although psychological and somatic factors such as depression, sleep disorders, pain and anaemia influence fatigue, the underlying pathophysiological mechanisms by which fatigue is generated and regulated are largely unknown. Increasing evidence points towards a genetic and molecular basis for fatigue as part of the innate immune system and cellular stress responses. Few studies have focused on fatigue in dermatological diseases. Most of these studies describe fatigue as a phenomenon related to psoriatic arthritis and describe the beneficial effects of biological agents on fatigue observed in clinical studies. It is therefore possible that this problem has been underestimated and deserves more attention in the dermatological community. In this review, we provide a definition and explanation for chronic fatigue, describe some commonly used instruments for measuring fatigue, and present hypothetical biological mechanisms with an emphasis on activation of the innate immune system and oxidative stress. An overview of relevant clinical studies covering the theme ‘psoriasis and fatigue’ is given

Severe headache in primary Sjögren's syndrome treated with intrathecal rituximab

A severe and persistent migrainous headache in a patient with primary Sjøgren's syndrome unresponsive to treatment with immunosuppressive drugs, triptans, opioids, and NSAIDs, responded successfully to intrathecal B‐cell depletion with rituximab. We hypothesize that brain‐resident autoreactive B cells were involved in headache pathogenesis and were eliminated by this procedure

Heat shock proteins and chronic fatigue in primary Sjögren's syndrome

Fatigue occurs frequently in patients with cancer, neurological diseases and chronic inflammatory diseases, but the biological mechanisms that lead to and regulate fatigue are largely unknown. When the innate immune system is activated, heat shock proteins (HSPs) are produced to protect cells. Some extracellular HSPs appear to recognize cellular targets in the brain, and we hypothesize that fatigue may be generated by specific HSPs signalling through neuronal or glial cells in the central nervous system. From a cohort of patients with primary Sjögren’s syndrome, 20 patients with high and 20 patients with low fatigue were selected. Fatigue was evaluated with a fatigue visual analogue scale. Plasma concentrations of HSP32, HSP60, HSP72 and HSP90α were measured and analysed to determine if there were associations with the level of fatigue. Plasma concentrations of HSP90α were significantly higher in patients with high fatigue compared with those with low fatigue, and there was a tendency to higher concentrations of HSP72 in patients with high fatigue compared with patients with low fatigue. There were no differences in concentrations of HSP32 and HSP60 between the high- and low-fatigue groups. Thus, extracellular HSPs, particularly HSP90α, may signal fatigue in chronic inflammation. This supports the hypothesis that fatigue is generated by cellular defence mechanisms

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