Biological mechanisms for chronic fatigue in primary Sjøgren`s syndrome

Abstract

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.