The majority of patients have autoantibodies against the ribonuclein particles SSA/Ro and/or SSB/La. Patients frequently have extraglandular manifestations such as muscle and joint pain, neuropathy, and fatigue. Moexipril HCl fatigue is a major cause of disability. Recently it was reported that 85% of pSS patients experience fatigue, and 40% of the patients report fatigue as their most severe symptom. It is well known that mood disorders influence fatigue, but in pSS fatigue occurs in non-depressed as well as depressed individuals. Other factors influencing fatigue in pSS are pain, sleep disorders, learned helplessness, and possibly neuroendocrine disturbances and autonomic dysfunction. In search of biological mechanisms for fatigue we and others have found sickness behaviour in animals to be a relevant model. In animals, this behaviour is an adaptive and appropriate response to infection and inflammation, and is characterised by increased sleep, decreased activity, social withdrawal, and loss of appetite. A number of animal studies have demonstrated that sickness behaviour is signalled through interleukin -1 receptors on neurons in the brain. This is exemplified by intraperitoneal or intracerebroventricular injections of IL-1b or lipopolysaccharide, which leads to sickness behaviour within a few hours. There is no such effect following LPS-injections in IL-1 knockout mice. IL-1 exists in a membrane bound form and a circulating form and has two receptors: IL-1RI induces signal transduction, while IL-1RII functions as a decoy receptor. A naturally occurring IL-1 receptor antagonist inhibits IL-1 signalling by competitive binding to IL-1RI. IL-1Ra crosses the blood-brain barrier and recombinant IL-1Ra administered systemically may inhibit the effect of IL-1 in the brain. Injection of recombinant IL-1Ra in animals before injection of LPS diminishes sickness behaviour. Injection of IL-1 in Diperodon humans leads to fever, fatigue, and nausea. We recently demonstrated that increased activation in the IL-1 system, as detected by raised levels of IL-1Ra in cerebrospinal fluid, is associated with more fatigue in pSS. The mapping of biological pathways associated with fatigue is important in order to understand the phenomenon and to point out possible new treatment targets. Anakinra is a recombinant IL1Ra used in the treatment of rheumatoid arthritis, adult Still��s disease, and autoinflammatory diseases. It is administered daily by a subcutaneous injection. Administration of anakinra reduced fatigue in a non-blinded pilot trial in RA patients. We hypothesised that fatigue in pSS is mediated through activation of IL-1 receptors in the brain analogue to sickness behaviour in animals. Inhibition of these receptors may lead to a reduction in fatigue; thus, the objective of the current study was to investigate the effect of IL-1 inhibition on fatigue in pSS. The participants, nurses, and investigators were blinded to the randomisation.