Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren’s syndrome

Background Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren’s syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. Methods Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). Results Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1β activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1β-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. Conclusions The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.publishedVersio

Headache in systemic lupus erythematosus and primary Sjogren's syndrome

Background Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease which can affect multiple organs. The central nervous system (CNS) is frequently affected, and headache, especially migraine, is among the most frequent manifestations. The existence of a strong and specific "lupus headache" has been debated for decades, and it is still controversial whether this type of headache is a reality or a myth, and whether headache in SLE is caused by the disease's brain involvement, something that may have implications for the treatment of SLE in the individual patient. Moreover, even less is known about headaches in other autoimmune diseases, such as primary Sjogren's syndrome (pSS), and there is therefore a need to obtain more knowledge on these issues. Main objectives Investigate prevalence and characteristics of headaches in the autoimmune disease SLE. Investigate whether headaches occur with the same pattern in another autoimmune disease, namely pSS. Investigate whether headache related disability is different in these diseases compared with the general population. Investigate whether clinical , biochemical , immunological or structural brain abnormalities influence the prevalence of headache in patients with SLE. Subjects and methods Nearly all patients with autoimmune diseases in Rogaland County, Norway, are allocated to Stavanger University Hospital (SUS), which served about 310 000 people at the time of the study. We aimed at identifying all known cases with SLE and pSS in this area, and the studies in this thesis are therefore near population based. Cross- sectional- and case-control designs were used. Sixty-seven SLE patients and 71 pSS patients, as well as their age- and gender matched healthy control subjects, gave written informed consent to participate. All participants were examined by an experienced internist and neurologist. Biochemical- and immunological analyses, and cerebral magnetic resonance imaging (MRI) were performed, in the patients also analyses of the cerebrospinal fluid (CSF). International criteria for SLE and pSS, for neuropsychiatric syndromes in SLE, and for headache classification were used. Reliable and validated instruments were used for assessing depression, fatigue, and headache-related disability. Biochemical- and immunological analyses were performed at the hospital's routine laboratories and in the research laboratory at SUS. Antibodies against ribosomal P-protein (anti-P) were analyzed in professor Hirohata's research laboratory in Tokyo, Japan. MRI analyses were performed with the SPM8 software. Results Twenty-four out of 67 SLE patients and 13 out of 67 matched healthy subjects had migraine (36 % vs 19 %, P = 0.03). Out of these, nine SLE patients and 4 healthy subjects had migraine with aura (13 % vs 6 %, P = 0.14). Prevalence of tension type headache (TTH) was equal in SLE patients (60 %) and healthy subjects (58 %). SLE patients had more depression and fatigue than the healthy subjects, and depression was associated with migraine in the patients. Headaches were, with the exception of SLE photosensitivity, not associated with any SLE disease specific factors such as disease activity, accumulated organ damage, biochemical- or immunological markers in blood, impairment of the blood-brain barrier, intrathecal immunoglobulin production or white matter hyperintensities (WMHs) on cerebral MRI. Eight pSS patients (11 %) had chronic TTH, while only one of the healthy subjects had chronic TTH last year, P = 0.05. This subtype of TTH was not associated with pSS- related antibodies, depression, fatigue, abnormalities on MRI, or any other clinical or laboratory variables. Migraines and migraines with aura were equally prevalent in patients (26.8 % and 11.3 %, respectively) and control subjects (28.2 % and 15.5 %, respectively, P = 0.61). On cerebral MRI, increasing gray matter (GM) volumes in the SLE patients reduced the odds for migraine (OR 0.95, P = 0.004). No localized loss of GM was observed. Increasing global white matter volumes in the patients increased the odds for migraine (OR 1.04, P = 0.007). These findings could not be replicated in the healthy subjects. No associations with headaches in SLE patients were revealed regarding anti-NR2-, anti-P antibodies, nor protein S1008. Conclusions SLE patients have more migraine than healthy subjects. It is associated with mental depression, but not with disease activity, abnormalities detected on cerebral MRI, abnormalities in CSF, or any SLE characteristics except from SLE photosensitivity. The distribution of headache types in pSS patients differ from that observed in the SLE patients, and migraine is not more prevalent than in the healthy control subjects. However, pSS patients have more chronic TTH than the healthy subjects. Headache-related disability is considerably higher in patients with SLE and pSS than in otherwise healthy headache-sufferers. Depressive mood significantly influenced headache severity in the patients. The high headache-related disability in patients with SLE and pSS may reflect the burden of chronic disease. SLE patients with migraine have a global diffuse reduction in GM compared to patients without migraine. This GM volume reduction was not observed in the healthy subjects with migraine. Analyses of the selected biomarkers did not indicate specific pathophysiological processes in the brain. These findings indicate that unknown pathogenic and pathophysiological processes are responsible for - or influence - the increased frequency of migraine in SLE patients

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

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren’s syndrome

Background Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren’s syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. Methods Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). Results Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1β activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1β-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. Conclusions The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway

Fatigue in primary Sjögren's syndrome: A proteomic pilot study of cerebrospinal fluid

Objectives: Fatigue is a frequent and often disabling phenomenon that occurs in patients with chronic inflammatory and immunological diseases, and the underlying biological mechanisms are largely unknown. Because fatigue is generated in the brain, we aimed to investigate cerebrospinal fluid and search for molecules that participate in the pathophysiology of fatigue processes. Methods: A label-free shotgun proteomics approach was applied to analyze the cerebrospinal fluid proteome of 20 patients with primary Sjögren’s syndrome. Fatigue was measured with the fatigue visual analog scale. Results: A total of 828 proteins were identified and the 15 top discriminatory proteins between patients with high and low fatigue were selected. Among these were apolipoprotein A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein 1, and complement factor B. Conclusion: Most of the discriminatory proteins have important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system. These proteins and their interacting protein networks may therefore have central roles in the generation and regulation of fatigue, and the findings contribute with evidence to the concept of fatigue as a biological phenomenon signaled through specific molecular pathways

Fatigue in primary Sjögren’s syndrome: A proteomic pilot study of cerebrospinal fluid

Objectives: Fatigue is a frequent and often disabling phenomenon that occurs in patients with chronic inflammatory and immunological diseases, and the underlying biological mechanisms are largely unknown. Because fatigue is generated in the brain, we aimed to investigate cerebrospinal fluid and search for molecules that participate in the pathophysiology of fatigue processes. Methods: A label-free shotgun proteomics approach was applied to analyze the cerebrospinal fluid proteome of 20 patients with primary Sjögren’s syndrome. Fatigue was measured with the fatigue visual analog scale. Results: A total of 828 proteins were identified and the 15 top discriminatory proteins between patients with high and low fatigue were selected. Among these were apolipoprotein A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein 1, and complement factor B. Conclusion: Most of the discriminatory proteins have important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system. These proteins and their interacting protein networks may therefore have central roles in the generation and regulation of fatigue, and the findings contribute with evidence to the concept of fatigue as a biological phenomenon signaled through specific molecular pathways

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