Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial.

OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

Oral Resveratrol supplementation attenuates exercise-induced Interleukin-6 but not Oxidative Stress after a high intensity cycling challenge in adults.

Previous studies demonstrated that resveratrol (RES) is able to enhance antioxidant, anti-inflammatory and insulin actions in humans. It is unclear whether RES can be used as ergogenic aids to enhance high-intensity cycling exercise performance and attenuate the high-intensity exercise-induced oxidative stress and inflammation. This study investigated the effect of RES supplementation on oxidative stress, inflammation, exercise-induced fatigue, and endurance performance. Eight male athletes participated in this single-blind crossover designed study and randomly instructed to receive four days of either oral RES (480 mg per day, totally 1920mg) or placebo supplementation. The cycling exercise challenge at 80% maximal oxygen consumption with 60 rpm was performed following 4 days of either RES or placebo supplementation. The total cycling performance time was recorded. In addition, blood samples were obtained to analyze the changes in blood glucose, plasma non-esterified fatty acid, serum lactate dehydrogenase, creatine kinase, uric acid, total antioxidant capacity, malondialdehyde, tumor necrosis factor-α, and interleukin-6. The exhausting time of cycling exercise challenge was not significantly increased in RES compared to that in placebo. However, IL-6 response was significantly decreased during exercise challenge in RES trial, and there were no differences in blood biomarkers, fatigue factors, and antioxidative response. Oral RES supplementation can attenuate exercise-induced IL-6 response but not fatigue and oxidative stress, inflammation response. However, we infer that 4-day oral RES supplementation has no ergogenic property on enhancing the high-intensity cycling exercise performance.

The biological basis of chronic fatigue: neuroinflammation and innate immunity.

PURPOSE OF REVIEW: Chronic fatigue is common in cancer, neurodegenerative, and chronic inflammatory diseases and is regarded by many patients as their absolutely worst problem. Lately, fatigue is increasingly understood to have a genetic and molecular basis. RECENT FINDINGS: Biologically, fatigue occurs as part of the sickness behavior response, a complex and automated behavior triggered by the activation of innate immunity and neuroinflammation. IL-1ß causes neuronal activation in the brain and subsequent fatigue. In addition to proinflammatory molecules, potential partners in the complex brain signaling of fatigue include downregulatory mechanisms for inflammation and cellular stress responses and the neuropeptide hypocretin-1. These mechanisms all become constantly activated in chronic conditions. Genetic studies indicate that fatigue may have evolved to enhance survival during infection and injury. SUMMARY: Fatigue is a major clinical problem. Finding the right treatment is challenging, as no specific options exist and only a few of the mechanisms contributing to fatigue are known. Because fatigue is generated in the brain, further studies should focus on proteomics and specific candidate proteins in cerebrospinal fluid. Studies on genetic variants, gene activation, and epigenetics are also required.

Fatigue and sleepiness responses to experimental inflammation and exploratory analysis of the effect of baseline inflammation in healthy humans.

Inflammation is believed to be a central mechanism in the pathophysiology of fatigue. While it is likely that dynamic of the fatigue response after an immune challenge relates to the corresponding cytokine release, this lacks evidence. Although both fatigue and sleepiness are strong signals to rest, they constitute distinct symptoms which are not necessarily associated, and sleepiness in relation to inflammation has been rarely investigated. Here, we have assessed the effect of an experimental immune challenge (administration of lipopolysaccharide, LPS) on the development of both fatigue and sleepiness, and the associations between increases in cytokine concentrations, fatigue and sleepiness, in healthy volunteers. In addition, because chronic-low grade inflammation may represent a risk factor for fatigue, we tested whether higher baseline levels of inflammation result in a more pronounced development of cytokine-induced fatigue and sleepiness. Data from four experimental studies was combined, giving a total of 120 subjects (LPS N = 79, 18 (23%) women; Placebo N = 69, 12 (17%) women). Administration of LPS resulted in a stronger increase in fatigue and sleepiness compared to the placebo condition, and the development of both fatigue and sleepiness closely paralleled the cytokine responses. Individuals with stronger increases in cytokine concentrations after LPS administration also suffered more from fatigue and sleepiness (N = 75), independent of gender. However, there was no support for the hypothesis that higher baseline inflammatory markers moderated the responses in fatigue or sleepiness after an inflammatory challenge. The results demonstrate a tight connection between the acute inflammatory response and development of both fatigue and sleepiness, and motivates further investigation of the involvement of inflammation in the pathophysiology of central fatigue.

Quality of Life Differences for Primary Immunodeficiency Patients on Home SCIG versus IVIG.

BACKGROUND: Patients with primary immunodeficiency disease (PIDD) and antibody deficiency require lifelong immunoglobulin replacement therapy. While both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) replacement therapy are effective in preventing infection, patients with PIDD still experience worse health-related quality of life (hrQOL) outcomes. OBJECTIVE: Assess differences in hrQOL for PIDD patients receiving home SCIG versus IVIG. METHODS: SF-36 surveys were administered by a specialty pharmacy to 630 PIDD patients receiving home SCIG and IVIG at baseline and then every 3 months between 2014 and 2016. Results were analyzed using two-sample t tests and linear mixed effects model. Analysis was repeated for different age categories and trended over time. RESULTS: Patients receiving SCIG reported statistically significant higher energy fatigue scores (+ 9 points, p < 0.001) but lower perceived role limitations due to physical health scores (- 14 points, p < 0.001). These differences were only observed in patients > 36 years of age. There were no differences in the composite SF-36 score for patients receiving SCIG versus IVIG (+ 1, p = 0.66). Immunoglobulin-naïve patients all improved their hrQOL, but a larger improvement was seen in those initiating SCIG versus IVIG. CONCLUSION: Patients with PIDD on home IVIG versus SCIG have similar composite hrQOL scores as measured by the SF-36. In the adult population, initiating immunoglobulin replacement with SCIG may result in more hrQOL improvement compared with IVIG, although personal preferences should also be considered. CLINICAL IMPLICATIONS: Patients with PIDD on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Patients with primary immune-deficiency on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Personal preferences are important in deciding whether to treat with IVIG or SCIG.

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

OBJECTIVES: We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy. RESULTS: We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies-independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies. CONCLUSION: The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.

Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity.

OBJECTIVES: To evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjögren's syndrome (pSS) in a double-blind, placebo-controlled, phase II, single-centre study. METHODS: Patients with pSS, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity. RESULTS: A similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration. CONCLUSIONS: Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.

Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms.

Today, inflammatory rheumatic disorders are effectively treated, but many patients still suffer from residual fatigue. This work presents pathophysiological mechanisms of fatigue. First, cytokines can interfere with neurotransmitter release at the preterminal ending. Second, a long-term increase in serum concentrations of proinflammatory cytokines increase the uptake and breakdown of monoamines (serotonin, noradrenaline and dopamine). Third, chronic inflammation can also decrease monoaminergic neurotransmission via oxidative stress (oxidation of tetrahydrobiopterin [BH4]). Fourth, proinflammatory cytokines increase the level of enzyme indoleamine-2, 3-dioxygenase activity and shunt tryptophan away from the serotonin pathway. Fifth, oxidative stress stimulates astrocytes to inhibit excitatory amino acid transporters. Sixth, astrocytes produce kynurenic acid that acts as an antagonist on the α7-nicotinic acetylcholine receptor to inhibit dopamine release. Jointly, these actions result in increased glutamatergic and decreased monoaminergic neurotransmission. The above-described pathophysiological mechanisms negatively affect brain functioning in areas that are involved in fatigue.

Fatigue in systemic lupus erythematosus and other autoimmune skin diseases.

BACKGROUND: Fatigue is a well-established symptom in systemic lupus erythematosus (SLE), but has not been well characterized in other skin-limited autoimmune diseases such as cutaneous lupus erythematosus (CLE), amyopathic dermatomyositis (ADM) or autoimmune blistering diseases (AIBD). OBJECTIVES: In this retrospective study, we compared fatigue in controls (n = 84) with that in patients enrolled in prospective longitudinal databases with SLE (n = 165), CLE (n = 226), ADM (n = 136) and AIBD (n = 79). METHODS: We used the 36-Item Short Form Survey (SF-36) vitality scale to analyse median scores and the percentages of patients with clinically significant fatigue (defined as a score ≤ 35) between experimental groups and controls. RESULTS: Median and interquartile range (IQR) vitality scores demonstrated greater fatigue in the experimental groups (SLE 35, IQR 20-55; CLE 50, IQR 30-70; ADM 50, IQR 30-65; AIBD 55, IQR 35-70) than in controls (73, IQR 65-85) (P < 0·05 for each experimental group vs. control). The SLE group had worse fatigue than all of the other groups (P < 0·05 SLE vs. each group), but there was no difference between the CLE, ADM or AIBD groups (all P > 0·05). In addition, the experimental groups had more clinically significant fatigue (score ≤ 35) (SLE 44·2%, CLE 25·2%, ADM 31·6%, AIBD 24·1%) than controls (2%) (P < 0·01 for each experimental group vs. control). The SLE group had more clinically significant fatigue than the CLE group (P < 0·01); however, there was no difference in clinically significant fatigue between SLE and either ADM (P = 0·17) or AIBD (P = 0·055). CONCLUSIONS: These findings demonstrate that patients with skin-limited autoimmune disease experience more fatigue than controls. Fatigue is an important symptom that negatively affects quality of life for patients. It should be addressed by clinicians and measured in future clinical trials.

Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab.

Interleukin 6 (IL-6) is a pleiotropic cytokine that plays a role in the neuroendocrine system, insulin resistance, lipid metabolism, vascular disease, mitochondrial activities, neuropsychological behaviour, and also mediates communications between the immune and central nervous system (CNS). Treatment with anti-IL-6 or anti-IL-6R agents seems to alleviate allodynia and hyperalgesia, so it may be a valid option when treating the many conditions involving pathological pain as rheumatoid arthritis.

The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjögren's Syndrome.

OBJECTIVES: Primary Sjögren's syndrome (pSS) sufferers have rated chronic fatigue as the most important symptom needing improvement. Emerging data suggest that stimulation of the vagus nerve can modulate immunological responses. The gammaCore device (electroCore), developed to stimulate the cervical vagus nerve noninvasively, was used to assess the effects of vagus nerve activation on immune responses and clinical symptoms of pSS. MATERIALS AND METHODS: Fifteen female pSS subjects used the nVNS device twice daily a 26-day period. At baseline, blood was drawn before and after application of the gammaCore device for 90 sec over each carotid artery. The following fatigue-related outcome measures were collected at baseline, day 7 and day 28: EULAR patient reported outcome index, profile of fatigue (Pro-F), visual analogue scale of abnormal fatigue, and Epworth sleepiness scale (ESS). Whole blood samples were stimulated with 2 ng/mL lipopolysaccharide (LPS) and the supernatant levels of IFNγ, IL12-p70, TNFα, MIP-1α, IFNα, IL-10, IL-1ß, IL-6, and IP-10 were measured at 24 hours. In addition, clinical hematology and flow cytometric profiles of whole blood immune cells were analyzed. RESULTS: Pro-F and ESS scores were significantly reduced across all three visits. LPS-stimulated production of IL-6, IL-1ß, IP-10, MIP-1α, and TNFα were significantly reduced over the study period. Patterns of NK- and T-cell subsets also altered significantly over the study period. Interestingly, lymphocyte counts at baseline visit correlated to the reduction in fatigue score. CONCLUSION: The vagus nerve may play a role in the regulation of fatigue and immune responses in pSS and nVNS may reduce clinical symptoms of fatigue and sleepiness. However, a sham-controlled follow-up study with a larger sample size is required to confirm the findings.

Clinical efficacy of tacrolimus for treating myasthenia gravis and its influence on lymphocyte subsets.

BACKGROUND: This study aimed to determine the clinical efficacy and effects of tacrolimus in treating myasthenia gravis (MG). METHODS: A total of 45 outpatients and inpatients were divided into a tacrolimus group (n=15) and non-tacrolimus group (n=30): those in the former group were treated with 3mg/day of tacrolimus for 24 weeks, while those in the latter (control) group took other immunosuppressants (prednisone, azathioprine combined with prednisone). Each group was evaluated at weeks 4, 8, 12, 16, 20 and 24 by Myasthenia Gravis Foundation of America Quantitative Myasthenia Gravis (MGFA-QMG) Test, activities of daily living (ADL) profiles, and manual muscle (MMT) and fatigue tests. Dynamic changes in CD4+CD25+high cells were tested by flow cytometry. Inflammatory cytokines were also evaluated in the tacrolimus group. RESULTS: Efficacy index scores decreased significantly compared with baseline at every test week in both groups (P<0.01), although improvements were more evident with than without tacrolimus treatment (F=9.312, P<0.01 vs. F=24.551, P<0.01 and F=10.710, P<0.01). At week 24, peripheral blood CD4+CD25+high T cells with tacrolimus decreased significantly (P<0.01), but increased significantly without tacrolimus (P<0.01). During treatment, CD19+BAFF-R B cells in peripheral blood decreased in both groups (P<0.05). Interferon (IFN)-γ concentrations in peripheral blood also diminished significantly with tacrolimus (P<0.01). CONCLUSION: A relatively low dose of tacrolimus can affect multiple immune-system targets and, thus, can treat MG effectively in terms of both clinical symptoms and immunological responses.

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials.

BACKGROUND: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment-related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune-related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion-related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. RESULTS: Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%). CONCLUSIONS: Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010-7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Genomic mechanisms of fatigue in survivors of colorectal cancer.

BACKGROUND: Many cancer survivors experience fatigue as a nagging symptom lasting years after treatment. To learn of the relevant biological pathways involved in fatigue among cancer survivors, the authors tested for an association between fatigue levels and leukocyte gene expression profiles and determined the specific mediating immune cell types. METHODS: A sample of 89 Hispanic/Latino adults aged 60.5 years, 62% of whom were male, who were diagnosed with colorectal cancer and were 2.9 years since diagnosis provided blood for transcriptome profiling and completed a validated measure of fatigue (Multidimensional Fatigue Symptom Inventory-Short Form). The authors applied genome-wide transcriptional profiling of leukocyte RNA to identify gene expression activity associated with fatigue, tested for the activity of specific transcription factors involved in previously established markers of inflammation and immunologic activation, and identified the specific cell types mediating these transcriptional alterations. RESULTS: In analyses adjusting for demographic and behavioral health risk factors, results linked fatigue with increased activation of B lymphocytes and CD8-positive T cells, as well as several transcription factors involved in immune activation (nuclear factor κB [NF-κB], signal transducer and activator of transcription [STAT], and cAMP responsive element-binding protein [CREB]). Results also replicated several specific genomic effects previously observed in fatigued cancer survivors, including upregulated expression of α-synuclein (SNCA) and hemoglobin subunits (HBA and HBB). CONCLUSIONS: Cancer survivors' heightened fatigue levels may be partially explained by activation of specific immune cell subsets, thereby providing a potential molecular biomarker for clinical interventions targeting the remediation of fatigue. Cancer 2018;124:2637-44. © 2018 American Cancer Society.

Assessment of physical fatigability and fatigue perception in myasthenia gravis.

INTRODUCTION: Fatigue includes both performance fatigability and fatigue perception. METHODS: In 32 stable patients with generalized myasthenia gravis (MG) and 17 controls, time-dependent physical performance was assessed by the arm movement test (AMT) and 6-minute walk test (6MWT). MG patients presented with low quantitative MG scores (mean 0.5, SD 0.5) and without pathologic decrement. Fatigability was based on calculation of linear trend (LT) reflecting dynamic performance within subsequent constant time intervals. Perception of physical fatigue was analyzed using fatigue questionnaires. RESULTS: MG patients showed a negative LT in both AMT and 6MWT, significantly differing from stable performance in controls. LT inversely correlated with elevation of acetylcholine receptor antibodies (r = -0.59, P < 0.005) but not with quantitative MG score and fatigue perception. CONCLUSIONS: LT allows quantification of fatigability as an objective measurement of decline in individual performance, even in patients without obvious neuromuscular deficits in routine testing. The missing correlation of experienced fatigue supports the multidimensional fatigue model. Muscle Nerve 55: 657-663, 2017.

Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy.

Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre- and post-radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre- and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre- to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted.

Cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus.

Cat scratch disease is an infectious disorder transmitted by cats that typically affects children and young adults. Immunosuppression is a well-known risk factor for the development of severe and atypical forms of the disease; hence it is under-diagnosed in patients with compromised immunity. We are reporting the first case of cat scratch disease, which presented as fever and fatigue, in a patient with systemic lupus erythematosus while receiving immunosuppressant therapy after a kidney transplant.

Effects of treatment with etanercept versus methotrexate on sleep quality, fatigue and selected immune parameters in patients with active rheumatoid arthritis.

OBJECTIVES: To compare sleep quality, disease activity and patient-reported outcomes such as fatigue and immune parameters in patients with rheumatoid arthritis treated with etanercept (ETA) or methotrexate (MTX). METHODS: Of 36 patients (28-joint Disease Activity Score, DAS28CRP≥3.2) in this 16-week (w), open, prospective study, 19 (11 women) received MTX 12.5-17 mg/w, and 17 (14 women) received ETA 25 mg x 2/w, alone or in combination with MTX. Clinical (DAS28CRP, visual analogue scale), laboratory (C-reactive protein [CRP]), sleep (polysomnography), functional (Multidimensional Fatigue Inventory; Health Assessment Questionnaire-Disability Index (HAQ-DI); 36-item Short-Form Health Survey (SF-36), immunological (humoral/cellular) and neuroendocrine (hormonal) parameters were recorded at baseline (BL), w8 and w16. RESULTS: BL characteristics did not differ significantly between the ETA and MTX groups except disease duration: mean age (years): 48.6±8.8 vs. 49.4±16.6; mean disease duration (months): 19.6±46.3 vs. 81.2±79.2; and DAS28CRP: 4.4±0.9 vs. 4.4±1.7, respectively. DAS28CRP, SF-36, and HAQ-DI improved significantly in both groups from BL to w16 (p≤0.05). The DAS28CRP improvements at w16 (mean changes -1.8 in the ETA group, and -1.4 in MTX group), were not statistically significant from each other. The absolute values of sleep efficiency, total sleep time, and stage 2 sleep duration increased significantly in the ETA group, but no significant changes were reported in the MTX group. CONCLUSIONS: Both therapies improved disease activity, CRP, SF-36 and HAQ-DI, with faster, more pronounced changes in DAS28CRP in the ETA group, which alone had significantly improved sleep parameters.

Effect of Pet Insects on the Psychological Health of Community-Dwelling Elderly People: A Single-Blinded, Randomized, Controlled Trial.

BACKGROUND: There is evidence that animal-assisted therapy has positive effects on mental health, especially in elderly people. Caring for insects is easy, relatively inexpensive, and does not require much space. OBJECTIVE: The aim of this 8-week randomized, controlled, single-blinded study was to investigate the effect of pet insects on the psychological health of community-dwelling elderly people. METHODS: Elderly subjects (≥65 years old) attending a community center in Daegu, Korea, were enrolled in the study between April and May 2014 and randomized at a 1:1 ratio to receive insect therapy and health advice or only health advice. The insect group received 5 crickets in a cage with sufficient fodder and a detailed instruction manual. At baseline and at 8 weeks, all subjects underwent psychometric tests via a direct interview [Beck Anxiety Inventory, Geriatric Depression Scale (GDS-15), Mini-Mental State Examination (MMSE), 36-Item Short Form Health Survey, Insomnia Severity Index, Fatigue Severity Scale, and Brief Encounter Psychosocial Instrument] and laboratory analyses of inflammatory and oxidative stress markers (erythrocyte sedimentation rate, high-sensitivity C-reactive protein, biological antioxidant potential, and derivatives of reactive oxygen metabolites). RESULTS: The insect-caring (n = 46) and control (n = 48) groups did not differ in baseline characteristics. The insect-caring group had significantly lower GDS-15 scores at week 8 (3.20 vs. 4.90, p = 0.004) and, after adjustment for baseline values, a significantly greater change in GDS-15 scores relative to baseline (-1.12 vs. 0.20, p = 0.011). They also had a significantly greater change in MMSE scores relative to baseline (1.13 vs. 0.31, p = 0.045). The two groups did not differ in terms of other psychometric and laboratory tests. No serious risks or adverse events were reported. CONCLUSION: Caring for insects, which is cost-effective and safe, was associated with a small to medium positive effect on depression and cognitive function in community-dwelling elderly people.