Systemic Activation of the Kynurenine Pathway in Graves Disease With and Without Ophthalmopathy

Context Graves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients. Objective This work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)–mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED). Methods We analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function. Results GD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED. Conclusion This study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically.publishedVersio

Outcomes of Patients With Graves Disease 25 Years After Initiating Antithyroid Drug Therapy

Context Graves disease (GD) is a leading cause of hyperthyroidism. Detailed investigations and predictors of long-term outcomes are missing. Objective This work aimed to investigate the outcomes in GD 25 years after initiating antithyroid drug treatment, including disease course, clinical and biochemical predictors of relapse, and quality of life. Methods A retrospective follow-up was conducted of GD patients that participated in a randomized trial from 1997 to 2001. Demographic and clinical data were obtained from medical records and questionnaires. Biobank samples were analyzed for inflammatory biomarkers and compared with age- and sex-matched healthy individuals. Results We included 83% (182/218) of the patients from the original study. At the end of follow-up, normal thyroid function was achieved in 34%. The remaining had either active disease (1%), spontaneous hypothyroidism (13%), or had undergone ablative treatment with radioiodine (40%) or thyroidectomy (13%). Age younger than or equal to 40 years, thyroid eye disease (TED), smoking, and elevated levels of interleukin 6 and tumor necrosis factor receptor superfamily member 9 (TNFRS9) increased the risk of relapsing disease (odds ratio 3.22; 2.26; 2.21; 1.99; 2.36). At the end of treatment, CD40 was lower in patients who maintained normal thyroid function (P = .04). At the end of follow-up, 47% had one or more autoimmune diseases, including vitamin B12 deficiency (26%) and rheumatoid arthritis (5%). GD patients who developed hypothyroidism had reduced quality of life. Conclusion Careful lifelong monitoring is indicated to detect recurrence, hypothyroidism, and other autoimmune diseases. Long-term ATD treatment emerges as a beneficial first-line treatment option, especially in patients with young age at onset or presence of TED.publishedVersio

Job Satisfaction and Burnout among Intensive Care Unit Nurses and Physicians

Introduction. Nurses and physicians working in the intensive care unit (ICU) may be exposed to considerable job stress. The study aim was to assess the level of and the relationship between (1) job satisfaction, (2) job stress, and (3) burnout symptoms. Methods. A cross-sectional study was performed at ICUs at Oslo University Hospital. 145 of 196 (74%) staff members (16 physicians and 129 nurses) answered the questionnaire. The following tools were used: job satisfaction scale (scores 10–70), modified Cooper's job stress questionnaire (scores 1–5), and Maslach burnout inventory (scores 1–5); high score in the dimension emotional exhaustion (EE) indicates burnout. Personality was measured with the basic character inventory. Dimensions were neuroticism (vulnerability), extroversion (intensity), and control/compulsiveness with the range 0–9. Results. Mean job satisfaction among nurses was 43.9 (42.4–45.4) versus 51.1 (45.3–56.9) among physicians, P<0.05. The mean burnout value (EE) was 2.3 (95% CI 2.2–2.4), and mean job stress was 2.6 (2.5–2.7), not significantly different between nurses and physicians. Females scored higher than males on vulnerability, 3.3 (2.9–3.7) versus 2.0 (1.1–2.9) (P<0.05), and experienced staff were less vulnerable, 2.7 (2.2–3.2), than inexperienced staff, 3.6 (3.0–4.2) (P<0.05). Burnout (EE) correlated with job satisfaction (r=-0.4, P<0.001), job stress (r=0.6, P<0.001), and vulnerability (r=0.3, P=0.003). Conclusions. The nurses were significantly less satisfied with their jobs compared to the physicians. Burnout mean scores are relatively low, but high burnout scores are correlated with vulnerable personality, low job satisfaction, and high degree of job stress

Mortality among head trauma patients taking preinjury antithrombotic agents: a retrospective cohort analysis from a Level 1 trauma centre

Background Bleeding represents the most well-known and the most feared complications caused by the use of antithrombotic agents. There is, however, limited documentation whether pre-injury use of antithrombotic agents affects outcome after head trauma. The aim of this study was to define the relationship between the use of preinjury antithrombotic agents and mortality among elderly people sustaining blunt head trauma. Methods A retrospective cohort analysis was performed on the hospital based trauma registry at Oslo University Hospital. Patients aged 55 years or older sustaining blunt head trauma between 2004 and 2006 were included. Multivariable logistic regression analyses were used to identify independent predictors of 30-day mortality. Separate analyses were performed for warfarin use and platelet inhibitor use. Results Of the 418 patients admitted with a diagnosis of head trauma, 137 (32.8 %) used pre-injury antithrombotic agents (53 warfarin, 80 platelet inhibitors, and 4 both). Seventy patients died (16.7 %); 15 (28.3 %) of the warfarin users, 12 (15.0 %) of the platelet inhibitor users, and two (50 %) with combined use of warfarin and platelet inhibitors, compared to 41 (14.6 %) of the non-users. There was a significant interaction effect between warfarin use and the Triage Revised Trauma Score collected upon the patients’ arrival at the hospital. After adjusting for potential confounders, warfarin use was associated with increased 30-day mortality among patients with normal physiology (adjusted OR 8,3; 95 % CI, 2.0 to 34.8) on admission, but not among patients with physiological derangement on admission. Use of platelet inhibitors was not associated with increased mortality. Conclusions The use of warfarin before trauma was associated with increased 30-day mortality among a subset of patients. Use of platelet inhibitors before trauma was not associated with increased mortality. These results indicate that patients on preinjury warfarin may need closer monitoring and follow up after trauma despite normal physiology on admission to the emergency department

Novel inflammatory biomarkers in thyroid eye disease

Purpose: The aim of this study is to identify biochemical inflammatory markers predicting the presence or risk of developing thyroid eye disease (TED) in patients with Graves' disease (GD). Methods: Patients with GD (n = 100, 77 females) were included from the National Norwegian Registry of Organ-Specific Diseases. Serum samples were analysed for 92 different inflammatory biomarkers using the proximity extension assay. Biomarker levels were compared between groups of patients with and without TED and healthy subjects (HS) (n = 120). Results: TED was found in 36 of 100 GD patients. Significant (P < 0.05) differences in the levels of 52 inflammatory biomarkers were found when GD patients and HS were compared (42 elevated and 10 decreased). Out of the 42 elevated biomarkers, a significantly higher serum level of interleukin-6 (IL6) (P = 0.022) and macrophage colony-stimulating factor (CSF1) (P = 0.015) were found in patients with TED compared to patients without TED. Patients with severe TED also had significantly elevated levels of Fms-related tyrosine kinase 3 ligand (FLT3LG) (P = 0.009). Furthermore, fibroblast growth factor 21 (FGF21) was significantly increased (P = 0.008) in patients with GD who had no signs of TED at baseline but developed TED later. Conclusion: We demonstrate an immunologic fingerprint of GD, as serum levels of several inflammation-related proteins were elevated, while others were decreased. Distinctly increased levels of IL6, CSF1, FLT3LG, and FGF21 were observed in TED, suggesting that these inflammatory proteins could be important in the pathogenesis, and therefore potential new biomarkers for clinical use.publishedVersio

Prevalence, Risk Factors, and Clinical and Biochemical Characteristics of Alemtuzumab-Induced Graves Disease

Objective Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD. Methods Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED). Results We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without. Conclusion GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.publishedVersio