Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis

Key messages Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients

HIV Replication Enhances Production of Free Fatty Acids, Low Density Lipoproteins and Many Key Proteins Involved in Lipid Metabolism: A Proteomics Study

BACKGROUND: HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood. RESULTS: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism. CONCLUSIONS: We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways

Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters

Background: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. Methods: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m3 particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4–6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. Results: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P &lt; 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P &gt; 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P &lt; 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P &gt; 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P &gt; 0.05 for all). Conclusions: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.Originally included in thesis in manuscript form.</p

The positive effect of posterolateral lumbar spinal fusion is preserved at long-term follow-up: a RCT with 11–13 year follow-up

Introduction Few studies have investigated the long-term effect of posterolateral lumbar spinal fusion on functional outcome. Aim To investigate the long-term result after posterolateral lumbar spinal fusion with and without pedicle screw instrumentation. Methods Questionnaire survey of 129 patients originally randomised to posterolateral lumbar spinal fusion with or without pedicle screw instrumentation. Follow-up included Dallas Pain Questionnaire (DPQ), Oswestry Disability Index (ODI), SF-36 and a question regarding willingness to undergo the procedure again knowing the result as global outcome parameter. Results Follow-up was 83% of the original study population (107 patients). Average follow-up time was 12 years (range 11–13 years). DPQ-scores were significantly lower than preoperatively in both groups (P < 0.005) and no drift towards the preoperative level was seen. No difference between the two groups were observed (instrumented vs. non-instrumented): DPQ Daily Activity mean 37.0 versus 32.0, ODI mean 33.4 versus 30.6, SF-36 PCS mean 38.8 versus 39.8, SF-36 MCS mean 49.0 versus 53.3. About 71% in both groups were answered positively to the global outcome question. Patients who had retired due to low back pain had poorer outcome than patients retired for other reasons, best outcome was seen in patients still at work (P = 0.01 or less in all questionnaires, except SF-36 MCS P = 0.08). Discussion Improvement in functional outcome is preserved for 10 or more years after posterolateral lumbar spinal fusion. No difference between instrumented fusion and non-instrumented fusion was observed. Patients who have to retired due to low back pain have the smallest improvement

Uninstrumented posterolateral spinal arthrodesis: is it the gold standard technique for I° and II° grade spondylolisthesis in adolescence?

We retrospectively reviewed the outcome of uninstrumented posterolateral spinal arthrodesis in 49 patients with lumbar isthmic spondylolisthesis grades I° and II° in adolescent patients in the time of surgery, who participate at follow-up, between 1980 and 1995. The goal of our study is to analyse the clinical and radiographic imaging at long follow-up in uninstrumented posterolateral arthrodesis and to evaluate the efficiency and the validity of surgical technique in young patients (<18 years). All patients had failed previous conservative treatment. The average age at follow-up was 33.5 years (range 25–42 years) and the average follow-up time was 19.7 years (range 12–27 years). The clinical outcome measures were the Oswestry Disability Index, the SF-36, and the visual analogic score. All measures assessed the endpoint outcomes at 20 years after surgery. The outcome of spinal fusion was good with 43 (87.7%) patients attaining solid fusion, pseudoarthrosis in 6 patients (12.3%). None of our patients complained of excessive postoperative wound pain. Additionally, no complications, such as wound infection, were encountered. Satisfactory results were obtained in 94% of patients and this was closely associated with the rate of successful fusion. The results suggest that clinical outcome is closely related to the attainment of solid fusion