Abstract Extraintestinal manifestations occur rather frequently in inflammatory bowel disease (IBD), e.g. ulcerative colitis (UC) and Crohn's disease (CD). The present paper provides an overview of ...the epidemiology, clinical characteristics, diagnostic process, and management of rheumatic, metabolic, dermatologic (mucocutaneous), ophthalmologic, hepatobiliary, hematologic, thromboembolic, urinary tract, pulmonary, and pancreatic extraintestinal manifestations related to IBD. Articles were identified through search of the PubMed and Embase databases, the Cochrane Library, and the web sites of the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) (cut-off date October 2009). The search terms 'Crohn's disease', 'inflammatory bowel disease', or 'ulcerative colitis' were combined with the terms 'adalimumab', 'anemia', 'arthritis', 'bronchiectasis', 'bronchitis', 'cutaneous manifestations', 'erythema nodosum', 'extraintestinal manifestations', 'hyperhomocysteinemia', 'infliximab', 'iridocyclitis', 'lung disease', 'ocular manifestations', 'osteomalacia', 'pancreatitis', 'primary sclerosing cholangitis', 'renal stones', 'sulfasalazine', 'thromboembolism', and 'treatment'. The search was performed on English-language reviews, practical guidelines, letters, and editorials. Articles were selected based on their relevance, and additional papers were retrieved from their reference lists. Since some of the diseases discussed are uncommon, valid evidence of treatment was difficult to obtain, and epidemiologic data on the rarer forms of extraintestinal manifestations are scarce. However, updates on the pathophysiology and treatment regimens are given for each of these disorders. This paper offers a current review of original research papers and randomized clinical trials, if any, within the field and makes an attempt to point out practical guidelines for the diagnosis and treatment of various extraintestinal manifestations related to IBD.
Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. MDD has been identified by the World Health ...Organization as a leading cause of disability worldwide.
Approximately 30% of patients are poor responsive to standard of care (SOC) treatment and novel therapeutic approaches are warranted.
Since chronic inflammation, as it is often observed in certain cancers, type 2 diabetes, psoriasis and chronic arthritis, are accompanied by depression, it has been suggested that immunoinflammatory processes may be involved in the pathogenesis of MDD.
Cytokines are a group of glycoproteins secreted from lymphoid and non-lymphoid cells that orchestrate immune responses. It has been suggested that a dysregulated production of cytokines may be implicated in the pathogenesis and maintenance of MDD. On the basis of their functions, cytokines can be subdivided in pro-inflammatory and anti-inflammatory cytokines. Since abnormal blood and cerebrospinal fluid of both pro and anti-inflammatory cytokines are altered in MDD, it has been suggested that abnormal cytokine homeostasis may be implicated in the pathogenesis of MDD and possibly to induction of therapeutic resistance.
We review current data that indicate that cytokines may represent a useful tool to identify MDD patients that may benefit from tailored immunotherapeutic approaches and may represent a potential tailored therapeutic target.
•MDD is a leading cause of disability worldwide.•Chronic immunoinflammation may be involved in the pathogenesis of MDD.•Cytokines are a group of glycoproteins secreted from lymphoid and non-lymphoid cells.•A dysregulated production of cytokines may play a role in MDD.•Cytokines may represent a useful diagnostic tool and therapeutic target in MDD.
Patients undergoing long-term highly active antiretroviral therapy treatment are probably at a higher risk of various HIV-related complications. Hyperactivation of The mammalian target of rapamycin ...(mTOR) has been found to contribute to dysregulated apoptosis and autophagy which determine CD4
+-T-cell loss, impaired function of innate immunity and development of neurocognitive disorders. Dysregulated mTOR activation has also been shown to play a key part in the development of nephropathy and in the pathogenesis of HIV-associated malignancies. These studies strongly support a multifunctional key role for mTOR in the pathogenesis of HIV-related disorders and suggest that specific mTOR inhibitors could represent a novel approach for the prevention and treatment of these pathologies.
Abstract
Introduction.
Reasons for infliximab failure in Crohn's disease and ulcerative colitis are debated. Serum levels of infliximab and anti-infliximab antibodies have been associated with loss ...of response. We aimed at determining cut-off levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to infliximab maintenance therapy.
Methods.
Patients with inflammatory bowel disease (n = 106) were retrospectively classified as having maintained response or loss of response to infliximab maintenance therapy. Trough concentrations were measured by fluid-phase radioimmunoassays.
Results.
Infliximab levels were significantly lower, and anti-infliximab antibody levels significantly higher, in Crohn's disease patients with loss of response (median infliximab 0 μg/ml, median anti-infliximab antibodies 35 U/ml) compared to patients with maintained response (median infliximab 2.8 μg/ml, median anti-infliximab antibodies 0 U/ml; p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cut-off values: infliximab <0.5 μg/ml, which was associated with loss of response with sensitivity 86% 64-97 and specificity 85% 72-94; and anti-infliximab antibodies ≥10 U/ml yielding a sensitivity of 81% 61-93 and specificity 90% 79-96. Combined measurements of infliximab and anti-infliximab antibodies using these cut-off values had higher accuracy yielding a sensitivity of 81% 57-94 and specificity 94% 82-98. Similar pattern was observed in a smaller cohort of patients with ulcerative colitis.
Conclusions.
Combined measurements of infliximab and anti-infliximab antibodies using cut-off levels provided high accuracy for discriminating between clinical response types to infliximab maintenance therapy. Cut-off levels are considered a prerequisite to further investigations of clinical usefulness of measurements of infliximab and anti-infliximab antibodies in patients failing infliximab therapy.
To investigate if the combined assessment of anti-infliximab antibodies (Ab) and the degree of TNF-alpha binding capacity (TNF-alpha-BC) afforded by infliximab may predict the response to infliximab ...treatment in patients with Crohn's disease (CD).
Three groups of CD patients, in total 33 patients, treated with infliximab were retrospectively selected: (a) patients with a maintained response throughout treatment; (b) patients with good initial response, but subsequent loss of response; and (c) patients with inadequate response to the first two or three doses. Blood samples were analyzed for TNF-alpha-BC and Ab using fluid-phase radioimmunoassay (RIA).
At 8 wk after last infliximab infusion, TNF-alpha-BC was significantly higher (P = 0.002) in patients maintaining response (median interquartile range 2.9 0.9-4.3 microg/mL), as compared to patients losing response (0.0 0-0.1 microg/mL). Conversely, Ab levels were significantly lower (P < 0.0001) in patients maintaining response (1.3 0-6% bound tracer/total tracer), as compared to patients losing response (19 14-27%). Ab were not present and TNF-alpha-BC was high (30 20-32) in patients with no primary response.
While secondary loss of response to infliximab is associated with high levels of Ab and low levels of TNF-alpha-BC, primary response failure may be seen in the presence of high effective levels of TNF-alpha-BC afforded by infliximab. The results suggest that combined assessment of anti-infliximab Ab and serum TNF-alpha-BC may pave the way for a more rational use of infliximab in patients with CD.
Immunogenicity of biopharmaceuticals is complex and influenced by both structural and pharmacological factors, and by patient-related conditions such as disease being treated, previous and ...concomitant therapies, and individual immune responsiveness. Essential for tailored therapeutic strategies based on immunopharmacological evidence from individual patients (personalized medicine) is the use of assays for anti-drug antibodies (ADA) that are accurate and relevant in the clinical setting. This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor-necrosis factor-α (TNF). Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies. The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug immunogenicity but may also prevent development of safe and cost-effective ways of using biological TNF-antagonists.
With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to ...identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs).
Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs. Clinical and demographic data were recorded as well.
During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels. The levels of other tested cytokines (TNF-α, TNF-β, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits. Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up. Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found.
The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs. In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease. Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure.
Background
Even though bacteria trigger inflammation, most of the tissue destruction in periodontitis is due to the host inflammatory response. In addition to immunological events that drive ...development of early periodontitis, numerous environmental factors like genetics and smoking play a role. We investigated whether the carriage of selected single nucleotide polymorphisms (SNP) of toll‐like receptors (TLR), NOD‐like receptors (NLR) and RIG‐I‐like receptors (RLR) was associated with the diagnosis of early periodontitis in a case‐control study.
Methods
Adolescents with positive (n = 87) and negative (n = 73) diagnosis for periodontitis had blood samples taken. All participants were genotyped for 42 SNP in the genes encoding TLR1‐10, NOD1‐2, DDX58, and IFIH1 using multiplex assays. Associations between SNP and periodontitis diagnosis were tested.
Results
TLR1‐rs5743611 showed protective effect for periodontitis (CC versus GG and GC, P = 0.01, odds ratio OR 0.10, 95% confidence interval CI 0.01‒0.78). Carriage of the TLR4‐rs7873784 was associated with higher odds for periodontitis (GG versus CC and GC, P = 0.05, OR 2.30, 95% CI 1.00‒5.63; GG versus GC, P = 0.05, OR 2.46, 95% CI 1.01‒5.99). In male participants, reduced susceptibility to periodontitis was observed in carriers of TLR7‐rs3853839 (CC versus GG and CG, P = 0.02, OR 0.30, 95% CI 0.11‒0.85) and TLR8‐rs3764879 (CC versus GG and CG, P = 0.02, OR 0.31, 95% CI 0.12‒0.82). Associations were maintained after adjustments for sex, smoking habits, and mother´s education.
Conclusion
This study demonstrated an association between TLR1‐rs5743611, TLR4‐rs7873784, TLR7‐rs3853839, and TLR8‐rs3764879 and susceptibility to periodontitis in adolescents.
Circadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. ...We aimed to investigate circadian variations in the host response in a human endotoxaemia model.
A cross-over study, where 12 healthy young men received E. coli endotoxin (lipopolysaccharide, LPS) 0.3 ng/kg at 12 noon and, on another day, at 12 midnight. Blood samples were analysed for pro- and anti-inflammatory cytokines: tumour-necrosis factor (TNF)-alpha, soluble TNF receptors (sTNF-R)-1 and -2, interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, and IL-10 as well as YKL-40 and the oxidative stress markers malondialdehyde (MDA), ascorbic acid (AA) and dehydroascorbic acid (DHA) before and at 2, 4, 6 and 8 hours after LPS administration.
The levels of MDA and IL-10 where significantly higher during the day time (P<0.05) whereas levels of TNF-alpha, sTNF-RI, sTNF-RII, IL-1Ra, IL-6, and YKL-40 were higher (P<0.01 for all comparisons) during the night time. No significant differences were seen in the levels of AA and DHA.
A day-night difference in the acute phase response to endotoxaemia exists in healthy volunteers with a more pronounced inflammatory response during the night time. This circadian difference in the response to endotoxaemia may play an important role in the clinical setting and should be investigated further.
Cholesterol deposits and pro-inflammatory cytokines play an essential role in the pathogenesis of atherosclerosis, a predominant cause of cardiovascular disease (CVD). Epidemiological evidence has ...linked periodontal disease (PD) with atherosclerotic CVD. Accordingly, viable periodontal pathogens, including Porphyromonas gingivalis, have been found in atherosclerotic plaques in humans and mice. We aimed to determine whether cholesterol crystals (CHCs) and oral bacteria synergize in the stimulation of human monocytes. Incubation of human monocytes with CHCs induced secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and IL-8. Moreover, CHCs markedly enhanced secretion of IL-1β by monocytes stimulated with the toll-like receptor (TLR) 4 agonist Escherichia coli lipopolysaccharide (LPS), and the TLR2 agonist Staphylococcus aureus lipoteichoic acid. Notably, CHCs also enhanced IL-1β secretion induced by P. gingivalis LPS and IL-1β secretion induced by whole P. gingivalis bacteria. This enhancement was abrogated by the NLRP3 inflammasome inhibitors Z-YVAD-FMK and glibenclamide. CHCs had no effect on cytokine production induced by P. gingivalis gingipains. Taken together, our findings support that CHCs, via stimulation of NLRP3 inflammasomes, act in synergy with the periodontal pathogen P. gingivalis to promote monocyte secretion of pro-atherogenic cytokines.
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