Paradoxical Side Effect Related With Anti-Tumor Necrosis Factor Alpha Treatment.
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ABSTRACT:
SUBMITTER: Askın A
PROVIDER: S-EPMC5511539 | biostudies-other | 2017 Apr
REPOSITORIES: biostudies-other
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Project description:ImportanceTumor necrosis factor α (TNF) inhibitor-induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor-induced psoriasiform eruptions in children.Design, setting, and participantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor-treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor-induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and relevanceIn this case series, paradoxical TNF inhibitor-induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.
| S-EPMC10099183 | biostudies-literature
Project description:Background: The immunologic response to stress is regulated by the cytokines. Anti-Tumor Necrosis Factor-α agents are antibodies directed against a key cytokine in the process angiogenesis and collagen synthesis. It is not known whether they intervene with surgical stress response increasing the rate of postoperative complications.
Method: Un-blinded prospective, non-interventional cohort single centre study including all the patients with Crohn’s disease and Ulcerative Colitis undergoing abdominal surgery. Immunological and endocrinological parameters will measured in blood samples taken from these patients before and after surgery. Power calculations showed that 17 patients in each arm are needed.
| 2154083 | ecrin-mdr-crc
Project description:Myocardial fibrosis caused by maladaptive extracellular matrix (ECM) remodeling is implicated in the dysfunction of the failing heart. Matrix metalloproteinases (MMPs) regulate ECM remodeling, and are regulated by cytokines. Transgenic mice with cardiac-specific overexpression of tumor necrosis factor alpha (TNF-alpha) (TNF1.6) develop heart failure. We hypothesized that modulation of TNF-alpha and/or MMP activity might alter the myocardial ECM remodeling process and the development of heart failure. To test this hypothesis, we took advantage of the TNF1.6 mice and studied soluble and total collagens and collagen type profiling by using hydroxyproline quantification, Sircol collagen assay, Northern blot analysis, and immunohistochemistry and studied myocardial function by using echocardiography. Progressive ventricular hypertrophy and dilation in the TNF1.6 mice were accompanied by a significant increase in MMP-2 and MMP-9 activity, an increase in collagen synthesis, deposition, and denaturation, and a decrease in undenatured collagens. In young TNF1.6 mice, these changes in the ECM were associated with marked diastolic dysfunction as demonstrated by significantly reduced transmitral Doppler echocardiographic E/A wave ratio. Anti-TNF-alpha treatment with adenoviral vector expressing soluble TNF-alpha receptor type I attenuated both MMP-2 and MMP-9 activity, prevented further collagen synthesis, deposition and denaturation, and preserved myocardial diastolic function in young, but not old, TNF1.6 mice. The results suggest a critical role of TNF-alpha and MMPs in myocardial matrix remodeling and functional regulation and support the hypothesis that both TNF-alpha and MMPs may serve as potential therapeutic targets in the treatment of heart failure.
| S-EPMC18835 | biostudies-literature
Project description:Background and aimAnti-tumor necrosis factor-α (anti-TNF-α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNF-α treatment are needed.MethodsPublicly available transcriptomic data from inflammatory bowel disease patients receiving anti-TNF-α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti-TNF-α-treated animal model (with lipopolysaccharide-induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers.ResultsA total of 449 samples were retrieved from control, baseline, and after primary anti-TNF-α therapy or placebo. No statistically significant differences were observed between anti-TNF-α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B-cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide-induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti-TNF-α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8-87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001).ConclusionsHyperactive neutrophil chemotaxis influences responses to anti-TNF-α treatment, and IL13RA2 is a potential biomarker to predict anti-TNF-α treatment response.
| S-EPMC9303672 | biostudies-literature
Project description:Inflammation is potentially associated with poor antidepressant treatment outcomes. Pro-inflammatory cytokines are influenced by hazardous alcohol consumption. The aim of the present study was to investigate the effects of the serum tumor necrosis factor-α (sTNF-α) level on antidepressant treatment outcomes in terms of the 12-week and 12-month remission rates and 24-month relapse rate, and to investigate the potential modifying effects of alcohol consumption on these associations in patients with depressive disorders. At baseline, sTNF-α was measured and alcohol-related data from the Alcohol Use Disorders Identification Test (AUDIT) and consumption history were collected from 1094 patients. Patients received stepwise antidepressant treatment. Remission at 12 weeks and 12 months was defined as a Hamilton Depression Rating Scale (HAMD) score ≤ 7. Relapse (HAMD score ≥ 14) was identified until 24 months for those who had initially responded (HAMD score <14) at 12 weeks. Higher sTNF-α levels were found to have significant effects on the 12-week and 12-month non-remission and 24-month relapse rates. These effects were more prominent in those with low levels of alcohol consumption (AUDIT score ≤ 8 or no current alcohol consumption); the effects were not significant in those exhibiting hazardous alcohol consumption (AUDIT score > 8 or current drinking). Significant interactions were found for the 12-month non-remission and relapse rates, although the interaction was not statistically significant for 12-week remission. In conclusion, baseline sTNF-α levels may be a useful predictor for both short- and long-term antidepressant treatment outcomes, and the consideration of alcohol consumption status may increase predictability, in particular for long-term outcomes.
| S-EPMC8413287 | biostudies-literature
Project description:IntroductionA high body mass index is known to adversely affect antitumor necrosis factor-alpha trough levels and secondary loss of response (SLOR) in patients with Crohn's disease. We hypothesize that high levels of adiposity negatively affect these outcomes and aimed to determine if this relationship exists.MethodsWe performed a retrospective cross-sectional study of 69 patients with Crohn's disease from two tertiary inflammatory bowel disease centers between February 1, 2015, and June 30, 2018. Primary responders to infliximab (IFX) or adalimumab (ADA) who had a trough level performed within 6 months of CT or MRI scan and at least 12 months of clinical follow-up were eligible for inclusion. Body composition as measured on CT/MRI scans were correlated with trough concentration and time SLOR. Multivariate adjustments were made for established risk factors known to affect trough levels and SLOR.ResultsOf 69 included patients, 44 (63.8%) and 25 (36.2%) patients received IFX and ADA, respectively. Multivariate analysis revealed that IFX trough concentrations were inversely correlated with visceral fat area (-0.02 [-0.04, -0.003], P = 0.03), visceral fat index (-0.07 [-0.12, -0.01], P = 0.02) and visceral fat: skeletal muscle area ratio (-3.81 [-7.13, -0.50], P = 0.03), but not body mass index (-0.23 [-0.52, 0.06], P = 0.11). No predictive factors were found for ADA. Increased total adipose area was associated with an increased risk of SLOR in ADA-treated patients, but not IFX-treated patients (hazard ratio = 1.01 [1.002, 1.016], P = 0.011).DiscussionVisceral adiposity is an important predictor of IFX trough levels, and high total adiposity predicts for SLOR to ADA.
| S-EPMC7515616 | biostudies-literature
Project description:Tumor necrosis factor-alpha (TNF-α) plays an important pathogenic role in cardiac hypertrophy and heart failure (HF); however, anti-TNF is paradoxically negative in clinical trials and even worsens HF, indicating a possible protective role of TNF-α in HF. TNF-α exists in transmembrane (tmTNF-α) and soluble (sTNF-α) forms. Herein, we found that TNF receptor 1 (TNFR1) knockout (KO) or knockdown (KD) by short hairpin RNA or small interfering RNA (siRNA) significantly alleviated cardiac hypertrophy, heart dysfunction, fibrosis, and inflammation with increased tmTNF-α expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-α secretion in transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro, respectively, indicating the beneficial effects of TNFR2 associated with tmTNF-α. Suppressing TNF-α converting enzyme by TNF-α Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-α expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-α into cardiomyocytes in vitro significantly reduced ISO-induced cardiac hypertrophy and transcription of the pro-inflammatory cytokines and induced proliferation. The beneficial effects of tmTNF-α were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-α displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-κB pathway via TNFR2. Our data suggest that tmTNF-α exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-α processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.
| S-EPMC7714153 | biostudies-literature
Project description:PurposeMacrophages are believed to promote choroidal neovascularization (CNV) in neovascular age-related macular degeneration (nvAMD); however, the underlying proangiogenic mechanism is poorly understood. Therefore, we examined this mechanism in proinflammatory macrophages derived from patients with nvAMD.MethodsMonocytes were isolated from patients with nvAMD and polarized to form an M1 proangiogenic phenotype. We then screened for the role of proangiogenic cytokines expressed by these macrophages, including TNF-α, VEGF, IL-6, IL-8, and IL-1β, using an ex vivo choroid sprouting assay and an in vivo rodent model of laser-induced CNV (LI-CNV). We also examined the value of inhibiting TNF-α inhibition with respect to reducing the proangiogenic effects of M1 macrophages. Finally, we analyzed the macrophage cytokine expression database to evaluate the feasibility of modulating the expression of TNF-α.ResultsThe cytokines above are expressed at high levels in patient-derived M1 macrophages. However, among the cytokines tested only TNF-α significantly increased choroid sprouting. Moreover, adoptive intravitreal transfer of M1 macrophages significantly increased LI-CNV, and blocking TNF-α abolished the proangiogenic effects of M1 macrophages in both models. An analysis of cytokine expression revealed that >50% of TNF-α expression is determined by modifiable factors.ConclusionsBlocking TNF-α can reduce the proangiogenic effects of M1 macrophages in nvAMD. Thus, activated macrophages may represent a potential therapeutic target for altering TNF-α expression in nvAMD.
| S-EPMC8645186 | biostudies-literature
Project description:Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) are chronic immune-mediated rheumatic diseases that cause joint destruction and/or ankylosis, with resulting disability and diminished quality of life. Golimumab is the first human monoclonal antibody to tumor necrosis factor (TNF) administered monthly by subcutaneous injection. It is approved by the US Food and Drug Administration and by the European Medicines Agency for the treatment of RA, PsA, and AS. It is produced by a murine hybridoma cell line with innovative recombinant DNA technology, which minimizes immunogenicity of the antibody after injection. This paper reviews the main studies on the efficacy and safety of golimumab in these disease settings, illustrates the latest clinical updates, and analyzes the pharmacoeconomic aspects. Golimumab is effective in improving the physical function of patients in both the short and long term, and its safety profile is in keeping with that of other anti-TNF agents; the use of golimumab is cost-effective, simple, and convenient for the patient. Electronic supplementary material The online version of this article (doi:10.1007/s13554-013-0012-y) contains supplementary material, which is available to authorized users.
| S-EPMC4079096 | biostudies-literature
Project description:This study aims to investigate the prevalence of short-term and long-term adverse events associated with tumor necrosis factor-α (TNF-α) blocker treatment in Chinese Han patients suffering from ankylosing spondylitis (AS).The study included 402 Chinese Han AS patients treated with TNF-α blockers. Baseline data was collected. All patients were monitored for adverse events 2 hours following administration. Long-term treatment was evaluated at 8, 12, 52 and 104 weeks follow-up for 172 patients treated with TNF-α blockers.Short-term adverse events occurred in 20.15% (81/402), including rash (3.5%; 14/402), pruritus (1.2%; 5/402), nausea (2.2%; 9/402), headache (0.7%; 3/402), skin allergies (4.0%; 16/402), fever (0.5%; 2/402), palpitations (3.0%; 12/402), dyspnea (0.5%; 2/402), chest pain (0.2%; 1/402), [corrected] abdominal pain (1.0%; 4/402), hypertension (2.2%; 9/402), papilledema (0.5%; 2/402), laryngeal edema (0.2%; 1/402) and premature ventricular contraction (0.2%; 1/402). Long-term adverse events occurred in 59 (34.3%; 59/172) patients, including pneumonia (7.6%; 13/172), urinary tract infections (9.9%; 17/172), otitis media (4.7%; 8/172), tuberculosis are (3.5%; 6/172) [corrected], abscess (1.2%; 2/172), oral candidiasis (0.6%; 1/172), elevation of transaminase (1.7%; 3/172), anemia (1.2%; 2/172), hematuresis (0.6%; 1/172), constipation (2.3%; 4/172), weight loss (0.6%; 1/172), exfoliative dermatitis (0.6%; 1/172). CRP, ESR and disease duration were found to be associated with an increased risk of immediate and long-term adverse events (P<0.05). Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc (P<0.01).This study reports on the prevalence of adverse events in short-term and long-term treatment with TNF-α blocker monotherapy in Chinese Han AS patients. Duration of disease, erythrocyte sedimentation rate, and c-reactive protein serum levels were found to be associated with increased adverse events with anti-TNF-α therapy. Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc.
| S-EPMC4357466 | biostudies-other