Efficacy Of Tumor Necrosis Factor Research Articles

Efficacy of tumor necrosis factor inhibitors in hand osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

ObjectivesThis study aimed at systematically review the evidence for the efficacy of Tumor Necrosis Factor (TNF) inhibitors on symptoms and structural outcomes in hand osteoarthritis. MethodsThree databases were searched for randomized controlled trials examining the efficacy of TNF inhibitors in hand osteoarthritis. Two authors extracted data and assessed the risk of bias. The mean difference (MD) was calculated, and a random-effects meta-analysis was performed. ResultsFour studies were identified involving 276 participants. Meta-analysis showed that TNF inhibitors had no effect on pain at 4–6 weeks (MD -0.93, 95%CI -7.41 to 5.55; 2 studies) and 24–26 weeks (MD -3.82, 95%CI -11.46 to 3.83; 2 studies) and no effect on grip strength at 12 months (MD -0.35, 95%CI -1.08 to 0.37; 2 studies). There was limited evidence for the effect of TNF inhibitors on structural outcomes at 12 months. Subgroup analysis from 2 studies showed beneficial effect of TNF inhibitors on reducing the progression of structural outcomes in hand OA patients with signs of inflammation but not in those without inflammation. The certainty of the evidence was low for the effect of TNF inhibitor on pain and moderate for the effect on grip strength. ConclusionThis study found no effect of TNF inhibitors on clinical outcomes in hand osteoarthritis over the short term (<6 weeks) and within one year, with some evidence for beneficial effect on structural outcomes.

Spondyloarthropathy in Inflammatory Bowel Disease: From Pathophysiology to Pharmacological Targets.

Spondyloarthritis (SpA) represents one of the most frequent extraintestinal manifestations of inflammatory bowel disease (IBD). Evidence of shared genetic and molecular pathways underlying both diseases is emerging, which has led to rational approaches when treating patients with concomitant diseases. Clinical efficacy of tumor necrosis factor (TNF) antagonists has been ascertained over the years, and they currently represent the cornerstone of treatment in patients with IBD and SpA, but the therapeutic armamentarium in these cases has been recently expanded. Evidence for vedolizumab is controversial, as it was associated both with improvement and development of arthralgias, while ustekinumab, the first anti-interleukin 12/23 (IL-12/23) approved for IBD, has demonstrated good efficacy, especially in peripheral arthritis, and more IL-23 inhibitors are being developed in IBD. Tofacitinib was the first Janus kinase (JAK) inhibitor to be approved in IBD, and as it demonstrated efficacy in treating ankylosing spondylitis, it may represent a good choice in axial arthritis, while more selective JAK inhibitors are yet to be approved. Unexpectedly, the first anti-IL17 that was studied in IBD (secukinumab) has shown not to be effective in treating IBD, and the role of anti-IL17 drugs in these diseases needs further investigation. Therefore, as availability of biologics and small molecules is increasing, their positioning in clinical practice is becoming more and more challenging, and multidisciplinary management needs to be implemented in both research and clinical settings in order to enhance early recognition of SpA in IBD patients, optimize treatment and ultimately improve the patients' quality of life.

Monitoring the efficacy of tumor necrosis factor alpha antagonists in the treatment of Ankylosing spondylarthritis: a pilot study based on MR relaxometry technique

BackgroundSpA is a disease that seriously affects the quality of life and working ability of patients. At present, there is a lack of scientific and effective quantitative indicators to evaluate the activity of sacroilitis and the efficacy of tumor necrosis factor-α antagonists in the treatment of active sacroilitis. MRI STIR sequence is the most commonly used method for the diagnosis of sacroiliac joint inflammation, but its response to the disease still lags behind the pathological changes and cannot provide quantitative indicators. This study aimed to evaluate the feasibility of using MRI Relaxometry technique to monitor the efficacy of TNF-α antagonists in the treatment of SpA, so as to provide an effective quantitative index for monitoring the efficacy.MethodsThis is a prospective study, 114 patients with sacroiliac joint were enrolled, including 15 patients as a control group, 99 patients as the case group, and 20 patients in the case group as the treatment group. The differences of T1 mapping, T2 mapping, T2* mapping of subchondral bone marrow of sacroiliac joint were compared among different groups. The diagnostic efficacy was analyzed by ROC, and the best quantitative index of diagnostic efficiency was used to monitor curative effects of different treatment cycles in the treatment group.Results1. Compared with the control group, values of three different relaxation times in the subchondral bone marrow region of the sacroiliac joint in the case group increased in varying degrees, and T1 mapping showed the best diagnostic efficacy. 2. The decreasing rate of T1 mapping in different treatment periods benefits the monitoring of curative effects.ConclusionThis study indicates that T1 mapping technique is preferred in quantitative diagnosis. T1 mapping is superior to T2* mapping and T2 mapping in the diagnosis of subchondral BME of SpA. It can quantitatively monitor edema changes during treatment, benefiting clinical individualized treatment and timely adjustment of the treatment plan.

Efficacy of adjunctive infliximab vs. placebo in the treatment of anhedonia in bipolar I/II depression

We investigated the efficacy of tumour necrosis factor (TNF)-α antagonist infliximab on a measure of anhedonia amongst individuals with bipolar I/II depression (ClinicalTrials.gov identifier NCT02363738). Adults (ages 18–65) with bipolar I/II disorder currently experiencing a major depressive episode with a higher probability of inflammatory activity (i.e., meeting one or more of the following inflammatory/metabolic criteria: obesity and dyslipidemia/hypertension, daily cigarette smoking, diabetes mellitus, migraine, inflammatory bowel disease, and/or C-reactive protein level of ⩾5 mg/L) were enrolled in a double-blind, 12-week clinical trial of adjunctive infliximab (5 mg/kg) and saline control, which were administered at weeks 0, 2, and 6. The primary outcome measure for the present secondary analysis was change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score between placebo- and infliximab-treated subjects from baseline to weeks 6 and 12. Plasma concentrations of TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. Sixty eligible adults received treatment with infliximab (n=29) or placebo (n=31); 47 subjects completed the study (infliximab: n=21, placebo: n=26). Overall, infliximab-randomized subjects exhibited significantly larger increases in SHAPS total score, denoting greater reductions in anhedonic symptoms, when compared to placebo-randomized subjects (treatment × time interaction effect: χ2=7.15,df=2,p=0.03). Anti-anhedonic efficacy was moderated by baseline plasma levels of TNF-α and sTNFR1, but not by changes in TNF-α or sTNFR1 concentrations. Baseline and changes in sTNFR2 concentrations did not moderate anti-anhedonic efficacy. Infliximab significantly improved a measure of anhedonia relative to placebo in adults with bipolar I/II depression at week 6; intervention efficacy was not sustained 6 weeks after the final infusion.

Ustekinumab for the treatment of refractory pediatric Crohn's disease: a single-center experience.

Background/AimsDespite the well-established efficacy of tumor necrosis factor (TNF) antagonists as treatment options for Crohn’s disease, many pediatric patients need a change in therapy due to adverse events and loss of response, highlighting the necessity for medications with a different mechanism of action. Ustekinumab has been shown to be effective in inducing clinical remission in some adults with disease refractory to anti-TNF agents, however, minimal data exists in the pediatric population.MethodsWe conducted a retrospective chart review of 11 pediatric patients receiving ustekinumab, specifically extracting baseline data, information on prior treatment and response, indications for starting ustekinumab, clinical information, and laboratory parameters pre- and post-therapy. Clinical response was defined as a decrease in abbreviated Pediatric Crohn’s Disease Activity Index score.ResultsPatients ranged from 12 to 17 years of age upon initiation of treatment with ustekinumab. Five of 11 patients demonstrated a clinical response. Among these patients, 2 remained in clinical remission, while the remaining 3 experienced a secondary loss of response. The other 6 patients were primary nonresponders who either remained unwell or demonstrated slight clinical worsening. All patients who clinically responded to ustekinumab and had an initially elevated CRP experienced complete normalization of their values. Mucosal healing was seen on endoscopy in 1 responder, with 2 other patients showing endoscopic improvement.ConclusionsThese results demonstrate for the first time that ustekinumab has the potential to induce not only clinical and biochemical remission, but also endoscopic improvement, in the pediatric population. Future research is needed to determine factors that influence response to therapy.

A229 USTEKINUMAB FOR THE TREATMENT OF REFRACTORY PEDIATRIC CROHN’S DISEASE: A SINGLE CENTRE EXPERIENCE

Abstract Background Despite the well-established efficacy of Tumor Necrosis Factor (TNF) antagonists as treatment options for Crohn’s Disease, many pediatric patients need a change in therapy due to adverse events, as well as primary and secondary loss of response, highlighting the necessity for medications with a different mechanism of action. Ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, has been approved to treat psoriatic arthritis, plaque psoriasis, and adults with Crohn’s disease. While utekinumab has been shown to be effective in inducing clinical remission in adults with Crohn’s disease refractory to anti-TNF agents, minimal data exists in the pediatric population. Aims We retrospectively describe 11 pediatric patients who received ustekinumab at the Montreal Children’s Hospital with the goal of assessing its efficacy in inducing clinical, biochemical, and endoscopic remission. Methods We abstracted baseline data, prior treatment and response, indications for starting ustekinumab, clinical response, endoscopic data, and laboratory parameters pre- and post- therapy. Clinical response was defined as decrease in abbrPCDAI (Pediatric Crohn’s Disease Activity Index) score. Results Patients ranged in age from 12–17 years old upon initiation of treatment with ustekinumab and had all previously failed either one (N=8) or both (N=3) anti-TNF therapies. Follow-up ranged from 6 to 22 months. We examined three indices of response to ustekinumab: symptomatic improvement, biomarker normalization, and endoscopic changes. Five of eleven patients demonstrated a clinical response – two maintained clinical remission across available follow-up data, while the remaining three experienced a secondary loss of response. The other six patients studied were primary non-responders. Two of these patients had normal abbrPCDAI scores upon initiation of ustekinumab and terminated therapy due to persistent stricturing disease. The other four non-responders either remained unwell or demonstrated clinical worsening, as measured by the abbrPCDAI. Of the clinical responders, 3/5 had elevated CRP values prior to initiating ustekinumab therapy, all of which normalized within one month of clinical improvement. Endoscopic data both pre- and post- ustekinumab was available in two responders and two non-responders, with endoscopic improvement seen in both of the responders and in one of the two non-responders. Conclusions These results demonstrate that ustekinumab has the potential ability to induce not only clinical and biochemical remission, but also endoscopic improvement, in the pediatric population. An area of concern is the fact that only one patient maintained remission for longer than one year. Future research should focus on maximizing and lengthening the effect of ustekinumab, as well as determining factors that influence response to therapy. Funding Agencies None

Salivary Tumour Necrosis Factor-α as a Biomarker in Oral Leukoplakia and Oral Squamous Cell Carcinoma.

Background:Oral cancer is one of the life threatening disease which requires an availability of a biomarker for its early detection and also for effective treatment strategies. The current study is done to evaluate the efficacy of one such biomarker i.e. TNF- α as an indicator for oral precancer and oral cancer. Objectives:To evaluate the efficacy of Tumour necrosis factor - alpha (TNF)-α as a salivary biomarker in histopathologically diagnosed cases of oral leukoplakia and Oral squamous cell carcinoma. To correlate the levels of TNF- α with varying histologic grading in Oral Squamous Cell Carcinoma and dysplasia grading in Oral leukoplakia or Hyperkeratosis. Materials and Methods:The study group included 90 subjects that were divided into three groups. OSCC (n=30), leukoplakia (n=30) and controls (n=30). Cases were selected based on inclusion and exclusion criteria of the study. Salivary samples were then collected from all three groups. Salivary levels of TNF-α were estimated using Enzyme Linked Immunosorbent Assay (ELISA). The data on concentration gradients obtained were subjected to appropriate statistical analysis. Results:The results of the present study demonstrated higher levels of salivary TNF-α in individuals with OSCC compared to leukoplakia and healthy control subjects with a high level of statistical significance. ROC curve analysis along with diagnostic parameter calculation also revealed that salivary TNF-α to be a better medium for detecting OSCC. There is also an increase in the salivary TNF-α levels with increase in the histological grade of differentiation in OSCC as well as leukoplakia. Conclusion:The present study concludes that salivary TNF – α can be used as a prognostic biomarker of OSCC. In view of the elevated levels of TNF – α in saliva of individuals with severe dysplasia, it can also be used to monitor the malignant transformation to leukoplakia to OSCC.

Absence of Therapeutic Benefit of the Anti-Inflammatory Protein TSG-6 for Corneal Alkali Injury in a Rat Model

ABSTRACTPurpose: To investigate the therapeutic efficacy of tumor necrosis factor (TNF)-α stimulated gene/protein 6 (TSG-6) in a rat model of corneal alkali injury.Methods: Corneal alkali injury was produced by placing an NaOH-soaked filter paper disk on the central cornea of the right eye of an anesthetized male Lewis (LEW/Crl) rat. Recombinant human TSG-6, or an equal volume of phosphate-buffered saline (PBS), was administered intravenously (IV), by anterior chamber (AC) injection, or as a topical drop. The affected eyes were photographed daily using a dissecting microscope and documented for clinical time course analysis of corneal opacification. Corneal tissue was excised at pre-determined therapeutic endpoints, with subsequent qRT-PCR or histological analyses.Results: The continuous monitoring of corneal alkali injury progression revealed TSG-6 treatments do not show sufficient effectiveness in vivo regardless of IV injection, AC injection, or topical application. Corneal opacification and neovascularization were not diminished, and gene expression was not impacted by these treatments. However, both IV and AC administration of TSG-6 significantly suppressed pro-inflammatory cytokines compared to PBS-treated eyes.Conclusion: We conclude that the therapeutic potential of TSG-6 is insufficient in a rat corneal alkali injury model.

Development and application of a PCR-HRM molecular diagnostic method of SNPs linked with TNF inhibitor efficacy

Background Clinical evidence indicates that genetic variations may interfere with the mechanism of drug action. Recently, it has been reported that the single nucleotide polymorphisms (SNPs) of STAT4, PTPN2, PSORS1C1 and TRAF3IP2RA genes are associated with the clinical efficacy of tumor necrosis factor (TNF) inhibitors in the treatment of rheumatoid arthritis (RA) patients. Therefore, the detection of the SNPs linked with TNF inhibitor efficacy may provide an important basis for the treatment of RA. This study intended to establish molecular diagnostic methods for genotyping the linked SNPs based on high resolution melting (HRM) curve analysis. Methods The polymerase chain reaction-HRM (PCR-HRM) curve analysis detecting systems were established by designing the primers of the four SNPs, rs7574865G>T, rs7234029A>G, rs2233945C>A and rs33980500C>T, and the performance and clinical applicability of which were evaluated by using the Sanger sequencing method and genotyping test for 208 clinical samples. Results The self-developed molecular diagnostic methods of PCR-HRM were confirmed to be able to correctly genotype the four SNPs, the sensitivity and specificity of which were 100% in this study. The repeatability and reproducibility tests showed that there is little variable in intra-assay and inter-assay (the coefficient of variation ranged from 0.01% to 0.07%). The slight changes of DNA template and primer concentrations, PCR cycle number and reaction system volume had no significant effect on the genotyping performance of the method. The PCR-HRM assays were also applied to other PCR thermocyclers with HRM function and use different saturation fluorescent dyes. Conclusions The PCR-HRM genotyping method established in this study can be applied to the routine molecular diagnosis of rs7574865, rs7234029, rs2233945 and rs33980500.

Efficacy of adalimumab and infliximab in recalcitrant retinal vasculitis inadequately responsive to other immunomodulatory therapies.

The primary aim of the study was to evaluate the efficacy of tumor necrosis factor (TNF)-α blockers adalimumab (ADA) and infliximab (IFX) in refractory sight-threatening retinal vasculitis (RV) during a 12-month follow-up period. Secondary aims were to evaluate (i) any impact of concomitant conventional disease-modifying anti-rheumatic drugs (cDMARDs) and different lines of biologic therapy; (ii) any difference in terms of efficacy between ADA and IFX; (iii) consequences of biotherapies on the best-corrected visual acuity (BCVA); (iv) corticosteroid-sparing effect; and (vi) ocular complications during anti-TNF-α treatment. Demographic, clinical, and therapeutic data were retrospectively collected from the medical records and statistically analyzed. Forty-eight patients (82 eyes) were recruited, 22 (45.8%) of which received IFX and 26 (54.2%) ADA. The percentages of patients achieving RV remission within 3 and 12months were 54 and 86%, respectively. A significant decrease in RV detection was identified from baseline to 3-month (p < 0.0001) and 12-month (p < 0.0001) assessments and between 3-month and 12-month visits (p = 0.004). No differences were identified in terms of RV resolution between (i) patients undergoing monotherapy and those co-administered with cDMARDs at 3-month (p = 0.560) and 12-month (p = 0.611) follow-up; (ii) biologic-naïve patients and those already exposed to other biologics at 3-month (p = 0.497) and 12-month (p > 0.99) visits; and (iii) patients treated with ADA and those treated with IFX (p = 0.357). During the study period, a statistically significant corticosteroid-sparing effect was observed (p = 0.0002), while BCVA values did not significantly change (p = 0.950). Anti-TNF-α monoclonal antibodies have proved excellent results in patients with recalcitrant sight-threatening RV.

High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study

BackgroundAlthough both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA.MethodsMethotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: “low/low-C” (RF < 55 IU/ml, anti-CCP < 42 U/ml), “high/high-C” (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and “middle-C” (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes.ResultsBaseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2–14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 μg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment.ConclusionsRF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment.Trial registrationClinicalTrials.gov, NCT00691028. Retrospectively registered on 3 June 2008.

Systematic Literature Review and Meta-analysis of Tumor Necrosis Factor–Alpha Experienced Rheumatoid Arthritis

PurposeThe goal of this study was to compile all available evidence regarding the efficacy of tumor necrosis factor–α (TNF) inhibitors, non-TNF biologics, and tofacitinib for TNF-experienced patients who have rheumatoid arthritis (RA). MethodsA systematic literature review of MEDLINE, EMBASE, and rheumatology conference abstracts was performed to identify observational studies and randomized controlled trials (RCTs) reporting American College of Rheumatology response rates (ACR 20/50/70) for adult patients with RA who switched from at least 1 TNF to another TNF or a non-TNF therapy. A direct random effects meta-analysis was performed to evaluate ACR 20/50/70 response rates for TNF and non-TNF therapies. Separate analyses were conducted among 3-, 6-, and 12-month observational studies and for 6-month RCTs. FindingsA total of 18 observational studies and 6 RCTs were selected. Among 3-month observational studies, the percentages of ACR20/50/70 responders switching to another TNF were similar to those switching to a non-TNF biologic (ACR20, 54.5% vs 58.6%; ACR50, 33.3% vs 33.3%; and ACR70, 13.0% vs 14.6%, respectively). Among 6-month observational studies, the percentages of TNF ACR20/50/70 responders were higher than those of non-TNF responders (ACR20, 67.7% vs 50.4%; ACR50, 50.4% vs 26.6%; and ACR70, 24.9% vs 11.6%). Among 6-month RCTs, the percentages of non-TNF biologic ACR20/50/70 responders were similar to those in the 6-month non-TNF observational studies (ACR20, 50.7% vs 50.4%; ACR50, 27.5% vs 26.6%; and ACR70, 11.9% vs 11.6%). For 12-month observational studies, TNF biologic ACR20/50/70 percentages were higher than those of non-TNF therapies (ACR20, 72.2% vs 57.0%; ACR50, 42.1% vs 28.9%; and ACR70, 22.9% vs 10.0%). ImplicationsFor TNF-experienced patients with RA, subsequent TNF therapy and non-TNF biologic therapy have comparable efficacy.

Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis

ObjectivesThis meta-analysis investigates the efficacy of tumour necrosis factor α (TNFα) blockers versus placebo for the treatment of ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA).MethodsA systematic literature search was...

Efficacy of Tumor Necrosis Factor and Interleukin-10 Analysis in the Follow-up of Nonalcoholic Fatty Liver Disease Progression

Tumor necrosis factor (TNF-α) is a cytokine involved in systemic inflammation during acute phase reactions. The current study was designed to investigate the levels of pro-inflammatory cytokine (TNF-α) along with the anti-inflammatory cytokine (IL-10) during progression of non-alcoholic fatty liver disease (NAFLD) from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis in diabetic patients, and correlate the levels of cytokines with the progression of NAFLD. Fifty-two diabetic patients compared to 18 healthy controls were participated in this study. Based on clinical diagnosis, patients were divided into three groups: simple steatosis, NASH and fibrosis. Serum liver function tests, fasting blood glucose, bilirubin, ALT, AST, TNF-α, IL-10 and lipid profile were measured. TNF-α levels were significantly higher in NAFLD patients compared to control subjects with a significant positive correlation with body mass index and fasting blood glucose (FBG) but with negative correlation with IL-10. Serum IL-10 levels were significantly lower in NAFLD patients compared with controls. A positive correlation between IL-10 and HDL-C with concomitant negative correlation between IL-10 and FBG and triacylglycerides was found. Cytokine analyses showed that there was a prominent imbalance between TNF-α and IL-10 in patients with NAFLD, and this imbalance increase by increasing the progression of NAFLD especially in obese diabetic patients. TNF-α and IL-10 could be used in diagnosis and follow-up of NAFLD stages in a way to avoid liver biopsies in greater proportion of patients.

Preclinical Evidence that Use of TRAIL in Ewing's Sarcoma and Osteosarcoma Therapy Inhibits Tumor Growth, Prevents Osteolysis, and Increases Animal Survival

Osteosarcoma and Ewing's sarcoma are high-grade neoplasms typically arising in the bones of children and adolescents. Despite improvement in therapy, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. Among new therapeutic strategies, the efficacy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models. The sensitivity of osteosarcoma and Ewing's sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing's sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells. In vitro, both osteosarcoma and Ewing's sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8-mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model. These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors.

Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon‐β/α ratios in rheumatoid arthritis patients: A post hoc analysis of a predominantly Hispanic cohort

AbstractObjectiveDespite the substantial clinical efficacy of tumor necrosis factor α (TNFα) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy.MethodsRA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin‐1 receptor antagonist (IL‐1Ra) were determined in baseline plasma samples using a commercial enzyme‐linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA.ResultsPlasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05–1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFNβ/α ratio &gt;0.8 (indicating elevated plasma IFNβ levels). Consistent with the capacity of IFNβ to induce IL‐1Ra, elevated baseline IL‐1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1–3.29], P = 0.027).ConclusionThe plasma type I IFN activity, the IFNβ/α ratio, and the IL‐1Ra level were predictive of the therapeutic response in TNF antagonist–treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents.

Anti-TNF treatment reduces rat skeletal muscle wasting in monocrotaline-induced cardiac cachexia

The aim was to explore efficacy of tumor necrosis factor (TNF) inhibitors in attenuating increases in anorexia and ubiquitin proteasome pathway transcripts in cardiac cachexia, a potentially lethal condition that responds poorly to current treatments. Cardiac cachexia was rapidly induced with monocrotaline in Sprague-Dawley rats. Either soluble TNF receptor-1 or the general inhibitor of TNF production, pentoxifylline, was given to diminish TNF action on the first indication of cachexia. Animals were anesthetized with a ketamine-xylazine-acepromazine cocktail, and then skeletal muscles were removed for subsequent measurements including ubiquitin proteasome pathway transcripts and Western blots. Both soluble TNF receptor-1 and pentoxifylline attenuated losses in both body and skeletal muscle masses and also reduced increases in selected ubiquitin proteasome pathway transcripts. The action of soluble TNF receptor-1 was partly through reversal of reduced food consumption, while the effects of pentoxifylline were independent of food intake. Here we demonstrate, for the first time, that attenuation of anorexia by soluble TNF receptor-1 treatment in monocrotaline-induced cardiac cachexia is responsible for attenuating increases in some ubiquitin proteasome pathway transcripts as well as preserving body mass and attenuating loss of skeletal muscle mass.

Efficacy and Safety of Tumor Necrosis Factor Antagonists in Crohn's Disease: Meta-Analysis of Placebo-Controlled Trials

We performed a meta-analysis of placebo-controlled trials to evaluate safety and efficacy of tumor necrosis factor (TNF) antagonists for Crohn's disease. We searched MEDLINE, Cochrane Library, and EMBASE. The primary end points were clinical remission for luminal Crohn's disease and fistula closure at > or =2 consecutive visits. Deaths, serious infections, and malignancies were also analyzed by the methods of Peto and Der Simonian and Laird. Fourteen luminal Crohn's disease trials enrolled 3995 patients. In overall analysis, anti-TNF therapy was effective for induction of remission at week 4 (mean difference, 11%; 95% confidence interval [CI], 6%-16%; P < .001) and maintenance of remission at weeks 20-30 in patients who responded to induction therapy and in patients randomized before induction (mean difference, 23%; 95% CI, 18%-28% and mean difference, 8%; 95% CI, 3%-12%, respectively; P < .001 for all comparisons). Ten studies evaluated anti-TNF for treatment of fistulizing Crohn's disease, involving 776 patients. In overall analysis, anti-TNF therapy was effective for fistula closure only in maintenance trials after open-label induction (mean difference, 16%; 95% CI, 8%-25%; P < .001). In 21 studies enrolling 5356 individuals, anti-TNF therapy did not increase the risk of death, malignancy, or serious infection. Infliximab, adalimumab, and certolizumab are effective in luminal Crohn's disease. Efficacy of anti-TNF agents other than infliximab in treating fistulizing Crohn's disease requires additional investigations. A longer duration of follow-up and a larger number of patients are required to better assess the safety profile of TNF antagonists in Crohn's disease.

Efficacy of tumor necrosis factor α blockade in primary central nervous system vasculitis resistant to immunosuppressive treatment

Efficacy of tumor necrosis factor α blockade in primary central nervous system vasculitis resistant to immunosuppressive treatment

Tumor Necrosis Factor Blockade: Mechanism of Action

Modulation of the immune response with tumor necrosis factor (TNF) blockers is not a new treatment strategy for many inflammatory disorders; however, relatively little is known about their specific mechanism of action. Understanding the mode of action, pharmacology, and pharmacokinetics of the monoclonal TNF antibodies, infliximab and adalimumab, and the soluble TNF receptor, etanercept, may therefore enable us to account for their differing clinical profiles. The aim of this supplement is to explore the roles and mechanisms of TNF and TNF blockade using in vitro pharmacological and in vivo animal modeling experiments, and in vivo studies of the effects of etanercept on the inflammatory cascade in patients with psoriasis.