Tumor necrosis factor ALPHA Inhibitor Associated Köhlmeier-Degos Disease as a Novel Iatrogenic Paradigm That Underscores Excessive Type I Interferon in Its Pathogenesis.

Clinical and Imaging Response to Tumor Necrosis Factor Alpha Inhibitors in Treatment of Cardiac Sarcoidosis: A Multicenter Experience

Recent studies have focused on treating cardiac sarcoidosis (CS) with corticosteroids primarily mitigating symptoms and reducing the risk of mortality and other cardiovascular complications. A promising new treatment approach involves tumor necrosis factor (TNF) alpha inhibitors. A systematic search was conducted on PubMed, the Cochrane Library, and Elsevier's Science Direct databases to identify studies comparing TNF alpha inhibitors with other drugs in CS patients who had heart failure. The analyses were conducted using the random-effects model. The study's primary outcome is an increase in ejection fraction (EF), secondary outcomes include a reduction in the dose of prednisone at 6 and 12 months, maximum standardized uptake value by cardiac tissue, and fluorodeoxyglucose uptake by cardiac myocytes on positron emission tomography scan. The total number of pooled participants was 154 out of which 140 met the Heart Rhythm Society criteria for CS. The pooled analysis showed that treatment with the TNF alpha inhibitors was associated with a significant increase in EF [weighted mean difference (WMD), 46.272; 95% confidence interval (CI), 40.60-51.94, P < 0.001; I2, 75.74%], reduction in the dose of prednisone at 6 months (WMD, 9.20; 95% CI, 7.65-10.75; P < 0.001; I2, 13.33%) and at 12 months (WMD, 6.40; 95% CI, 4.74-8.07; P < 0.001; I2, 9.37%); decrease in myocardial maximum standardized uptake value (WMD, 1.99; 95% CI, 0.91-3.06; P < 0.001; I2: 97%) and reduction in fluorodeoxyglucose uptake by cardiac myocytes (WMD, 1.55; 95% CI, 1.09-2.00; P < 0.001; I2, 32.29) on positron emission tomography scans. The research findings suggest that TNF alpha inhibitors improve EF, reduce required steroid dosage, and improve clinical outcomes. Nonetheless, further high-quality randomized controlled trials with large sample sizes are needed to assess other impacts of this therapy on patients with CS.

IntroductionAlthough there is a significant utilization gap of biologic medicines in the EU, many studies estimate equity in patient access to biopharmaceuticals only based on their availability on the national list of reimbursed medicines. Hidden access barriers may facilitate financial sustainability of pharmaceuticals in less affluent EU countries; however, they have rarely been documented in scientific publications. Our objective was to explore these access barriers for tumor necrosis factor (TNF) alpha inhibitors in rheumatoid arthritis (RA) in five Central and Eastern European countries.MethodsA detailed interview guide was developed based on multi-stakeholder workshops and a targeted literature review. In each participant country 3-3-3-3 interviews with payers, rheumatologists, patients/patient representatives, and industry representatives were conducted. Responses were aggregated at a country level and validated by primary investigators in each country.ResultsLimited number of RA centers and consequently significant travelling time and cost for patients in distant geographical areas, uneven budget allocation among centers, limited capacity of nurses, narrowed patient population in national financial protocols compared to international clinical guidelines in initiating or continuing biologics, high administrative burden in prescribing biologics and limited health literacy of patients were the most relevant barriers to timely patient access in at least three participant countries.ConclusionAssessing only the availability of TNF alpha inhibitors on the national list of reimbursed medicines provides limited information about real-world patient access to these medicines. Revealing hidden access barriers may contribute to initiate policy actions which could reduce inequity in patient access.

Mechanisms Involved in the Induction of Human Endothelial Cell Necrosis

BackgroundAnkylosing spondylitis (AS) is chronic inflammatory disease that affects primarily the spine and the sacroiliac joints. ASAS/EULAR guidelines describe regular exercise as the cornerstone of non-pharmacological treatment and pharmacological treatments...

Purpose: Tumor necrosis factor alpha (TNF-α) inhibitors are approved for the treatment and maintenance of rheumatoid arthritis (RA). Immunosuppression has been shown to induce ischemic colitis in animal models. A relationship between TNF-inhibitors and ischemic colitis has rarely been reported in published literature. We reviewed the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) and published literature for reports of ischemic colitis associated with TNF-α inhibitors in RA patients. Methods: 2,562,390 files between January 2003 and June 2011 from the FDA AERS were downloaded and analyzed using SPSS 20 (IBM Co. Armonk, NY, USA). A search was conducted for reports limited to ‘primary suspect' reactions of ischemic colitis with TNF-α inhibitors, used for treatment of RA. Full length reports were obtained and analyzed to establish authenticity with cases having more likely causes for ischemic colitis such as sepsis eliminated from analysis. The cases were organized by age, gender, specific TNF-α inhibitors, concomitant drugs, and medical comorbidities that are risk factors for ischemic colitis. A PubMed search was performed using MESH terms: “anti-TNF” or “tumor necrosis factor inhibitor” or “TNF-alpha” and “ischemic colitis” separated by the Boolean operator “AND” between the first three and last terms. Results: Thirty-seven primary suspect reports of TNF-α inhibitors associated with ischemic colitis in RA patients were identified. Thirteen (35.1%) cases were reported with infliximab, 12 with adalimumab, eight with etanercept, and four with certolizumab. The majority of the cases were in females (31/37) and those between the ages of 50 and 65 (20/37). Evidence of a colonoscopy, biopsy, or other documented medical confirmation for ischemic colitis was present in 21 cases. One patient had heart disease and five had diabetes. There were no reports describing vasculitis or congestive heart failure. In 20 cases, concomitant medications presented as potential risks for ischemic colitis: 12 patients were on NSAIDs, four on ACE inhibitors, three on estrogen, two each on lisinopril, amlopidine, and beta blockers, and one each on benidipine, olmesartan, and simvastatin. Sixteen patients did not have any listed risk factors or concomitant medications that could increase the risk of ischemic colitis. In the literature, one report of ischemic colitis associated with adalimumab was identified. Conclusion: Our study suggests that TNF-α inhibitors may be initiating factors or co-factors in the development of ischemic colitis in RA patients. Further research to determine the mechanism of this association is warranted.

Objective To evaluate the risk of infection in monotherapy of tumor necrosis factor alpha (TNF-α) inhibitor. Methods The database of Pubed, Embase, Cochrane library, and Web with Science were searched from the inception to November, 2014. The literatures of randomized controlled trials in English which included reports that only used TNF-α inhibitor (the test group) and placebo or positive controlled drug (the control group)were selected. The methodological quality of the literatures which enrolled into the study were assessed by Jadad scale (inferior quality: <3 points, high quality: 3-5 points). The software RevMan 5.2 was used for Meta-analysis. The infection rate and the severe infection rate were expressed by relative risk (RR), Peto odds ratio (Peto OR)and 95% confidence interval (CI). Results A total of 33 trials presented by 32 reports, and 11 819 patients (7 408 cases in the test group using adalimumab or golimumab or infliximab or etanercept, respectively, and 4 411 cases in the control group using placebo, positive control drug such as methotrexate or salazosulfapyridine, respectively )were enrolled into the Meta-analysis. The Jadad scores of the 33 trials were all≥3 points. The results of the Meta-analysis showed that the overall total incidence of infection in patients who used TNF-α inhibitors only was higher than that in the patients who used placebo [33.03% (1 702/5 153) vs.29.53%(873/2 956), RR=1.17, 95%CI: 1.09-1.25, P 0.05). Conclusions The monotherapy with TNF-α inhibitor may increase the overall incidence of infection, but will not increase the incidence of severe infection. The monotherapy with TNF-α inhibitor is relatively safety in clinical practice. Key words: Tumor necrosis factor-alpha; Infection; Meta-analysis

The US Food and Drug Administration has approved TNF(Tumor necrosis factor) alpha inhibitors to manage a range of inflammatory conditions, including Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and...

Source: Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011; 63(4): 465– 482; doi: 10.1002/acr.20460Over the past 12 years, treatment options for juvenile idiopathic arthritis (JIA) have increased due to the introduction of a new class of medicines, the biologics such as tumor necrosis factor (TNF) alpha inhibitor. This expansion of JIA therapeutic options has made feasible the first evidence-based treatment recommendations for a pediatric rheumatic disease.1 These guidelines were developed after a systematic review of 221 articles by a large, interdisciplinary team convened by the American College of Rheumatology.Five JIA treatment groups were defined: systemic arthritis patients with active systemic features (ie, fever, rash) but no active arthritis; systemic arthritis patients lacking active systemic features but having active arthritis; patients with no more than four active joints; patients with at least five active joints; and patients with active sacroiliac joint involvement.For each group, stepwise recommendations were made based upon the level of disease activity (low, moderate, or high) and the presence of poor prognostic features. Active joints were defined as joints with swelling or limited range of motion and pain or tenderness. For patients with no more than four active joints of any activity level, intra-articular glucocorticoid injections (IAC) with triamcinolone hexacetonide were recommended as initial treatment. Patients with low activity and no poor prognostic factors can be started on a nonsteroidal anti-inflammatory drug (NSAID), but then should receive IAC if they continue to have activity after two months, while patients with high activity and a poor prognostic feature should be started on methotrexate immediately. Poor prognostic features were defined as radiographic damage (ie, bone erosion), hip or cervical spine arthritis, or ankle or wrist arthritis associated with marked or prolonged elevated inflammatory marker (ie, erythrocyte sedimentation rate, C-reactive protein).For patients with at least five active joints, initial treatment with NSAIDs alone was considered inappropriate beyond two months. Initial treatment with methotrexate was recommended for all high activity patients, and for moderate activity patients who have a poor prognostic feature. Methotrexate was also recommended for low activity patients with a poor prognostic feature following one month of NSAID and for moderate activity patients without features of poor prognosis after one to two months of NSAIDs. If a patient continues to have moderate or high disease activity after three months of methotrexate treatment, the addition of a TNF alpha inhibitor was recommended; this was also recommended for low disease activity patients after six months of methotrexate treatment. Patients who continue to have active disease could be changed to a different TNF alpha inhibitor or switched to abatacept, an anti-T cell agent.Systemic arthritis patients can be treated with NSAIDs alone during their initial evaluation, but those with active fever and physician global assessment of very high disease activity should be treated with systemic glucocorticoids and possibly the biologic anakinra. Methotrexate was considered inappropriate for initial management of these patients, but considered appropriate for systemic patients with active arthritis following no more than one month of NSAIDs.These recommendations are a useful reference for pediatricians, but are not intended to serve as a treatment protocol. Treatment still needs to be individualized based upon specific patient features, and initiated and managed by a physician familiar with treating JIA.

With the growing number of patients with immune-modulated diseases treated with tumor necrosis factor (TNF) alpha inhibitors, we are more frequently encountering the occurrence of so-called paradoxical drug reactions. These are basically situations where during the course of the treatment of one disease, the manifestation of another with similar etiopathogenesis occurs, although under normal conditions this newly developed disease responds well to treatment with TNF alpha inhibitors and is indicated for this treatment. Skin reactions are most frequently recorded in the form of induced psoriasis and psoriasiform exanthems. A less common paradoxical reaction is the induction of Crohn's disease, which is most often described in association with the treatment of inflammatory joint diseases with etanercept. We present a case of induction of Crohn's disease during therapy with etanercept, where the primary disease being treated was psoriasis. In the literature, similar cases have only been described sporadically.

Factors associated with the use of tumor necrosis factor alpha inhibitors in a population of Colombian patients with spondyloarthritis

Inhibition of Glycogen Synthase Kinase 3β (GSK3β) Decreases Inflammatory Responses in Brain Endothelial Cells

SummaryThe functions of Nr4a1-dependent Ly6Clow monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid “danger” signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6Clow monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6Clow monocyte development, crawling, or retention in Nr4a1−/−, Itgal−/−, and Tlr7host−/−BM+/+ and Cx3cr1−/− mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7host+/+BM−/− mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6Clow monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.

Objective: A strong link between psoriasis and obesity, type 2 diabetes, insulin resistance dyslipidaemia and metabolic syndrome has been documented. The aim of this study was to investigate the effects of methotrexate (MTX), a conventional antipsoriatic agent, and tumour necrosis factor (TNF)-alpha inhibitors (TNFi) on insulin resistance in patients with psoriasis. Material and Methods: Thirty-one patients with psoriasis treated with MTX and TNFi were prospectively evaluated. Seventeen patients received MTX, while 14 received the TNFi treatment. At the baseline and at week 12 values of serum C-reactive protein (CRP), the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and lipid parameters were evaluated. Results: The decrease in CRP levels after the treatment was significantly higher in the TNFi group than in the MTX group (-1.76 vs. -0.1, p = 0.005; respectively). The levels of serum glucose showed increases in both therapy groups, which was statistically significant in only TNFi group (p = 0.012). Although it was not statistically significant, increases in the HOMA-IR values were noted in MTX and TNFi therapy groups (0.26 ± 1.77 vs. 0.59±1.81, p = 0.558, p = 249; respectively). Conclusion: In the present study, a significant increase in the levels of fasting serum glucose was observed in TNFi group, and an increase in HOMA-IR values was noted in both therapy groups, which is not consistent with the literature. Despite the short follow-up period and small sample size, we believe that the effects of the TNFi and MTX demand caution for the follow-up of psoriasis, which is already an insulin-resistant condition.

Background:Glucocorticoids (GCs) remain a common co-treatment in arthritic diseases. Tumour necrosis factor alpha inhibitors (TNFi) effectively reduce disease activity and should allow for GC tapering. There have been few studies...