The Anti-tumor Necrosis Factor Research Articles

TNFRSF1B Signaling Blockade Protects Airway Epithelial Cells from Oxidative Stress.

Progressive respiratory airway destruction due to unresolved inflammation induced by periodic infectious exacerbation episodes is a hallmark of cystic fibrosis (CF) lung pathology. To clear bacteria, neutrophils release high amounts of reactive oxygen species (ROS), which inflict collateral damage to the neighboring epithelial cells causing oxidative stress. A former genome-wide small interfering RNA (siRNA) screening in CF submucosal gland cells, instrumental for mucociliary clearance, proposed tumor necrosis factor receptor superfamily member 1B (TNFRSF1B; TNFR2) as a potential hit involved in oxidative stress susceptibility. Here, we demonstrate the relevance of TNFRSF1B transcript knock-down for epithelial cell protection under strong oxidative stress conditions. Moreover, a blockade of TNFR signaling through its ligand lymphotoxin-α (LTA), overexpressed in airway epithelial cells under oxidative stress conditions, using the anti-tumor necrosis factor (TNF) biologic etanercept significantly increased the viability of these cells from a toxic oxidizing agent. Furthermore, bioinformatic analyses considering our previous RNA interference (RNAi) screening output highlight the relevance of TNFRSF1B and of other genes within the TNF pathway leading to epithelial cell death. Thus, the inhibition of the LTα3-TNFR2 axis could represent a useful therapeutic strategy to protect the respiratory airway epithelial lining from the oxidative stress challenge because of recurrent infection/inflammation cycles faced by CF patients.

Amnion responses to intrauterine inflammation and effects of inhibition of TNF signaling in preterm Rhesus macaque

Intrauterine infection/inflammation (IUI) is a frequent complication of pregnancy leading to preterm labor and fetal inflammation. How inflammation is modulated at the maternal-fetal interface is unresolved. We compared transcriptomics of amnion (a fetal tissue in contact with amniotic fluid) in a preterm Rhesus macaque model of IUI induced by lipopolysaccharide with human cohorts of chorioamnionitis. Bulk RNA sequencing (RNA-seq) amnion transcriptomic profiles were remarkably similar in both Rhesus and human subjects and revealed that induction of key labor-mediating genes such as IL1 and IL6 was dependent on nuclear factor κB (NF-κB) signaling and reversed by the anti-tumor necrosis factor (TNF) antibody Adalimumab. Inhibition of collagen biosynthesis by IUI was partially restored by Adalimumab. Interestingly, single-cell transcriptomics, flow cytometry, and immunohistology demonstrated that a subset of amnion mesenchymal cells (AMCs) increase CD14 and other myeloid cell markers during IUI both in the human and Rhesus macaque. Our data suggest that CD14+ AMCs represent activated AMCs at the maternal-fetal interface.

Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.

Anti-TNF treatment in ankylosing spondylitis patients with chronic kidney disease: Is it effective and safe?

This study aims to examine the efficacy and safety of the antitumor necrosis factor (TNF) drugs in ankylosing spondylitis (AS) patients with chronic kidney disease. In this study, 24 male patients with a glomerular filtration rate (GFR) of <60 mL min􏰁1 1.73 m􏰁2 were included among 863 patients who were followed-up once in 3 months regularly from 2010 to 2018years. Twenty-four patients were chosen for the control group among 420 male patients whose renal functions were normal using random sampling. We examined C-reactive protein, erythro- cyte sedimentation rate, serum creatinine, and GFR values, and also the measurements of Bath Anky- losing Spondylitis Disease Activity Index (BASDAI) were recorded at the beginning of the treatment with anti-TNF agents and in the 3rd, 6th, 9th, 12th, and final visit months. Eleven (45.9%) of the patients included in the study were in the routine dialysis program. The initial anti-TNF treatments were etanercept (62.5%), infliximab (16.7%), adalimumab (16.7%), and goli- mumab (4.1%). Treatment was effective in 22 (91.7%) of the patients. When the values of the two groups' patients were compared at the beginning of the treatment, there was a substantial reduction regarding BASDAI (P < .001). Pleural effusion, infective endocarditis, septic arthritis, and prosthesis infection were major side effects (n 1⁄4 4). The mortality rate of the 24 patients was 29.2% (n 1⁄4 7). This study demonstrated that anti-TNF drug treatment is effective and safe in patients with AS who have chronic kidney disease.

Positioning Infliximab and Vedolizumab in the Treatment of Moderate-to-Severe Ulcerative Colitis

Positioning Infliximab and Vedolizumab in the Treatment of Moderate-to-Severe Ulcerative Colitis

TNF-α: The shape of small molecules to come?

In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira® generated US$165.8 billion in cumulative sales and snatched the crown for the industry’s most successful drug from Lipitor (atorvastatin). TNF-α is a major component in beneficial and disease-related inflammation and TNF-α-inhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-α inhibitors, such as Alzheimer’s disease (AD) or major depression. However, the nature of TNF-α-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.

Positioning biologics in the management of moderate to severe Crohn's disease.

Since there is a lack of head-to-head randomized controlled trials, little direction is provided from guidelines on the positioning of biologics for the treatment of Crohn's disease (CD). This review utilizes comparative effectiveness and safety results from real-world data and network meta-analyses to inform clinical practice for positioning of biological therapies in the treatment of moderate-to-severe CD. We summarize the results of studies pertaining to the identification of predictors for response to biologics in CD. Recently published studies about the management of moderate-to-severe CD are discussed and a positioning algorithm is proposed for the therapeutic approach of these patients. Different classes of biologics are comparable with regards to safety and almost similar in effectiveness in the management of CD. There are certain clinical scenarios in which one biologic is more effective than another. For instance, patients with a more aggressive disease phenotype such as fistulizing disease would benefit from infliximab over other biologics, whereas in older patients at a higher risk for infectious complications, it may be more appropriate to use ustekinumab or vedolizumab over the anti-tumor necrosis factor (TNF) agents. More data pertaining to identifying predictors of response to the different available therapies and head-to-head comparison trials are needed to personalize our therapeutic approach of CD patients.

Postoperative outcomes after preoperative ustekinumab exposure in patients with Crohn's disease: a systematic review and meta-analysis.

BackgroundRecent studies have reported conflicting data on the risk of postoperative complications in patients with Crohn’s disease (CD) exposed to ustekinumab (UST) preoperatively. We performed a systematic review and meta-analysis to better assess and quantify the risk of postoperative complications in this population undergoing major abdomino-pelvic surgery.MethodsWe conducted a comprehensive search of multiple electronic databases and conference proceedings (earliest inception through October 2020) to identify studies that reported the postoperative outcomes in CD patients with preoperative UST exposure. We estimated and compared the pooled rates of postoperative complications, including intra-abdominal sepsis, surgical site infection, any infection, any adverse event, readmission, and reoperation.ResultsA total of 5 studies were included in the analysis. The last dose of the drug was at most 16 weeks prior to abdomino-pelvic surgery. A total of 172 CD patients (61% female; median age 35 years) were included. The pooled rate of any complication and any infectious complications was 23.5% (95% confidence interval [CI] 16-33.1) and 20.2% (95%CI 10.3-35), respectively. There was no difference in rates of intra-abdominal sepsis between the UST group (7.2%, 95%CI 3-16.4) and the anti-tumor necrosis factor (TNF) group (11.9%, 95%CI 5.9-22.5; P = 0.4). The rates of readmission and reoperation in the UST group were 17.4% (95%CI 7.9-34) and 14.6% (95%CI 9-22.7), respectively.ConclusionsThe postoperative complication rate in patients with preoperative UST exposure may be similar to that for anti-TNF medication. Preoperative exposure to UST does influence postoperative complication risk. Future prospective studies are needed to validate these findings.

Interrupted Etanercept Therapy: A New Case Report

Psoriasis is a chronic, immune-mediated, inflammatory disease with a high prevalence in the general population (2%). The anti-tumor necrosis factor receptor etanercept is Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe plaque psoriasis. Both continuous and interrupted etanercept therapy is effective and well-tolerated. This report aims to document a new case presentation of psoriasis on intermittent etanercept injection throughout 36 weeks with long-lasting sustained efficacy and no risk factor. Case Report: A 39-year-old adult male patient with long-standing chronic plaque psoriasis for 15 years duration without joint involvement started loading dose treatment of etanercept injection in whom due to his work circumstances not taken maintenance therapy and showed-up at the clinic after 36 weeks from first induction therapy when partial relapse of psoriatic lesions appear in last week with continued improvement when reintroducing loading treatment on followed-up over the next 36 weeks. Conclusion: Intermittent etanercept therapy considers effective for 36 weeks with prolonging sustained efficacy and without adverse effect.

PF-06410293: An Adalimumab Biosimilar.

PF-06410293 (Amsparity™/Abrilada™) is a biosimilar of the anti-tumor necrosis factor (TNF)-α antibody adalimumab. It is approved for use in all indications for which adalimumab is approved, including inflammatory joint diseases (e.g. rheumatoid arthritis), uveitis, psoriasis and Crohn's disease. PF-06410293 has similar physicochemical and pharmacodynamic properties to those of EU- and US-sourced reference adalimumab, and the pharmacokinetic similarity of the agents is supported. PF-06410293 demonstrated therapeutic equivalence to EU-sourced reference adalimumab in patients with rheumatoid arthritis, and was generally well tolerated in this population. The tolerability, efficacy, safety and immunogenicity profiles of PF-06410293 were similar to those of EU-sourced reference adalimumab, and switching from reference adalimumab to PF-06410293 appeared to have no impact on safety or efficacy. The role of adalimumab in the management of immune-mediated inflammatory diseases is well established and PF-06410293 provides an effective biosimilar alternative for patients requiring adalimumab therapy.

Long-Term Efficacy of Anti-Tumor Necrosis Factor Agents in Pediatric Luminal Crohn's Disease: A Systematic Review of Real-World Evidence Studies.

PurposeTo determine the long-term efficacy of the anti-tumor necrosis factor (TNF) agents, infliximab (IFX) and adalimumab (ADA), in pediatric luminal Crohn's disease (CD) by performing a systematic literature review.MethodsAn electronic search was performed in Medline, Embase, and the Cochrane Library from inception to September 26, 2019. Eligible studies were cohort studies with observation periods that exceeded 1 year. Studies that reported time-to-event analyses were included. Events were defined as discontinuation of anti-TNF therapy for secondary loss of response. We extracted the probabilities of continuing anti-TNF therapy 1, 2, and 3 years after initiation.ResultsIn total, 2,464 papers were screened, 94 were selected for full text review, and 13 studies (11 on IFX, 2 on ADA) met our eligibility criteria for inclusion. After 1 year, 83–97% of patients were still receiving IFX therapy. After 2 and 3 years the probability of continuing IFX therapy decreased to 67–91% and 61–85%, respectively. In total, 5 of the 11 studies subgrouped by concomitant medication consistently showed that the probabilities of continuing IFX therapy in patients with prolonged immunomodulator use were higher than those in patients on IFX monotherapy.ConclusionThis review of real-world evidence studies confirms the long-term therapeutic benefit of IFX therapy in diverse cohorts of children with luminal CD. Moreover, it supports the view that combination therapy with an immunomodulator prolongs the durability of IFX therapy in patients who previously failed to recover following first-line therapy. The limited number of time-to-event studies in patients on ADA prevented us from drawing definite conclusions about its long-term efficacy.

P039 Integrating Maintenance Efficacy and Safety of Vedolizumab and Other Advanced Therapies for the Treatment of Ulcerative Colitis: A Network Meta-Analysis

BACKGROUND: Comparative efficacy and safety data for therapeutic options in ulcerative colitis (UC) are lacking. Intravenous (IV) vedolizumab (VDZ) was recently shown to be superior to subcutaneous (SC) adalimumab (ADA) in VARSITY, the first head-to-head randomized controlled trial (RCT) of biologic therapies in UC. The objective of this study is to provide estimates of the efficacy and safety of other biologic therapies and tofacitinib (TOFA) relative to VDZ IV, by means of a network meta-analysis (NMA). METHODS: Relevant RCTs of VDZ (IV and SC), ADA, infliximab (IFX), golimumab (GOL), ustekinumab (UST), and tofacitinib (TOFA) were identified through a targeted literature review. Efficacy outcomes in the maintenance period were remission and response at 52/54 weeks. Differences in study design (treat-through vs re-randomized) across the relevant RCTs were accounted for by assessing efficacy outcomes conditional on response at start of maintenance. For treat-through studies, this was response at 6/8 weeks. Safety outcomes were overall adverse events (AEs), serious AEs (SAEs), overall infections, serious infections, and AEs leading to discontinuation as reported at 52/54 weeks. Odds ratios (ORs) with 95% credible intervals (CrIs) were estimated using probit and binomial NMA models, with results presented with VDZ IV 300 mg Q8W as the reference group. Analyses were conducted for the overall study population, as well as separately for the anti-tumor necrosis factor (TNF)–naïve and –experienced populations. RESULTS: Sixteen RCTs evaluating 13 therapies were included in the NMAs. Connected networks could be created for all three populations in the maintenance (10 trials) period. In the overall population, relative to VDZ 300 mg Q8W, ADA 40 mg, GOL 50 mg, and UST 90 mg Q12W had significantly lower rates for maintenance of response (OR: 0.62 [95% CrI 0.45, 0.86], 0.54 [95% CrI 0.31, 0.94], 0.58 [95% CrI 0.34, 0.98], respectively) and maintenance of remission (OR: 0.62 [95% CrI 0.45, 0.86], 0.54 [95% CrI 0.30, 0.94], 0.58 [95% CrI 0.34, 0.98], respectively). All other treatments had similar maintenance of efficacy to VDZ 300 mg Q8W. For safety outcomes, GOL had significantly higher rates of overall AEs (GOL 100 mg OR: 2.17 [95% CrI 1.18, 4.00]; GOL 50 mg OR: 1.90 [95% CrI 1.02, 3.54]) relative to VDZ 300 mg Q8W. Both GOL 100 mg (OR: 1.84 [95% CrI 1.07, 3.18]) and TOFA 10 mg (OR: 2.03 [95% CrI 1.19, 3.55]) had significantly higher rates of infections, while UST 90 mg Q12W had significantly lower rates of infections (OR: 0.58 [95% CrI 0.33, 0.98]) relative to VDZ 300 mg Q8W. GOL 100 mg also had significantly higher rates of discontinuation due to AEs (OR: 3.43 [95% CrI 1.18, 10.22]). ADA 40 mg, IFX 10 mg/kg, and IFX 5 mg/kg were similar to VDZ 300 mg Q8W across all safety outcomes. CONCLUSION(S): Results from this NMA based on RCTs indicate a favorable benefit-risk profile for VDZ 300 mg Q8W compared with other advanced therapeutic options available for UC.

Nurse and Patient Perceptions and Preferences for Subcutaneous Autoinjectors for Inflammatory Joint or Bowel Disease: Findings from a European Survey.

IntroductionImraldi™ is a biosimilar of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab and was recently approved in Europe for the treatment of various inflammatory conditions. Imraldi is administered via an autoinjector device that features distinct design attributes compared with other biologic TNF inhibitor autoinjectors, such as the Humira (adalimumab) Pen® and Enbrel® (etanercept) MyClic® Pen were developed by the relevant pharmaceutical companies. The aim of this study was to evaluate patients’ and nurses’ preferences for the Imraldi versus Humira or Enbrel MyClic autoinjectors in the UK and Germany.MethodsPatients with inflammatory joint or bowel disease and nurses with experience in educating patients with these conditions on self-injection participated in two survey studies, the first comparing the Imraldi and Humira autoinjectors and the second comparing the Imraldi and Enbrel MyClic autoinjectors.ResultsOverall, 101 nurses (UK, n = 50; Germany, n = 51) and 151 patients (UK, n = 90; Germany, n = 61) participated in both studies. In the first study, 85% of nurses and 78% of patients preferred the Imraldi autoinjector over the Humira autoinjector (P < 0.001); in the second study, 86% of nurses and 79% of patients preferred the Imraldi autoinjector over the Enbrel MyClic autoinjector (P < 0.001). Top reasons for preferring the Imraldi autoinjector included ease of use, ease of grip, and its button-free initiation mechanism. Most nurses indicated they would recommend the Imraldi autoinjector over the Humira and Enbrel MyClic autoinjectors, and most patients indicated they would choose the Imraldi autoinjector over the Humira and Enbrel MyClic autoinjectors to continue treatment.ConclusionNurses and patients in the UK and Germany preferred the Imraldi autoinjector over both the Humira and Enbrel MyClic autoinjectors, which may be a consideration, along with other factors, for treatment decisions in the management of patients with inflammatory joint or bowel disease.FundingBiogen International GmbH.Electronic supplementary materialThe online version of this article (10.1007/s40744-019-0144-8) contains supplementary material, which is available to authorized users.

Clinical and Laboratory Evaluation of Response to Biological Agents in Rheumatoid Arthritis and Ankylosing Spondylitis

Our aim was to evaluate the anti-tumor necrosis factor (TNF) response to treatment, which has been in place in the treatment of Rheumatoid Arthritis(RA) andAnkylosing Spondylitis(AS) patients in recent years and has achieved successful results. In this regard, the follow-up of the disease is more predictable after the initiation of anti-TNF therapy; it is aimed to interpret the parameters used in follow-up more correctly.This cross-sectional, retrospective study was performed in auniversity hospital between 2010-2016. Files of 24 patients with AS and 53 patients with RAwere retrospectively screened. Their clinical situations and laboratory levels were compared before and after the biological agent treatment. Treatment response with RA was evaluated by Disease Activity Score-28 (DAS28) scale and AS patients’ treatment response was evaluated by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scale..A total of 77 patients were included in the study. Of the participants, 53 were diagnosed as RA and 24 were diagnosed as AS. After our study we have determined statistically reasonable decrease in C-Reactive protein (CRP), white blood cell (wbc), Platelete, erythrocyte sedimentation rate (ESR) levels but an increase in blood urea nitrogene (BUN), haemoglobine (Hb), Albumin levels. The mean baseline score of BASDAI assessed before the treatment in 24 patients with AS was 6.08 and after the treatment was 3.42; DAS-28 assessed before the treatment was 5,77 and after the treatment was 3,58 and these differences was statistically significant. Patients treated with biological agents showed a significant improvement in clinical assessment evaluated by BASDAI in patients with AS and DAS28 in patients with RA. Significant decrease in CRP, ESH, wbc levels, improvement in chronic disease anemia, increase in albumin level as a negative acute phase reactant and decrease in thrombocyte levels were determined because of acute phase response and regression of inflammation.

A New Venue of TNF Targeting.

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases.

90K immunostimulatory glycoprotein in children with juvenile idiopathic arthritis

Objectives: To assess whether circulating levels of 90K glycoprotein are increased in children with juvenile idiopathic arthritis (JIA) at different stages of the disease, compared to healthy controls and to evaluate potential over time changes in its concentrations following treatment with the antitumor-necrosis factor (TNF) drug etanercept.Methods: 90K glycoprotein, C-reactive protein, erythrocyte sedimentation rate, TNF, antinuclear antibodies, rheumatoid factor and the Juvenile Arthritis Disease Activity Score were assessed in 71 children: 23 with newly diagnosed JIA, 23 with established and active JIA and 25 healthy controls. Patients, eligible for anti-TNF treatment, underwent a similar clinical/laboratory assessment after 6- and 12-month etanercept therapy.Results: At baseline, significant differences were found in 90K levels between the three study groups: JIA at onset (157.7 [131.4–241.5] μg/ml), JIA on treatment (90.0 [68.8–120.2] μg/ml) and control group (58.0 [44.5–79.0] μg/ml), (p for trend <.001), with the JIA at onset group showing the highest values. In the JIA on treatment group, following one-year etanercept treatment, a significant reduction in 90K was detected already at 6 months (74.3 [56.0–104.1] μg/ml p = .001) and a further decline was observed at 12 months (49.3 [46.0–67.6] μg/ml p < .001).Conclusion: Our study showed that 90K glycoprotein levels are increased in JIA children compared to healthy controls, suggesting a potential pathogenetic role in the JIA. Besides, 12 months of therapy with etanercept can reduce 90K levels.

Biologic therapy: let the Copernican revolution begin!

SummaryNon‐infectious uveitis can be a potentially sight‐threatening disease. The advent of biologic drugs has represented a Copernican revolution for ocular inflammatory diseases therapies: biologic treatments are a great opportunity for those patients affected by severe, non‐responder, sight threatening uveitis. The availability of such drugs has significantly improved the uveitis outcome. Several publications have reported the efficacy of biologic agents in a progressively larger number of refractory uveitides, suggesting a central role for biologic drugs in selected cases. On the other hand, the medical literature has not provided yet significant numbers and most of the biologic drugs available have been reported in small case series. The anti‐tumor necrosis factor (TNF)‐α is the category with the most consistent medical literature in uveitis and, very recently, Adalimumab has recently obtained the indication for the treatment of non‐infectious posterior, intermediate, pan‐uveitis, representing the first on label biologic agent used in ophthalmology for the therapy of uveal inflammation.

Antibodies in the Treatment of Psoriasis: IL-12/23 p40 and IL-17a.

The anti-tumor necrosis factor (TNF)-α agents represent the second generation of psoriasis therapy. Research has produced a third generation of biologic treatments, some of which offer greater efficacy than the TNF-α inhibitors. This article reviews the data documenting the efficacy and safety of three types of biologics. Semin Cutan Med Surg 35(supp4):S74-S77.

Assessment of serum asymmetric dimethylarginine levels and left ventricular diastolic function in patients with ankylosing spondylitis.

To assess left ventricular diastolic functions and serum dimethylarginine (ADMA) concentrations, as well as the effect of different treatment strategies on ADMA concentrations and diastolic function parameters, in patients with ankylosing spondylitis (AS). Sixty AS patients and 40 control subjects without classical cardiovascular (CV) risk factors were included in the study. Baseline clinical and echocardiographic variables were obtained. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and ADMA levels were measured. Spinal mobility, disease activity and functional status were assessed using Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index. CRP, ESR and ADMA levels were significantly higher in the AS group as compared to the control group. Two (5%) control subjects and six (10%) AS patients met the criteria for left ventricular diastolic dysfunction (DD) on conventional Doppler echocardiography, but the difference was not statistically significant (P=0.36). However, using tissue Doppler imaging, 12 (20%) patients in the AS group and three (8%) subjects in the control group were diagnosed with left ventricular DD (P=0.08). The anti-tumor necrosis factor (TNF)-α group, conventional therapy group and control group were compared in terms of ADMA, CRP, ESR levels and echocardiographic parameters. ADMA levels were significantly lower in anti-TNF-α group as compared to the conventional therapy group (P<0.001). In the control group, ADMA levels were significantly lower than both treatment groups (P<0.001). Increased ADMA levels reveal impaired nitric oxide metabolism in a relatively young group of patients with AS, who have no classical CV risk factors. Anti-TNF-α may have beneficial effect on endothelial function in AS patients by reducing ADMA levels.

Interferon-gamma promotes infection of astrocytes by Trypanosoma cruzi.

The inflammatory cytokine interferon-gamma (IFNγ) is crucial for immunity against intracellular pathogens such as the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (CD). IFNγ is a pleiotropic cytokine which regulates activation of immune and non-immune cells; however, the effect of IFNγ in the central nervous system (CNS) and astrocytes during CD is unknown. Here we show that parasite persists in the CNS of C3H/He mice chronically infected with the Colombian T. cruzi strain despite the increased expression of IFNγ mRNA. Furthermore, most of the T. cruzi-bearing cells were astrocytes located near IFNγ+ cells. Surprisingly, in vitro experiments revealed that pretreatment with IFNγ promoted the infection of astrocytes by T. cruzi increasing uptake and proliferation of intracellular forms, despite inducing increased production of nitric oxide (NO). Importantly, the effect of IFNγ on T. cruzi uptake and growth is completely blocked by the anti-tumor necrosis factor (TNF) antibody Infliximab and partially blocked by the inhibitor of nitric oxide synthesis L-NAME. These data support that IFNγ fuels astrocyte infection by T. cruzi and critically implicate IFNγ-stimulated T. cruzi-infected astrocytes as sources of TNF and NO, which may contribute to parasite persistence and CNS pathology in CD.