Extended indications for anti‐tumor necrosis factor‐α therapy

Tumour necrosis factor‐α is a pleiotropic cytokine which has a broad range of actions in inflammation, infection and immunity. TNF‐α is supposed to play a crucial role in the pathogenesis of various autoimmune diseases. TNF‐α blocking agents have been demonstrated to be highly effective in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. TNF‐α inhibitors also have been tried with other rheumatic diseases and have emerged as promising treatments. We here review the current evidences of effectiveness of the anti‐TNF‐α therapy in various autoimmune diseases.     

Regional variations in the concentrations of ketone bodies in cirrhosis and hepatic encephalopathy: a study in patients with TIPSS

Background: Little is known about the metabolism of acetoacetate and β‐hydroxybutyrate in patients with cirrhosis and encephalopathy. Aims: We investigated the fate of ketone bodies in these conditions. Materials and methods: We studied 18 cirrhotic patients with encephalopathy and 17 cirrhotics without. At the time of insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS) or at the time of portographical assessment of the shunt's patency, we collected blood from the internal jugular, the right atrium, the inferior vena cava, the hepatic, the portal, the splenic veins and the radial artery. We used nuclear magnetic resonance spectroscopy to measure the concentrations of acetoacetate and β‐hydroxybutyrate. Results: There was no difference in the total ketone body concentrations between the two groups. The mitochondrial redox potential was significantly higher in the encephalopathics (142/54=2.63 vs 52/83=0.62) (P<0.01). β‐hydroxybutyrate was significantly lower in the portal vein of encephalopathics (52 ± 4 vs 28 ± 3) (P<0.02) and in the splenic vein (48 ± 6 vs 32 ± 5) (P<0.04). Acetoacetate was significantly higher in encephalopathics in the internal jugular vein (134 ± 12 vs 92 ± 16) (P<0.03), the right atrium (112 ± 18 vs 68 ± 11) (P<0.03), the hepatic vein (162 ± 25 vs 115 ± 19) (P<0.05), the portal vein (133 ± 20 vs 81 ± 14) (P<0.02) and the splenic vein (167 ± 24 vs 122 ± 21) (P<0.04). All measurements are expressed in μmols/L. Conclusions: There are significant variations in the regional concentrations of the ketone bodies in encephalopathy.     

Clinical experience with tumor necrosis factor blockers in Korean rheumatoid arthritis patients

Tumor necrosis factor (TNF) blockers have become an important treatment in rheumatoid arthritis (RA) with its proven effectiveness. But it is not universally effective in all patients and it comes with a relatively high economic burden. We should use them effectively. Advances in pharmacoeconomics and pharmacogenetics may be able to help us reach this goal. This article will review our clinical experience of biological agents to treat RA at Hanyang University in Korea, with emphasis on the current therapies targeting TNF and the rational use of theses agents in RA.     

The infectious profiles of anti‐tumor necrosis factor agents in a Thai population: a retrospective study a the university‐based hospital

Aims: Anti‐tumour necrosis factor‐α (anti‐TNF) agents represented treatment advances in a number of rheumatologic diseases. However, adverse effects of anti‐TNF agents have been identified through both clinical trials and post‐marketing surveillance, especially an increased risk of serious infections. This study firstly described the infectious profiles of anti‐TNF agents in a Thai population. Methods: We retrospectively reviewed all infectious incidences from 100 consecutive medical records of patients who were treated with either etanercept or infliximab for any rheumatologic and non‐rheumatologic conditions. Results: Indications for anti TNF‐α agents were mainly rheumatoid arthritis (46%) and spondyloarthropathy (SpA) (41%). Seventy‐seven patients were treated with etanercept and 23 with infliximab. For those whose initial treatment was etanercept, there were two events of suspected active pulmonary tuberculosis (TB) and suspected hepatitis‐B virus (HBV) reactivation. Two out of 23 patients (8.7%) who were firstly treated with infliximab had herpes zoster skin infection. Incidence of overall infection before anti‐TNF treatment were significantly higher in patient who started with etanercept (0.065 vs. 0.019 cases per person‐years in etanercept and infliximab respectively, P < 0.0001). Incidence of overall infection post‐anti‐TNF treatment were 0.122 and 0.201 cases per person‐years in patients who started with etanercept and infliximab with no significant difference (P > 0.05). The overall infection rates were significantly increased after infliximab treatment (P < 0.0001). Conclusion: Even thought there were two new events of TB and HBV reactivation after etanercept treatment, incidence of overall infection seemed to be increased after infliximab treatment. The infectious screening and monitoring with high index of suspicion as well as the pre‐emptive treatment are still important whenever either etanercept or infliximab is started.     

TNF‐α polymorphisms in Korean adult‐onset Still's disease patients

Aim: To investigate the role of TNF‐α promoter polymorphisms in the pathogenesis of Korean adult‐onset Still's disease (AOSD) patients. Methods: DNA was isolated from blood samples collected from 58 patients with AOSD meeting Yamaguchi's criteria and 105 healthy controls. TNF‐αpromoter polymorphisms at positions –1013, –863, –857, –308 were analysed by polymerase chain reaction‐restriction fragment length polymorphism method. Genotype, allele, and estimated haplotype frequencies were compared between the AOSD group and controls. Results: The genotype, allele distributions, and estimated haplotype frequencies of the TNF‐αpolymorphism between AOSD patients and controls were not significantly different. In addition, TNF‐αpolymorphisms did not appear to have an effect on the disease course of the Korean AOSD patients. Conclusion: Genetic polymorphisms of TNF‐αdo not play a significant role in the development or in their course of Korean AOSD patients.     

Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase‐1 expression and up‐regulates matrix metalloproteinase‐9 in toxic liver injury

Abstract: Background: Tissue inhibitor of metalloproteinases (TIMP)‐1, the most important endogenous inhibitor of matrix metalloproteinases, plays a pivotal role in the pathogenesis of liver fibrosis and may represent an effective therapeutic target in the design of antifibrotic strategies for chronic liver diseases. Methods: Intraperitoneal application of a single dose of either tumor necrosis factor (TNF)‐α or interleukin (IL)‐1β in mice led to an enhanced expression of hepatic TIMP‐1 after 4–16 h. Male Sprague–Dawley rats were treated with carbon tetrachloride (CCl₄) in the presence and absence of specific TNF‐α and IL‐1β inhibitors. Results: Real‐time PCR revealed a significant increase of TIMP‐1 mRNA in total rat liver 24 h after CCl₄ injection. Repetitive injection of both, etanercept and anakinra, before and after CCl₄ injection effectively inactivated TNF‐α and IL‐1β. Anticytokine pretreatment reduced the increase of TIMP‐1 expression after a single CCl₄ injection by 50% and 75%, respectively. In contrast to CCl₄‐treated rats with and without TNF‐α blockade, IL‐1β inactivation caused a sevenfold increase in matrix metalloproteinases‐9 mRNA levels. Conclusions: In conclusion, TIMP‐1 expression is up‐regulated in the early phase of toxic liver injury by proinflammatory cytokines such as TNF‐α and IL‐1β in rodents. Pharmacological inactivation of these cytokines significantly reduces TIMP‐1 gene expression. Our data provide a potential new antifibrotic approach.     

Effect of peroxisome proliferator‐activated receptors‐γ and co‐activator‐1α genetic polymorphisms on plasma adiponectin levels and susceptibility of non‐alcoholic fatty liver disease in Chinese people

Background/Aims: Peroxisome proliferator‐activated receptors‐γ (PPAR‐γ) and its co‐activator‐1α (PGC‐1α) are involved in the regulation of lipid and glucose metabolisms. This study aimed to investigate the genetic polymorphisms of PPAR‐γ and PGC‐1α in Chinese people and their influence on plasma adiponectin levels and non‐alcoholic fatty liver disease (NAFLD) susceptibility. Methods: Ninety‐six patients with NAFLD and 96 healthy controls were included. The single nucleotide polymorphisms (SNPs) of C161T PPAR‐γand Gly482Ser PGC‐1α genes were analysed by polymerase chain reaction and restriction fragment length polymorphism. Result: The CC, CT and TT genotypic distributions of the NAFLD group were significantly different from those of controls (55.2, 39.6, 5.2 vs. 74.0, 25.0, 1.0%; P=0.015). The allelic frequencies of C and T were also different between the two groups (P=0.004). As for the PGC‐1α gene, there was no difference of the genotypic and allelic frequencies between the two groups (P>0.05). In NAFLD patients, the plasma adiponectin concentrations were lower in the PPAR‐γ CT/TT genotypes compared with those in the CC genotype group (3.0±0.6 vs. 4.3±0.9, P=0.02). Multivariate logistic regression analysis showed that CT/TT genotypes of PPAR‐γ, TG, waist hip ratio, hypoadiponectinaemia and homoeostasis model assessment (HOMA)‐IR were the risk factors for NAFLD. Conclusion: SNPs in the PPAR‐γ, but not PGC‐1α, gene are associated with NAFLD susceptibility possibly through the adiponectin pathway.     

Self‐reported outcomes during treatment with tumour necrosis factor α inhibitors in patients with rheumatoid arthritis

Objective: To study how patients with rheumatoid arthritis (RA) self‐report their experience of disease‐related symptoms (fatigue, morning stiffness, pain) and their ability to cope with everyday life (capacity) using a nurse‐led structured follow‐up during the first year after starting treatment with tumour necrosis factor α (TNF‐α) inhibitors. Methods: Thirty‐nine patients, who were being treated for their RA in our outpatient rheumatology clinic and were beginning treatment with TNF‐α inhibitors, agreed to evaluate and self‐report their experience of fatigue, morning stiffness, pain, and capacity using the visual analogue scale (VAS) every third month during their first year of treatment. A quantitative method was used to study the changes in these four variables. In addition, at the same time, we studied the relationship between self‐reported capacity and each of the three symptoms. Results: After 12 months' treatment with TNF‐α inhibitors, the change (median interquartile range [IQR]) measured with VAS was ?14 (?38, ?7) mm for fatigue, ?22 (?47, ?4) mm for morning stiffness, ?28 (?50, 0) mm for pain and ?27 (?48, ?6) mm for capacity. All changes were statistically significant (p < 0.001). Baseline and 12 months' capacity correlated significantly with fatigue, morning stiffness and pain (all p < 0.01). In addition, the median change in self‐reported capacity correlated significantly with the median change in each of the three symptoms (p < 0.01). Conclusion: During the first year of treatment with TNF‐α inhibitors, patients reported decreased fatigue, morning stiffness and pain, while their capacity increased. The increased capacity rate closely followed the decrease in symptom rate. Copyright © 2009 John Wiley & Sons, Ltd.     

‘It's magic stuff’: The experiences of patients with ankylosing spondylitis taking anti‐TNF‐α medication

Introduction: Several studies have identified the efficacy of anti‐tumour necrosis factor‐alpha (anti‐TNF‐α) treatment in ankylosing spondylitis (AS). However, few studies have explored the perceptions of patients taking this new medication. The aim of this study was to explore the impact of anti‐TNF‐α on the quality of life of people with AS. Methods: A qualitative approach was adopted to provide a holistic understanding of participants' views and experiences in the context of their overall lives. Semi‐structured interviews were undertaken and transcribed verbatim. Data were analysed using thematic analysis. Ethical approval and informed consent were obtained. Results: Eight people participated and described a significant improvement in their physical and psychological status, leading to a more positive outlook on their life. Specific areas highlighted were employment, activities of daily living, hobbies and relationships with partners and family, some of which are not captured by current AS‐specific outcome measures. Negative aspects of anti‐TNF‐α use were described as the inconvenience of monitoring and issues relating to travelling abroad. All participants expressed concern about the possibility of being withdrawn from treatment and the perceived impact this would have on their lives. Conclusions: Anti‐TNF‐α treatment has a positive impact on the lives of people with AS, such that a major concern is being withdrawn from treatment, highlighting the need to provide tailored support to people being withdrawn from treatment. To capture the full impact of anti‐TNF‐α treatment, further consideration needs to be given to the choice of appropriate outcome measures. Copyright © 2008 John Wiley & Sons, Ltd.     

Increased prevalence of intestinal inflammation in patients with liver cirrhosis

lNTRODUCTlONGastr0intestinalsympt0msarecomm0ninpatientswithlivercirrhosisandportalhypertensi0n.Theirpathophysiologyremains,f0rthem0stpart,obscure.Itiswellknownthates0phagealvaricesandportalhypertensiveg.,t,.p.thy[i'2jarec0mmoncausesofuppergastr0intestinal(GI)bleedinginpatientswithlivercirrh0sis.Recently,portalhypertensivecolopathy,suchascolonicvascularectasiaandrectalvarices,wererec0gnizedascausesoflowergastrointestinalbleedingincirrhoticpatients["'J.Otherthanbleeding,variouspathol0gical…     

Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non‐alcoholic steatohepatitis

OBJECTIVE:  The objectives of this study were to investigate the use of non‐invasive biochemical markers to evaluate the severity of liver fibrosis in patients with non‐alcoholic steatohepatitis (NASH). METHODS:  This was a cross‐sectional study of patients with histopathologically confirmed NASH between January 2005 and December 2006. The patients’ characteristics were recorded and the body mass index was calculated for each patient. All patients underwent ultrasound‐guided liver biopsy and a fibrosis assessment was performed using the Brunt criteria. The non‐invasive laboratory markers measured were insulin resistance, tumor necrosis factor (TNF‐α), type IV collagen and hyaluronic acid (HA). RESULTS:  Thirty patients were recruited, of whom 18 (60%) were men. Their mean age was 45 ± 13.9 (18–71) years. About 83% of patients had fibrosis stage 1–2. In bivariate analysis, age, TNF‐α and type IV collagen concentrations showed a weak but significant correlation with the fibrosis stage. When the patients were grouped into mild fibrosis (stages 1–2) and advanced fibrosis (stages 3–4), the mean concentrations of HA and type IV collagen were significantly higher in those with advanced fibrosis than those with mild fibrosis (180.8 ± 49.63 vs 543.6 ± 360.45 ng/mL; for HA; P = 0.026 and 125.3 ± 32.11 vs 288.0 ± 171.22 ng/mL for type IV collagen; P = 0.010). CONCLUSION:  Our study showed that the degree of liver fibrosis was significantly correlated with age, TNF‐α and type IV collagen concentrations. The level of HA and type IV collagen could differentiate between mild (F1–2) and advanced fibrosis (F3–4).     

Increased apoptosis in HepG2.2.15 cells with hepatitis B virus expression by synergistic induction of interferon‐γ and tumour necrosis factor‐α

Background: Interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) were thought to be important immune mediators in host defence against hepatitis B virus (HBV) infection. Aims: To examine the synergistic effect of IFN‐γ and TNF‐α on HBV‐expressing HepG2.2.15 cells and its potential mechanisms. Methods: Cell viability was quantitatively measured by 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide assay. Cell morphology was captured using light microscopy. The typical DNA ladder test was performed using agarose gel electrophoresis. HBsAg and HBeAg titre changes were quantified by the enzyme‐linked immunosorbent assay method. Gene expression was analysed using cDNA macroarrays. Results: Interferon‐γ (1000 U/ml) alone or combined with TNF‐α (5 ng/ml) treatment resulted in apoptosis in HepG2.2.15 cells, but no significant apoptosis in the parent non‐virus expressing HepG2 cells. IFN‐γ‐ and TNF‐α‐mediated apoptosis was reduced by lamivudine treatment in HepG2.2.15 cells. IFN‐γ combined with TNF‐α reduced the titre of hepatitis B surface antigen and hepatitis B e antigen in the HepG2.2.15 cell line. For apoptosis‐related gene changes, IFN regulatory factor 1 (IRF‐1) (12.2‐fold), c‐myc (V00568 4.7‐fold, L00058 2.4‐fold) and caspase 7 (2.3‐fold) genes were upregulated in the combination treatment group. Conclusion: Interferon‐γ and TNF‐α play a role in the cell death of HBV‐expressing HepG2.2.15 cells. Expression of HBV leads to IFN‐γ‐ and TNF‐α‐mediated apoptosis in the cells. Increased IRF‐1, c‐myc and caspase 7 gene expression may be responsible for the synergistic induction of apoptosis by IFN‐γ and TNF‐α.     

Hepatic changes of erythropoietin gene expression in a rat model of acute‐phase response

An acute‐phase response is the systemic reaction of an organism to insult (e.g. infection, trauma and burning). It represents the ‘first line’ of defence of the body to tissue‐damaging attacks. In the present work, we used a rat model of an intra‐muscular turpentine oil (TO) injection to analyse erythropoietin (EPO) gene expression changes in the liver, one of the main target organs of acute‐phase cytokines. EPO began to increase in the serum of TO‐treated animals 6 h after injection and reached a maximum at 24 h (125±20 pg/ml). The detection of total RNA by polymerase chain reaction analysis showed that the levels of EPO gene expression in the liver were considerably increased between 2 and 12 h by up to 20‐fold at the peak after TO administration, followed by a gradual decrease over the next 48 h, although the values remained significantly higher compared with the control group. In the kidney, after a sudden slight increase, the values declined progressively to 3.5‐fold decrease at 12 h after the injection. In the liver, a parallel upregulation of the hypoxia‐inducible factor‐1 (HIF‐1) α gene was observed (up to 4.7‐fold increase), while HIF‐2 α gene expression remained unaltered. On the other hand, the protein of both genes became detectable after the injection and increased progressively over 24 h, with a subsequent decline. These results suggest that EPO may be added to the increasing group of positive acute‐phase proteins and the liver might represent the major source of the hormone under these conditions in the rat.     

Melatonin attenuates TNF‐α and IL‐1β expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis

The hormone melatonin has many properties, including antioxidant, anti‐inflammatory, and immunomodulatory effects. Melatonin has been demonstrated to be beneficial in several inflammatory autoimmune diseases, but its effects in rheumatoid arthritis (RA) remain controversial. We sought to determine how melatonin regulates inflammation in RA. We found that melatonin dose‐dependently inhibits tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐1β expression through the PI3K/AKT, ERK, and NF‐κB signaling pathways. We also identified that melatonin inhibits TNF‐α and IL‐1β production by upregulating miR‐3150a‐3p expression. Synovial tissue specimens from RA patients and culture of human rheumatoid fibroblast‐like synoviocytes confirmed that the MT1 receptor is needed for the anti‐inflammatory activities of melatonin. Importantly, melatonin also significantly reduced paw swelling, cartilage degradation, and bone erosion in the collagen‐induced arthritis mouse model. Our results indicate that melatonin ameliorates RA by inhibiting TNF‐α and IL‐1β production through downregulation of the PI3K/AKT, ERK, NF‐κB signaling pathways, as well as miR‐3150a‐3p overexpression. The role of melatonin as an adjuvant treatment in patients with RA deserves further clinical studies.