Effects Of Anti-tumor Necrosis Factor Research Articles

Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis

Lower adiponectin levels in circulation are shown to be associated with endothelial dysfunction, which is a crucial feature in the evolution of atherosclerosis. The aim of our study is to evaluate the effect of anti-tumor necrosis factor (TNF) therapy on adiponectin levels with endothelial function and arterial stiffness. Fifteen Japanese patients with rheumatoid arthritis (RA) received infusions with infliximab (3 mg/kg) at weeks 0, 2, and 6. Serum concentrations of adiponectin, endothelial function, and pulse wave velocity (PWV) were measured before each infusion. Endothelium-dependent vasodilatation and endothelium-independent vasodilatation were evaluated as forearm blood flow response to reactive and nitroglycerin-induced hyperemia using strain-gauge plethysmography. Endothelium-dependent vasodilatation was significantly improved at 2 weeks and 6 weeks by treatment with infliximab. PWV remained unchanged. Anti-TNF therapy significantly increased serum adiponectin levels at 2 weeks and 6 weeks. The adiponectin levels were positively correlated with the endothelium-dependent vasodilatation, and negatively with the disease activity score of 28 joints. Our study shows a short-term efficacy of infliximab on adiponectin levels and endothelial dysfunction of patients with RA, and provides additional evidence to support the regulatory role of TNF-α on the expression of adiponectin in vivo.

Minimal disease activity, remission, and the long‐term outcomes of rheumatoid arthritis

To determine the prevalence of minimal disease activity (MDA) and remission in patients with rheumatoid arthritis (RA), to assess the effect of anti-tumor necrosis factor (anti-TNF) therapy on MDA, and to determine the extent to which MDA status improves long-term outcomes. Using the Patient Activity Scale (PAS) as a surrogate, we assessed the prevalence of MDA and remission in 18,062 patients with RA using the newly developed Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria for MDA. MDA was noted in 20.2% of 18,062 patients and persistent MDA, operationally defined as having MDA during >or=2 consecutive 6-month observation periods, occurred in 13.5% of 7,433 patients followed longitudinally. Disease activity at remission levels was noted in 7%. Among patients with MDA, 82% received disease-modifying antirheumatic drugs or biologic agents. Following anti-TNF initiation, the cumulative probability of achieving MDA at 2 and 6 years was 4.1% and 7.6%, respectively, and persistent MDA probabilities were 2.7% and 4.5%, respectively. Regardless of RA duration, patients with MDA had substantially better outcomes, including a 10-fold reduction in work disability and an approximately 2-fold reduction in total joint replacement and mortality. Remission remains uncommon in RA, and the prevalence of new remission in community practice is substantially lower than noted in published trials of biologic therapy. On average, persons with MDA appear to have persistently mild RA. This might be the effect of milder RA and/or more effective treatment in early RA. The PAS had satisfactory levels of agreement with the full MDA criteria and appears suitable for use in clinical and epidemiologic research.

Tolerance and effectiveness of anti–tumor necrosis factor α therapies in elderly patients with rheumatoid arthritis: A population‐based cohort study

Limited data have been published on tolerance to and efficacy of classic or biologic disease-modifying antirheumatic drugs in elderly patients with rheumatoid arthritis (RA). The goal of the present study was to evaluate the tolerance to and effectiveness of anti-tumor necrosis factor (anti-TNF) agents in elderly patients (> or =65 years old) with RA (ERA) in comparison with younger patients (YRA). The Swiss Clinical Quality Management program for RA is a longitudinal population-based cohort. All patients who had received at least 1 dose of anti-TNF agents between January 1997 and November 2005 were included and categorized according to their age. Tolerance was assessed by analyzing discontinuation rates of anti-TNF agents. Effectiveness of these agents was assessed by analyzing RA disease activity (Disease Activity Score in 28 joints [DAS28]) and functional disability (Health Assessment Questionnaire [HAQ]) after anti-TNF initiation. Among 1,571 patients with RA treated with anti-TNF agents, 344 were > or =65 years of age at treatment initiation. Drug discontinuation rates (median time 3 years) and mean change in DAS28 scores at 2 years (-0.65 versus -0.58) were identical in ERA and YRA. However, HAQ score improved significantly less in ERA (-0.02) than in YRA (-0.1) and a subsequent analysis revealed that this finding was essentially due to patients >75 years of age. Age in itself should not interfere with the decision to treat elderly patients with RA with anti-TNF agents. In a subset of patients ages >75 years, no functional improvement according to HAQ should be expected despite improvements in disease activity.

Anti–Tumor Necrosis Factor–α Treatment ActivatesBorrelia burgdorferiSpirochetes 4 Weeks after Ceftriaxone Treatment in C3H/He Mice

The effect of anti-tumor necrosis factor (TNF)-alpha treatment in Borrelia burgdorferi-infected and ceftriaxone-treated C3H/He mice was evaluated. Mice were infected with B. garinii A218 or B. burgdorferi sensu stricto N40. At 2 weeks of infection, one group was treated simultaneously with ceftriaxone and anti-TNF-alpha, whereas another received ceftriaxone at 2 weeks and anti-TNF-alpha 4 weeks later. One group received ceftriaxone treatment only. Infected and noninfected control groups were sham treated. At 14 weeks of infection, B. burgdorferi could not be detected by cultivation or by polymerase chain reaction in tissue samples of any mouse treated with ceftriaxone only. However, spirochetes grew from the tissue samples of one-third of the mice treated with anti-TNF-alpha simultaneously or 4 weeks after ceftriaxone. These activated spirochetes showed ceftriaxone sensitivity rates, plasmid profiles, and virulence rates similar to those of bacteria used to infect the mice. All infected control mice and mice given anti-TNF-alpha only were culture positive. This report shows that, after ceftriaxone treatment for 5 days, a portion of B. burgdorferi-infected mice still have live spirochetes in their body, which are activated by anti-TNF-alpha treatment.

The Effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis

Objective To assess the effect of anti-tumor necrosis factor (TNF) α therapies on the immunogenicity of pneumococcal vaccination in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Methods A group of 16 consecutive patients (11 with RA and 5 with AS) treated either with infliximab or etanercept, and a control group of 17 age-matched RA patients treated with disease-modifying medications other than anti-TNF-α, received intradeltoid injection with 0.5 mL of pneumococcal vaccine. Pneumococcal polysaccharide (PPS)-specific IgG to 7 vaccine PPS (representing high- and low-prevalence serotypes) was measured by enzyme-linked immunosorbent assay in sera obtained before and 1 month after pneumococcal immunization. Results One month after vaccination, both groups had significant increases in the geometric mean concentration of capsule PPS-specific antibody and in the mean fold increase in antibody levels to all 7 serotypes, compared with prevaccination levels. However, compared with the control group, the TNF-α blockade-treated patients tended to have lower antibody increases for all the serotypes tested except serotype 14. In addition, lower proportions of TNF-α blockade-treated patients responded to pneumococcal vaccination compared with patients on other therapies. Similarly, more TNF-α blockade-treated patients were poor responders compared with patients not on anti-TNF-α treatment. Conclusion Treatment of groups of patients with etanercept or infliximab does not impair their mean antibody responses to pneumococcal vaccination. However, a larger proportion of RA patients may not respond adequately to pneumococcal vaccination once on TNF-α blockade therapies. Consequently, pneumococcal vaccination before starting TNF-α blockade therapy is recommended.

Effects of anti-tumor necrosis factor ? on synovium in patients with spondylarthropathy: Comment on the article by Baeten et al

Effects of anti-tumor necrosis factor ? on synovium in patients with spondylarthropathy: Comment on the article by Baeten et al

Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: histologic findings in eight patients from an open-label pilot study.

To assess the effects of treatment with anti-tumor necrosis factor alpha (anti-TNFalpha) on synovial histology in patients with spondylarthropathy (SpA) in order to confirm the effect on peripheral synovitis and to investigate the immunologic mechanisms involved in anti-TNFalpha therapy. Patients with treatment-resistant SpA were treated with infliximab (5 mg/kg) at weeks 0, 2, and 6 in an open-label pilot study. In 8 patients, synovial biopsy tissues obtained at baseline, week 2, and week 12 were used for histologic and immunohistochemical evaluation. In all 8 patients (3 with ankylosing spondylitis, 1 with undifferentiated SpA, and 4 with psoriatic arthritis), there was a clear clinical improvement in the peripheral arthritis after anti-TNFalpha therapy. Histologic analysis of the synovial biopsy tissues indicated that the synovial lining layer thickness tended to decrease, with a significant reduction of CD55+ synoviocytes, at week 12. In the sublining layer, vascularity was reduced at week 12, with a decreased endothelial expression of vascular cell adhesion molecule 1 but not intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, and E-selectin. Although at week 2 and week 12, the number of neutrophils and CD68+ macrophages in the sublining layer was decreased, the overall degree of inflammatory infiltration remained unchanged. This could be related to the lymphocyte infiltration since at week 12, only CD4+ cells (but not CD3+, CD45RO+, and CD8+ cells) tended to decrease, while CD20+ lymphocytes and plasma cells were clearly increased. The reduction in lining layer thickness, vascularity, and infiltration with neutrophils and macrophages paralleled the beneficial effect of anti-TNFalpha therapy on peripheral synovitis in 8 patients with different subtypes of SpA. The adhesion molecule expression, T cell infiltration, and, most important, B cell infiltration seemed to contrast with previous observations in RA. Although these preliminary data need to be confirmed in a larger cohort, they suggest distinct immunomodulatory mechanisms of anti-TNFalpha in SpA.

Effect of Polyclonal Anti-TNFα Antibody on Endotoxic Shock in Suckling Rats

The aim of this study was to evaluate the effect of anti-tumor necrosis factor α (TNFα) antibodies on the TNFα gene expression in a neonatal septic shock model. Ten-day-old Sprague-Dawley rats were divided into four groups and given intraperitoneal (ip) injection as follows: group 1: 0.1 ml saline; group 2: 0.1 mg/kg Salmonella enteritidis lipopolysaccharide (LPS); group 3: 1 mg/kg of anti-TNFα antibodies (Ab); group 4: 0.1 mg/kg of LPS and 1 mg/kg of Ab. We found that in group 2, LPS induced shock, demonstrating hypoglycemia and lactacidemia (p < 0.05) and death (81.8%). Ab decreased the mortality significantly (35%) and attenuated the hypoglycemia (35 ± 8 mg/dl in group 2 vs. 53 ± 3 mg/dl in group 4) and lactacidemia (5.40 ± 0.63 vs. 2.35 ± 0.45 mmol) at 8 h in group 4 when compared to group 2. Northern blot demonstrated a significant decrease in TNFα mRNA expression in group 4 as compared to group 2, at 2 h after LPS injection. We conclude that the beneficial effects of anti-TNFα antibodies on LPS-induced shock may be due to decreased TNFα gene expression.

Role of TNF-α in Local Surgical Trauma-Induced Microvascular Dysfunction

Background/Aim: The aim of this study was to gain insight into the mechanisms of microvascular dysfunction after local surgical trauma. Methods: The effect of anti-tumor necrosis factor (TNF)-α antibody (Ab) on microvascular function, including arteriolar diameter response, nutritive perfusion, leukocyte-endothelial cell interaction and endothelial integrity disruption, was studied in hamster skinfold chamber preparations using intravital fluorescence microscopy. Results: Directly after the surgical procedure, arteriolar diameters were found to be markedly (p < 0.05) reduced, but recovered significantly at 8 h and reached plateau levels after 24 h. Surgical trauma further induced a strong inflammatory response characterized by a significant (p < 0.05) increase in leukocyte adherence to the endothelium of postcapillary venules. This inflammatory response was associated with an increase in microvascular permeability, indicating endothelial integrity disruption. Anti-TNF-α Ab had no significant effect on the surgical trauma-induced arteriolar vasomotor dysfunction; however, it effectively (p < 0.05) reduced venular leukocyte adherence and attenuated the increase in microvascular permeability. Conclusion: Our study indicates that arteriolar constriction, leukocyte-endothelial cell interaction and endothelial macromolecular leakage have to be considered as the characteristic microvascular response after local surgical trauma. It is conceivable that TNF-α plays a role in mediating the inflammatory response, but not the dysfunction of vasomotor control.

Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor.

To determine the effects of anti-tumor necrosis factor (anti-TNF) therapy in the inflammatory and autoimmune disease in motheaten (me/me) mice, which exhibit a Fas apoptosis signaling defect. Arthritis, pneumonitis, and mortality were analyzed in me/me mice treated with a novel, soluble, dimeric TNF receptor I (sTNFRI) molecule capable of high-affinity binding and neutralization of TNFalpha. Soluble TNFRI reduced serum levels of TNFalpha and led to a 2-fold increase in the lifespan of me/me mice, compared with the control treatment group. The treatment also reduced the development of the "motheaten" skin patches and alleviated pneumonitis and inflammatory lesions in the extremities of me/me mice compared with controls. However, the serum levels of IgM and IgM anti-double-stranded DNA autoantibody were comparable to those of untreated control mice. TNFalpha is an important cytokine involved in the pathogenesis of inflammatory disease in me/me mice, resulting in tissue damage and early mortality. Therapies directed at blocking TNF/TNFR interactions, such as the sTNFRI used in these experiments, may be effective in diseases associated with apoptosis defects leading to overutilization of the TNF/TNFR pathway.

Anti-Tumor Necrosis Factor Antibodies Inhibit the Influx of Granulocytes and Monocytes into an Inflammatory Exudate and Enhance the Growth of Listeria monocytogenes in Various Organs

This study concerns the effect of anti-tumor necrosis factor (TNF) antibodies on the course of a sterile inflammatory reaction in the peritoneum and a generalized infection with gram-positive bacteria. Mice received an intravenous injection of rabbit anti-TNF serum or normal rabbit serum 24 h before an intraperitoneal injection of heat-killed Listeria monocytogenes or an intramuscular injection of live L. monocytogenes. The course of the leukocytes in blood and the peritoneal cavity was followed for 72 h; the infection was evaluated for 144 h. The results lead to the conclusion that anti-TNF inhibits the migration of granulocytes and monocytes from bone marrow to the circulation and from the circulation to the peritoneal cavity during an acute inflammation. Furthermore, treatment of mice with anti-TNF serum enhanced the growth of Listeria monocytogenes in thigh muscle, liver, and spleen. The results of this study indicate that treatment with anti-TNF antibodies can inhibit the development of a cellular inflammatory exudate and can have a deleterious effect on the course of an infection with gram-positive bacteria.

The effect of anti-tumor necrosis factor (TNF)-α monoclonal antibody on allergic cutaneous late phase reaction in mice

Biphasic cutaneous reaction with peak response at 1 (early phase) and 24 to 48 hour (late phase)was elicited by epicutaneous challenge with antigen in actively and passively sensitized mice. Mice were actively immunized with dinitrophenylated (DNP) ascaris antigen and challenged with dinitrofluorobenzene (DNFB). Passively sensitization was carried out by the injection of monoclonal anti-DNP-IgE antibody into mice and challenge was elicited with DNFB. Prednisolone at doses of 3 to 10 mg/kg clearly inhibited both early and late phase reactions in either sensitized mice. Monoclonal anti-tumor necrosis factor (TNF)-α antibody inhibited the late phase cutaneous reaction in actively sensitized mice. Anti-interleukin-5 (IL-5) monoclonal antibody has no effect on both phase reactions in either actively and passively sensitized animals. These results indicate the possible participation of TNF-α in allergic cutaneous late phase reaction in actively sensitized mice.