Necrosis Factor Alpha Antibody Infliximab Research Articles

Serial Changes in Intestinal Stenotic Stiffness in Patients with Crohn's Disease Treated with Biologics: A Pilot Study Using Ultrasound Shear Wave Elastography.

Intestinal strictures represent an important serious complication of Crohn's disease. Shear wave elastography is a promising noninvasive ultrasound technique for assessing tissue stiffness. This study aimed to evaluate stiffness in the areas of intestinal stricture in patients with Crohn's disease using shear wave elastography and the changes in stiffness after biologics. We enrolled 21 Crohn's disease patients having intestinal stricture. The patients consisted of 3 groups, which were the infliximab naïve (n = 6) group, the ustekinumab naïve (n = 8), and the bio-switch from infliximab to ustekinumab (n = 7) group. Bowell wall thickness was examined by ultrasound sonography, and the stiffness of Crohn's disease stricture lesions was evaluated using Shear wave speed before and 1 year after anti-tumor necrosis factor-alpha antibody infliximab, anti-interleukin 12/23 antibody ustekinumab, and bio-switch from infliximab to ustekinumab. Bowell wall thickness was significantly improved after infliximab, ustekinumab, and the bio-switch. However, shear wave speed indices only in the ustekinumab group significantly decreased after treatment (P = .028), but not in the other group. Shear wave elastography might be a useful method to evaluate stiffness in the areas of intestinal stricture in patients with Crohn's disease treated with biologics. However, a prospective randomized study evaluating the development of obstruction after biological treatment is needed to validate the study findings.

P6286Old age significantly worsens stroke outcome in old mice through a mechanism of inflamm-aging successfully countered by the tumour necrosis factor alpha antibody infliximab

Abstract Background Stroke is the second leading cause of death and the number one cause of adult disability worldwide. As a strongly age-dependant disease, its prevalence is expected to rise along with the average age in western populations. While the epidemiological evidence linking stroke to age is non-refutable, the specific and independent effects of age on stroke remain elusive. This presents an important missing link for developing targeted treatments tailored to the growing elderly population. A potential mechanism pertinent to stroke outcome in the elderly is a chronic low-grade inflammatory state, coined “inflamm-aging”. Such a phenomenon could not only increase the risk for stroke, but also negatively affect its outcome and thus offers both preventive and therapeutic value. Purpose To determine the specific effects of age on the outcome after stroke in mice and delineate culprit molecular pathways with a focus on inflammatory mediators and to assess the efficacy of specific anti-inflammatory treatment with the TNF-α antibody Infliximab in this setting. Methods Old (18–20 months) C57BL/6 wildtype mice were compared to young (12 weeks) controls. Baseline levels of inflammatory cytokines were assayed in plasma and brain homogenates by ELISA. Ischemic stroke was induced by transient middle cerebral artery occlusion (30 minutes/48 h). Neurological function was assessed by a Bederson based score and the RotaRod test. Anti-inflammatory treatment with Infliximab was administered to a subset of old mice via weekly intraperitoneal injections (10 mg/kg) for 4 weeks prior to stroke induction. Young and old control animals received vehicle. Results At baseline (prior to stroke), old animals showed significantly higher plasma levels of TNF-α compared to young (Fig. 1A), while IL-6 and IL-1β remained below detection level in both groups. In brain homogenates of healthy old and young animals, TNF-α and IL-1β did not differ, while IL-6 was below detection level. Old mice showed significantly larger stroke sizes (Fig.1B), performed worse neurologically (Fig. 1C) and suffered from higher post-stroke mortality compared to young (Fig. 1D). Pre-treatment with the TNF-α inhibitor Infliximab significantly decreased stroke size, neurological impairment and mortality in old animals (Fig1B-D). Figure 1 Conclusions In a model lacking additional confounding factors, we demonstrate a direct adverse effect of age per se on stroke outcome and mortality. Elevated TNF-α plasma levels in old mice outline the mechanism of “inflamm-aging” as a possible culprit. This concept is strongly supported by the beneficial effect of Infliximab on stroke outcome in old animals. Further investigation of the downstream mediators of the observed effect could help in tailoring treatments to the particularly vulnerable and growing elderly population.

Sudden Progression from Impaired Glucose Tolerance to Type 2 Diabetes after Discontinuation of Administration of Anti-Tumor Necrosis Factor-Alpha Antibody Infliximab

We present the case of a 45-year-old man with psoriasis and psoriatic arthritis and concomitant impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). In this patient, refractory to DMARD's, infliximab was started to control the arthritis. After achieving clinical remission of the disease, infliximab was discontinued and a 75 g- oral glucose tolerance test (OGTT) was performed. After the test, we observed a conversion from IFG/IGT glucose tolerance status to type 2 diabetes. No diet, lifestyle or therapy modifications were made during the observation period. Autoimmune diabetes was ruled out by serum antibodies determination and body weight remained constant, sustaining a protective role in infliximab in the worsening of glucose tolerance.

IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab

The chimeric anti-tumor necrosis factor-alpha antibody infliximab is known to induce antibodies-to-infliximab (ATI) in some treated patients. Immunogenicity in murine variable domains is expected; however, constant domains of its human heavy gamma1 chain may also be implicated as it expresses G1m1 and G1m17 allotypes. This allelic form may be immunogenic in patients that are homozygous for the G1m3 allotype commonly expressed in Caucasoid populations. As G1m allotypic divergence may explain the presence of ATI or may influence their concentration, a genotyping method was developed and validated to determine antithetical (i.e. mutually exclusive) G1m3 and G1m17 allotypes (amino acid 120 of CH1 according to the international ImMunoGeneTics information system unique numbering) at the IGHG1 gene level (CH1 359g/a nucleotide polymorphism). Two hundred forty-five blood donors and 118 previously described patients suffering from Crohn's disease, treated with infliximab, and having developed ATI in 73 of them, were genotyped. The IGHG1 CH1 359g/a polymorphism does not depart from the Hardy-Weinberg equilibrium in the control population, and allele frequencies were similar in controls and patients. No association was found between the patient G1m allotypes and the presence of ATI or their concentration. It remains possible that anti-Gm1 antibodies are not well detected by the enzyme-linked immunosorbent assays used for ATI detection and/or that the G1m allotypes are minor antigens on IgG1. The IGHG1 polymorphism does not seem to play a major role in the induction of ATI. Further analyses will be required to determine whether it is also the case for humanized or fully human antibodies bearing the same G1m allotypes.

Palmoplantar Pustulosis and Acrodermatitis in a Patient Treated With Infliximab for Crohn's Sacroiliitis

A 35-year-old woman developed pustules of the palmar and plantar skin after infusion of the chimeric tumor necrosis factor–alpha antibody infliximab (Remicade; Schering-Plough Inc, Kenilworth, NJ) for Crohn's sacroiliitis. The patient was diagnosed with Crohn's disease of the colon and terminal ileum in 1994 at the age of 22. Remission was maintained with standard medications. In 2007 she presented with bilateral sacroiliitis that did not respond to treatment with physical therapy, NSAIDs, mesalamine, corticosteroids, and azathioprine.

Infliximab for pediatric Crohn's disease

The natural history of Crohn's disease (CD) is characterized by recurrent flares combined with periods of inactive disease. The goal of therapy should be to induce and maintain clinical remission, to strive for endoscopic healing of the intestinal mucosa and to improve the quality of life. The nineties have been characterized by the introduction of biological therapies designed to block or neutralize pro-inflammatory cytokines which play a role in the pathogenesis of the disease. Biologic treatment with the anti-human tumor necrosis factor alpha antibody infliximab has dramatically changed the therapeutic approach even in pediatric patients. Numerous studies are available and report the beneficial effect of infliximab in pediatric CD patients with moderate to severe disease, refractory and steroid-dependent patients. The safety profile of infliximab is overall favorable although continued vigilance, especially for the occurrence of infrequent but serious events, including opportunistic infection and lymphomas, remains necessary.

Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumor necrosis factor alpha antibody infliximab

Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumor necrosis factor alpha antibody infliximab

Clinical response to the anti-tumor necrosis factor alpha antibody infliximab in patients with ankylosing spondylitis over 3 years

Clinical response to the anti-tumor necrosis factor alpha antibody infliximab in patients with ankylosing spondylitis over 3 years

Combining infliximab and methotrexate in fistulizing Crohn's disease resistant or intolerant to azathioprine.

Crohn's disease is complicated by fistulas in 20-40% of patients at some time during the course of their illness. Azathioprine has been reported to heal fistulas in 30-40% of cases. Long-lasting effects by the anti-tumour necrosis factor-alpha antibody infliximab most often require repeated infusions. Methotrexate has been shown to be an effective drug in maintaining remission in Crohn's disease. To evaluate the combination of infliximab and methotrexate as therapy for fistulas in patients with Crohn's disease. Twelve consecutive patients (mean age, 29.5 years) with fistulizing Crohn's disease resistant or intolerant to azathioprine were followed prospectively. Patients received three infusions of infliximab (5 mg/kg) and long-term methotrexate (20 mg/week). Therapy success was defined as sustained closure of fistulas > or = 6 months after fistula closure. In four of the 12 patients, complete closure of fistulas that persisted for > or = 6 months (median follow-up, 13.25 months) was observed. In three further patients, a partial response was noted. In five patients, persistent therapy success could not be achieved or therapy had to be stopped due to side-effects. A combination of infliximab with long-term methotrexate may be a promising concept in fistulizing Crohn's disease. Our data indicate the need for larger controlled trials.

Tumor necrosis factor α blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue

To determine whether treatment with the chimeric anti-tumor necrosis factor alpha antibody infliximab could reduce cellularity by the induction of apoptosis in synovial tissue. Twenty-four rheumatoid arthritis patients with active disease were randomized to receive either infliximab (3 mg/kg) (n = 12) or placebo (n = 12) intravenously. All patients were subjected to arthroscopic synovial biopsy directly before initiation of treatment. A second arthroscopic synovial biopsy of the same index joint was performed 48 hours after the first arthroscopy. After the second arthroscopy, the patients who had initially received placebo were also treated with infliximab in an extension study. A third arthroscopy was performed in all patients on day 28. Immunohistologic analysis was performed to characterize the cell infiltrate. In situ detection of apoptotic cells was performed by TUNEL assay and electron microscopy. At 48 hours after initiation of infliximab treatment, there was a significant reduction in the number of intimal macrophages; this was not observed in the placebo group. The number of sublining macrophages, T cells, and plasma cells also tended to be decreased in infliximab-treated patients, but not in the placebo group. Of interest, we did not detect any increase in the number of apoptotic cells after infliximab treatment. Infliximab therapy may reduce the number of inflammatory cells in rheumatoid synovial tissue as soon as 48 hours after initiation of treatment, but apparently not by induction of apoptosis. Conceivably, decreased cell infiltration primarily results from early inhibition of cell migration.