Monoclonal Antibody Infliximab Research Articles

Infliximab Treatment of Intravenous Immunoglobulin–Resistant Kawasaki Disease

To investigate the safety, tolerability, and pharmacokinetics of the anti-tumor necrosis factor-alpha monoclonal antibody infliximab in subjects with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). We conducted a multicenter, randomized, prospective trial of second IVIG infusion (2 g/kg) versus infliximab (5 mg/kg) in 24 children with acute KD and fever after initial treatment with IVIG. Primary outcome measures were the safety, tolerability, and pharmacokinetics of infliximab. Secondary outcome measures were duration of fever and changes in markers of inflammation. Study drug infusions were associated with cessation of fever within 24 hours in 11 of 12 subjects treated with infliximab and in 8 of 12 subjects retreated with IVIG. No infusion reactions or serious adverse events were attributed to either study drug. No significant differences were observed between treatment groups in the change from baseline for laboratory variables, fever, or echocardiographic assessment of coronary arteries. Both infliximab and a second IVIG infusion were safe and well tolerated in the subjects with KD who were resistant to standard IVIG treatment. The optimal management of patients resistant to IVIG remains to be determined.

Update on the use of etanercept across a spectrum of rheumatoid disorders

Etanercept is a soluble TNF receptor p75 fusion protein which is approved for subcutaneous use (50 mg weekly) in the treatment of patients with active rheumatoid arthritis (RA), juvenile RA, ankylosing spondylitis, and psoriatic arthritis. Etanercept binds to both TNFalpha and lymphotoxin and has quite a short mean half-life (70 hours). Numerous randomized clinical trials have demonstrated its efficacy to improve signs and symptoms in early and established RA and other inflammatory arthritis. Furthermore, etanercept has shown its ability to prevent radiographic progression and to improve health-related quality of life in patients with RA and psoriatic arthritis. A combination of etanercept plus methotrexate was more efficacious than etanercept monotherapy in RA patients but there is currently no evidence that such rheumatic combination is better than monotherapy in other disorders. Etanercept was generally well tolerated both in controlled trials with withdrawal rates being similar to the comparator groups and in large observational studies. Infections and injection-site reactions were the most frequently reported events. Serious infections were slightly increased but the occurrence of tuberculosis seemed less frequent than with anti-TNF monoclonal antibodies (infliximab and adalimumab). The benefit-risk ratio of etanercept appeared to be very positive, and this drug has now emerged as a major therapy in patients with active inflammatory arthritis. Furthermore, it is more frequently considered as an emerging and valuable option in patients with early disease.

Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: one-year outcome of joint destruction (RECONFIRM-2J)

The anti-TNF-alpha chimeric monoclonal antibody infliximab is the first biologic to be approved for rheumatoid arthritis (RA) in Japan, and post-marketing surveillance of all of the Japanese cases treated with infliximab has been conducted to explore the safety of infliximab therapy. In addition, a retrospective clinical study on the notable efficacy and related factors of infliximab therapy in an RA management group in Japan (RECONFIRM and RECONFIRM-2) has demonstrated clinical responses. However, information on the effect of infliximab on joint destruction in Japanese RA patients remains insufficient. In this study, we retrospectively analyzed X-ray data from 67 patients in whom both hand and foot X-rays at baseline and at 54 weeks had been available among the 410 cases in the RECONFIRM-2 study. By scoring the X-rays according to the modified van der Heijde (vdH)-Sharp method, we found that the total vdH-Sharp score in the RA patients before infliximab therapy was 104.40+/-87.34 and the yearly progression was 21.33, indicating relatively rapid progression. After infliximab therapy for 54 weeks, the total vdH-Sharp score at 54 weeks was 104.37+/-86.87 and the estimated yearly progression was -0.03, indicating the almost complete inhibition of progression. The RECONFIRM-2J study confirmed the significant ability of infliximab to halt joint destruction in Japanese RA patients, and showed that joint destruction was significantly associated with disease activity and the dose of MTX in the patients with moderate and advanced disease durations, respectively, before infliximab therapy.

Effect of anti-TNF-alpha on laser-induced choroidal neovascularization

To investigate the role of TNF-alpha in the development of laser-induced choroidal neovascularization (CNV) in the mouse. Laser photocoagulation was used to induce CNV in wild-type C57BL/6J mice by making four separate choroidal bums in each eye. Animals were treated 3 days before or after laser injury with recombinant TNF receptor P75 (etanercept, 5 microg/h, group 1, n = 12), chimeric monoclonal antibody (infliximab, 5 microg/h, group 2, n = 12) for 7 days by intraperitoneally implanted osmotic pumps. PBS was used as control (group 3, n = 12). The left eyes were removed for histopathologic examination and the right eyes were removed for flatmounts immunohistochemistry immediately after fluorescein angiography. In mice treated with medications 3 days before laser injury, left eyes were collected at 1 or 2 weeks after laser injury. In mice treated with medications 3 days after laser injury, left eyes were collected at 10 days after laser injury. CNV responses were compared by flatmount analysis of CNV-related fluorescence area and by determination of fluorescein angiographic leakage. The level of protein expression of TNF-alpha was semiquantitatively evaluated by Western blot analysis of the choroidal and RPE layer from mice with or without laser treatment. Western blotting demonstrated that TNF-alpha was highly expressed in choroidal and RPE cells of wild type mice 1 week after laser treatment as compared to the control mice without laser treatment. Etanercept and infliximab administrated 3 days before laser-damage significantly reduced CNV size and pathological fluorescein leakage in comparison to the control group one and two weeks after laser injury. Only etanercept administered 3 days after laser injury still significantly reduced the development of CNV lesions. Histopathological examination confirmed that CNV lesions in treated mice had smaller diameter and thinner center as compared to the control animals. Anti-TNF-alpha treatment reduces the size and leakage of laser-induced CNV. These results suggest the involvement of TNF-alpha in the development of laser-induced CNV and its potential use as a therapeutic agent in the age related macular degeneration.

Anti-Adhesion Molecule Strategies for Crohn Disease

The last few years have been highlighted by further knowledge and optimism regarding the use of biologic therapy in Crohn disease. The introduction of anti-tumor necrosis factor (TNF) therapy into clinical practice in the form of the murine chimeric monoclonal antibody infliximab, and more recently the fully human monoclonal antibody adalimumab, has significantly advanced treatment for Crohn disease. Despite the introduction of the anti-TNF agents, 20-40% of patients will fail to respond to initial induction therapy, and of the initial responders only 60-70% will have a sustained response at 1 year. Therefore, there remains a significant unmet need in the treatment of patients with Crohn disease. A novel approach in suppressing inflammation is to intervene in the mechanisms responsible for the migration of leukocytes into inflamed tissue. One such method is by selective adhesion molecule inhibition. Several agents based on this strategy have been evaluated in the treatment of inflammatory bowel disease. It is expected that these agents will offer an alternative to the anti-TNF agent class in patients with moderate to severe Crohn disease.

Regression of Vasoproliferative Tumor with Systemic Infliximab

The anti-tumor necrosis factor (TNF) monoclonal antibody infliximab inhibits the pleiotropic actions of TNF and is widely used for the treatment of inflammatory diseases, such as uveitis. A pathogenetic role of TNF in ocular inflammatory conditions has recently emerged. The authors describe a patient with collagen mixed disease who had decreased vision in the left eye. Fundus examination disclosed bilateral peripheral vasoproliferative tumors and macular edema in the left eye. The patient underwent treatment with infliximab intravenously for his systemic condition. Regression of the vasoproliferative tumors in both eyes and improvement of macular edema in the left eye was observed. Although the data are limited, anti-TNF antibodies such as infliximab may be useful in the treatment of retinal vascular tumors.

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Non-alcoholic fatty liver disease, induced by nutritional factors, is one of the leading causes of hepatic dysfunction in the modern world. The activation of proinflammatory signaling in the liver, which is induced by systemic and locally produced cytokines, and the development of hepatic insulin resistance are two important factors associated with the progression from steatosis to steatohepatitis, a pre-cirrhotic condition. The objective of the present study was to evaluate the effect of inhibition of tumour necrosis factor (TNF)-alpha , using the monoclonal antibody infliximab, on the expression of cytokines, induction of steatosis and fibrosis, and insulin signal transduction in the liver of Wistar rats fed a high-fat diet. Ten days of treatment with infliximab significantly reduced the expression of the proinflammatory markers, TNF-alpha , IL-6, IL-1beta , and SOCS-3, in the liver of rats fed a high-fat diet. This was accompanied by reduced fat deposition and fibrosis and by improved insulin signal transduction through insulin receptor (IR)/IR substrate/Akt/FOXO1 and JAK2/STAT3 pathways. In conclusion, short-term inhibition of TNF-alpha with infliximab reduces inflammation and steatosis/fibrosis, while improving insulin signal transduction in an animal model treated with a high-fat diet.

Infliximab Restores Glucose Homeostasis in an Animal Model of Diet-Induced Obesity and Diabetes

TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.

Tumour necrosis factor alpha down-regulation parallels inflammatory regression in ulcerative colitis patients treated with infliximab

Background Treatment with the anti-tumour necrosis factor α monoclonal antibody infliximab has been shown to be effective in moderate-to-severe ulcerative colitis. However, its effect on the mucosal histopathological abnormalities of this disease is largely unknown. This study aimed to assess the immunohistological effect of infliximab in ulcerative colitis. Methods Nine patients with moderate-to-severe ulcerative colitis received infliximab (5 mg/kg) at weeks 0, 2 and 6, respectively. Colonic biopsies were collected before therapy and at week 10, when the Mayo score (including the endoscopic subscore) was also assessed. Severity of inflammation was evaluated by histologic score and histomorphometry. Immunohistochemical staining with antibody against tumour necrosis factor α was performed on all biopsies and expressed as percentage of positive stromal cells/1000 counted (tumour necrosis factor α score). Results A profound down-regulation of mucosal tumour necrosis factor α occurred in all the six patients who achieved a clinical response, but not in the three who did not respond. Median tumour necrosis factor α score dropped from 44.8 (range 35–58.3) to 12.8 (range 5.3–15.3) in the responders ( p = 0.03), whilst it remained unchanged in the non-responders. Such effect was related with a dramatic regression of the median histologic score, which dropped from 2.7 (range 2–3) to 0.5 (range 0.0–1.5) in responder patients ( p = 0.002). This was related to a virtual disappearance of neutrophils in responders ( r = 0.72; p = 0.002; Spearman's test), but not in those who did not improve. Tumour necrosis factor α score appeared to be correlated with the histologic, endoscopic and clinical activity. Conclusions A profound tumour necrosis factor α down-regulation appears to be strictly associated with a dramatic regression of the inflammation in patients with moderate-to-severe ulcerative colitis treated with infliximab. Such immunohistochemical effect seems to be critical for a clinical and endoscopic response to therapy.

Treatment with infliximab may contribute to the development of peripheral neuropathy among the patients with rheumatoid arthritis

Sir, We have read with the interest the paper of Tektonidu et al. [1] reporting the two cases of peripheral neuropathy in patients with rheumatoid arthritis treated with anti-tumor necrosis factor (anti-TNF) alpha monoclonal antibody infliximab. The paper addresses the problem of potential side effects of infliximab upon peripheral nervous system. In spite of the fact that peripheral nervous system damage is not often reported in patients with rheumatoid arthritis on anti-TNF alpha treatment, the observation is of great clinical values when taking into consideration thousands of patients treated with a such an agent [2]. The role of TNF alpha in pathogenesis of nervous system damage is not fully elucidated. TNF alpha is thought to play a significant role in the pathogenesis of inflammatory demyelinating disease of the central nervous system, which was demonstrated in humans and in animal models [3–5]. If it is true, anti-TNF alpha agents would exert protective activity against demyelination of central and peripheral nervous systems. Many facts however suggest otherwise. The study with lenarcept, a soluble dimeric p55 TNFR–IgG fusion protein in patients with multiple sclerosis (MS), was terminated prematurely because of unexpected exacerbation of the disease. The study was designed to verify a good therapeutic response observed in animal model of MS [6]. These facts are instructive into two ways: Firstly, it is difficult to translate the results from animal models directly to man, and secondly, toxic effect of anti-TNF alpha blockers may be due to imbalance of TNF alpha and TNF alpha receptor levels in the patients. Rapid changes in concentrations of TNF alpha may thus potentially evoke or worsen underlying latent demyelinating process. As the problem of peripheral neuropathy in patients receiving anti-TNF alpha agents was not explained well in prospective studies, we undertook the 1 year observational study. During this period of time, 28 patients (26 women and 2 men) with active, refractory to standard diseasemodifying anti-rheumatic drug (DMARD) therapy were investigated. All patients were treated with infliximab within 1 year (cumulative dose, 36 mg/kg of body mass). Before administration of the first dose of infliximab and after 12 months of therapy, electromyography was carried out in all patients. The examination included measurement of motoneuronal conduction velocity and amplitude in the following nerves: median, peroneal, tibial and ulnar and sensory neuronal velocity, and amplitude in the median, sural, and ulnar nerves. Before the first administration of infliximab, all patients were characterized by normal nervous function. There were no disturbances in conduction velocity and amplitude in examined nerves. After 12 months of the treatment with TNF alpha antagonist, we observed statistically significant changes in following electromyographic parameters: an increased motoneuronal amplitude in median nerve (4.93 vs 8.06 mV) and a decrease in conduction velocity in the nerves of lower limbs; tibial and sural 50.88 vs 47.08 m/s, and 48.73 vs 44.93 m/s respectively [7]. These results were still in normal limits, and the patients continued to be asymptomatic. Data obtained from our study suggests, however, that anti-TNF alpha treatment exerts impact on peripheral nervous system function and, in some predisposing circumstances, may result in overt neuropathy. In the light of the Clin Rheumatol (2007) 26:1595–1596 DOI 10.1007/s10067-007-0657-3

Reactivation of Latent Tuberculosis by TNF Blockade: The Role of Interferon γ

Tumor necrosis factor (TNF) plays a pathogenic role in psoriasis and rheumatoid arthritis but is essential for host defenses against mycobacteria and other granulomatous pathogens. The risk of reactivation of latent Mycobacterium tuberculosis infection is significantly greater with the TNF monoclonal antibody infliximab than with the soluble TNF-receptor etanercept. We have examined the biologic basis of this difference using whole blood culture. Infliximab and adalimumab reduced the proportion of T buciclate-responsive cells by 70 and 50%, respectively, and suppressed antigen-induced IFN-gamma production by 70 and 64%. In contrast, etanercept produced no significant effect. The difference between infliximab and etanercept remained whether one compared equal or peak therapeutic drug concentrations, suggesting a relationship to mechanism of action rather than pharmacokinetics. Adalimumab and etanercept caused divergent, concentration dependent effects on control of intracellular growth of M. tuberculosis. None of the drugs induced significant levels of apoptosis or necrosis in monocytes or T cells, excluding T-cell death as a mechanism for suppression of antigen-induced responses. IL-10 production was equally suppressed by all three drugs, excluding excess IL-10 as a regulatory mechanism. The tuberculosis risk posed by infliximab may reflect its combined effects on TNF and IFNgamma.

Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety

Tumor necrosis factor-α (TNFα), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFα activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U.S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger controlled trials have demonstrated efficacy for etanercept in RA patients who have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA approval for RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.

TUMOR NECROSIS FACTOR ANTAGONISTS

The anti-tumor necrosis factor (TNF) monoclonal antibody infliximab and the soluble TNF receptor etanercept inhibit the pleiotropic actions of TNF and are widely used for the treatment of rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), spondyloarthropathies (SpA), Crohn's disease, and psoriasis with an acceptable safety profile. A pathogenetic role of TNF in ocular inflammatory conditions has recently emerged from small trials reporting preliminary results on the efficacy of these agents in patients with noninfectious uveitis, regardless of the origin of the disease. The authors review the published experience, derived mostly from investigator-sponsored trials and uncontrolled case series, on the use of TNF antagonists in approximately 280 patients with various ocular conditions who were inadequately controlled on currently available therapy. These reports suggest that TNF antagonists, mainly infliximab, which may have better efficacy than etanercept, are useful in the treatment of ocular inflammation associated with Adamantiades-Behçet's disease, RA, JIA, SpA, Crohn's, sarcoidosis, and Graves' disease ophthalmopathy. Infliximab was also beneficial in small numbers of patients with idiopathic uveitis or scleritis, birdshot retinochoroiditis, uveitic and diabetic cystoid macular edema, and age-related macular degeneration. The currently available data are nonrandomized and thus preliminary, providing the foundation and justification for randomized trials to assess efficacy and safety. Until such results are available, knowledge regarding the use of anti-TNF regimens in ophthalmology is incomplete. However, the preliminary evidence points to a growing optimism for targeting TNF in patients with ocular inflammation.

Early changes in rectal nitric oxide and mucosal inflammatory mediators in Crohn’s colitis in response to infliximab treatment

Treatment with tumor necrosis factor-alpha monoclonal antibody (infliximab) reduces clinical activity and intestinal inflammation in Crohn's disease. To study the time-course of the effects of infliximab with reference to mucosal cytokine and inducible nitric oxide synthase expression. Thirty-two patients with Crohn's disease were treated with single dose infliximab (5 mg/kg). Disease activity was assessed days 1, 3, 7 and 28 using Harvey-Bradshaw index. Rectal nitric oxide levels were determined and rectal biopsies collected before treatment, 1 h after infusion and on days 3, 7 and 28. Immunohistochemical staining against inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1beta and interferon-gamma were performed. Clinical response was seen in 14 patients with down-regulation of global immunohistochemistry expression, reaching nadir day 3. Rectal nitric oxide was increased at baseline (3578 +/- 1199 parts per billion, ppb) compared with controls (89 +/- 13 ppb) (P < 0.001). In patients with clinical response, rectal nitric oxide decreased from 3926 +/- 1687 ppb to 1050 +/- 428 ppb day 28 (P < 0.05). Down-regulation of mucosal inflammatory mediators occurs after infliximab. Rectal nitric oxide levels parallel down-regulation of inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1beta and interferon-gamma and may serve as a quantitative biomarker of intestinal inflammation.

Tumor necrosis factor α acceleration of inflammatory responses by down‐regulating heme oxygenase 1 in human peripheral monocytes

To examine the interaction between heme oxygenase 1 (HO-1), a stress-induced antiinflammatory protein, and tumor necrosis factor alpha (TNFalpha) in human peripheral blood monocytes. Peripheral blood mononuclear cells (PBMCs) were obtained from healthy donors or from patients with rheumatoid arthritis (RA) receiving the anti-tumor necrosis factor alpha (anti-TNFalpha) monoclonal antibody infliximab. CD14+ cells were isolated by magnetic cell sorting, cultured with TNFalpha or auranofin, and transfected with a plasmid encoding HO-1 or an HO-1-specific small interfering RNA vector. Protein and messenger RNA (mRNA) levels were examined by immunoblotting and real-time polymerase chain reaction. Cytokine levels in culture supernatants were measured by enzyme-linked immunosorbent assay. HO-1 gene transcription was evaluated using a luciferase reporter gene assay. Actinomycin D and cycloheximide were used to monitor the stability of mRNA and protein. HO-1 is constitutively expressed by CD14+ PBMCs from healthy donors. TNFalpha suppressed HO-1 expression by accelerating the decay of mRNA without affecting gene transcription or protein stability. Forced expression or selective knock-down of the HO-1 gene expression resulted in down-regulation or up-regulation, respectively, of proinflammatory cytokine synthesis by monocytes. Treatment with infliximab significantly increased HO-1 mRNA levels and reduced TNFalpha synthesis by PBMCs from RA patients. TNFalpha accelerated inflammatory responses by down-regulating HO-1 expression in human monocytes. TNF antagonists may block this TNF-dependent suppression of HO-1 expression, resulting in an amelioration of inflammation.

Infliximab treatment influences the serological expression of matrix metalloproteinase (MMP)-2 and -9 in Crohnʼs disease

Matrix metalloproteinases (MMPs) are actively involved in the pathogenesis of Crohn's disease (CD). We assessed the effect of the anti-tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody infliximab on the in vitro and in vivo expression of MMP-2 and MMP-9 in CD. Infliximab-treated fistulizing (n = 10) or active disease (n = 7) CD patients, from an in-house study, and fistulizing CD patients (n = 42) and active CD patients (n = 24) from 2 placebo controlled studies were evaluated for serum MMP levels and clinical response. Biopsies were evaluated immunohistochemically for the MMPs. Whole blood cultures stimulated with lipopolysaccharide (LPS)/infliximab were evaluated for MMP mRNA and protein levels. Serum MMP-2 levels in CD patients increased during follow-up, similarly in responders and nonresponders, by infliximab. Immunohistochemistry showed no clear MMP-2 change in biopsies. Serum MMP-9 levels, however, showed a consistent pattern of decrease in most CD patients, particularly in those responding, and MMP-9-positive polymorphonuclear leukocytes in biopsies also decreased by infliximab. LPS stimulation of whole blood increased the MMP-9 levels in plasma significantly in CD patients and controls, but infliximab had no effect on the secretion. Long-term LPS stimulation raised leukocyte MMP-9 mRNA levels 16-fold and infliximab inhibited this induction by 80%. Infliximab treatment increases MMP-2 and decreases MMP-9 in serum of patients with CD, the latter also in the intestine, which extends and confirms our previous ex vivo explants observations. However, these changes were not strictly associated with the response to treatment. The enhanced leukocyte MMP-9 expression in CD seems to be regulated by TNF-alpha.

Therapeutic Effects of Anti-Tumor Necrosis Factor Monoclonal Antibody on Experimental Uveitis

Purpose: We investigated the therapeutic effects of monoclonal anti-TNF antibody (infliximab) on experimental uveitis. Methods: Twenty New Zealand White rabbits were immunized with Mycobacterium tuberculosis H37Ra antigen and then challenged with intravitreal injection of tuberculin antigen to introduce a uveitis. Then infliximab was injected into rabbit eyes at an intravenous concentration of 5 mg/kg and intravitreal concentrations of 1 mg/0.1mL and 100 microg/0.1mL. As a control, the vehicle was injected intravenously or intravitreally. To evaluate the therapeutic effects, inflammation was assessed by slit lamp biomicroscopy and scored according to the severity of inflammation. The animals were also evaluated by electroretinography and histopathology. Results: Regardless of the administration route, inflammatory activities of anterior chamber and engorgement of vascular structures were reduced in the infliximab treated group compared to control. Different administration routes and different concentrations of infliximab did not affect the therapeutic outcome of the clinical scoring. Intravenous (5 mg/kg) and intravitreal diluted (100 microg/0.1mL) infliximab injection groups showed significant improvement in electroretinographic findings and significant reduction of inflammatory cells with preservation of retinal tissue architecture on histopathologic examination. However, focal loss of the photoreceptor outer segment is observed in intravitreal undiluted (1 mg/0.1 mL) infliximab injected eyes. Conclusions: Infliximab may be a useful treatment modality to suppress ocular inflammation in experimental uveitis models in rabbits.

Antitumor Necrosis Factor (TNF-a) Antibodies in the Treatment of Renal Cell Cancer

The kinase inhibitors sorafinib and sunitinib have demonstrated significant activity in renal cell carcinoma (RCC), and are now approved by the FDA for use in advanced disease. There still remains a need for novel therapies. Our group were the first to demonstrate activity of thalidomide in RCC, believed to be in part related to the modulation of tumor necrosis factor (TNF-a), a cytokine secreted by RCC with a number of tumor promoting properties. We subsequently conducted a phase II trial of the TNF-a monoclonal antibody infliximab in patients with previously treated advanced RCC. The drug was well tolerated. The response rate was 16% and stability was achieved in a further 16% of patients. Anti-TNF-a therapy may represent an important approach in the treatment of this disease.

A patient with neuro-Behçet's disease is successfully treated with etanercept: Further evidence for the value of TNFα blockade

Behçet's disease is a chronic relapsing multisystem vasculitis with 49% of cases involving the CNS. Recently there have been two reports of neuro-Behçet's disease (NB) successfully treated with the tumour necrosis factor α (TNFα) monoclonal antibody infliximab. We describe a patient with longstanding NB who was poorly responsive to azathioprine, cyclosporin, thalidomide and methotrexate. She showed a remarkable response when treated with the recombinant human TNFα receptor protein, etanercept. To the best of our knowledge this is the first report of NB successfully treated with etanercept.

Bacterial and opportunistic infections during anti-TNF therapy

Tumour necrosis factor alpha (TNF-alpha) plays a crucial role in host defence against bacterial infections. Summarizing the results, the findings of immunological and clinical research suggest a higher infection risk in rheumatoid arthritis and ankylosing spondylitis patients receiving anti-TNF treatment. This is especially true for granulomatous infections in patients treated with the monoclonal TNF-alpha antibodies infliximab or adalimumab. Furthermore, patients treated with TNF inhibitors have a higher susceptibility to infections because of their higher active and more severe disease. Therefore, patients receiving anti-TNF treatment should be closely monitored for serious infections. A rapid and sufficient treatment of infections that are not mild and transient is recommended. There are atypical signs and symptoms as well as atypical pathogen that should be considered. Patients should be educated about how to avoid infectious complications.