BACKGROUND: Systemic inflammation such as rheumatoid arthritis (RA) and Crohn's disease (CD) may be responsible for vascular comorbidity. TNF-alpha blockade was expected to lower these comorbidities but several cases of arterial and venous thromboembolic events (TE) have been reported. OBJECTIVES: The aim of this work was to study retrospectively the main characteristics of spontaneously notified TNF-alpha blockers related TE over a 7-year period. METHODS: TE related to infliximab, etanercept and adalimumab spontaneously notified to the French adverse drug reporting system database between January 2000 and December 2006 were analyzed. Separate analysis of arterial TE and venous TE was performed. Risk factors for each category of TE were assessed with consensual criteria. RESULTS: 85 TE were analyzed, representing 4.5% of all the spontaneously notified adverse reactions of the 3 TNF-alpha blockers in the database. 42 were arterial events and 43 were venous events. The incidence was not significantly different between the 3 TNF-alpha blockers. Mean delay of TE onset after treatment initiation was 10.6 months. It was significantly shorter for etanercept (6.1 months, p=0.001) especially for venous TE (2.4 months). 16 among the 42 patients with arterial TE had 2 or more risk factors whereas 39 among the 43 patients with venous TE had no RF or only one. Most of patients (79/85) received concomitant systemic corticosteroids and/or methotrexate and/or COX-2 selective inhibitors. 23 patients had been investigated for autoimmunity, 13 had antinuclear and/or antiphospholipid antibodies. Main limitations of this study were underreporting and heterogeneous report contents. CONCLUSION: Despite its limitations, this study suggests that venous TE could be favoured by TNF-alpha blockers therapy since they occurred in patients with no or few risk factors for venous thrombosis. However, this needs to be more evaluated by controlled studies. less...

Acute stretch caused by volume overload (VO) of aorto-caval fistula (ACF) induces a variety of myocardial responses including mast cell accumulation, matrix metalloproteinase (MMP) activation and collagen degradation, all of which are critical in dictating long term left ventricle (LV) outcome to VO. Meanwhile, these responses can be part of myocardial inflammation dictated by tumor necrosis factor-alpha (TNF-alpha) which is elevated after acute ACF. However, it is unknown whether TNF-alpha mediates a major myocardial inflammatory response to stretch in early VO. In 24 hour ACF and sham rats, microarray gene expression profiling and subsequent Ingenuity Pathway Analysis identified a predominant inflammatory response and a gene network of biologically interactive genes strongly linked to TNF-alpha. Western blot demonstrated increased local production of TNF-alpha in the LV (1.71- and 1.66-fold in pro- and active-TNF-alpha over control, respectively, P < 0.05) and cardiomyocytes (2- and 4-fold in pro- and active-TNF-alpha over control, respectively, P < 0.05). TNF-alpha neutralization with infliximab (5.5 mg/kg) attenuated the myocardial inflammatory response to acute VO, as indicated by inhibition of inflammatory gene upregulation, myocardial infiltration (total CD45+ cells, mast cells and neutrophils), MMP-2 activation, collagen degradation and cardiac cell apoptosis, without improving LV remodeling and function. These results indicate that TNF-alpha produced by cardiomyocytes mediates a predominant inflammatory response to stretch in the early VO in the ACF rat, suggesting an important role of TNF-alpha in initiating pathophysiological response of myocardium to VO. less...

Fully-human monoclonal antibodies (mAbs) derived from transgenic mice or human antibody libraries are the current state of the art for reducing the immunogenicity risk of antibody drugs. Here we describe a novel method for generating fully-human mAbs from non-human variable regions using information from the human germline repertoire. Central to our strategy is the rational engineering of residues within and proximal to CDRs and the V(H)/V(L) interface by iteratively exploring substitutions to the closest human germline sequences using semi-automated computational methods. Starting from the parent murine variable regions of three currently marketed mAbs targeting CD25, VEGF, and TNFalpha, we have generated fully-human antibodies with 59, 46, and 45 substitutions, respectively, compared to the parent murine sequences. A large number of these substitutions were in the CDRs, which are typically avoided in humanization methods. Antigen affinities of the fully-human variants were comparable to the chimeric mAbs in each case. Furthermore, in vitro functional characterization indicated that all retain potency of the chimeric mAbs and have comparable activity to their respective marketed drugs daclizumab, bevacizumab, and infliximab. Based on local and global sequence identity, the sequences of our engineered mAbs are indistinguishable from those of fully-human mAbs isolated from transgenic mice or human antibody libraries. This work establishes a simple rational engineering methodology for generating fully-human antibody therapeutics from murine mAbs produced from standard hybridoma technology. less...

The present study was designed to investigate the interaction between platelet indices (mean platelet volume (MPV), platelet count (PLC) and platelet mass (PLM)), inflammatory markers and disease activity in ankylosing spondylitis (AS) subjects. The effects of anti-TNF-alpha therapy and conventional treatment on platelet indices were also compared. We studied 68 patients with AS (group I, 46 men, age: 36.4 +/- 6.9 years) and as control group 34 age and sex-matched healty subjects. All patients received conventional therapy (CT) at the beginning (Group I). The patients were reevaluated after 3 months according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Group II consisted of 35 subjects who responded to the CT and continued to take the same therapy for 3 months additionally. Group III consisted of 33 subjects who had a high disease activity score (BASDAI > 4) after 3 months and were accepted refractory to the CT therapy. In Group III the treatment was switched to infliximab and continued for 3 months at the standard intravenous dose. Significantly higher baseline MPV, PLC and PLM was reported as compared to controls decreased by therapy (9.12 +/- 1.20 vs. 8.35 +/- 0.94 fl, p < 0.001, 340 +/- 69 vs. 251 +/- 56 (x10(3)/ microL) p < 0.0001, 3096 +/- 736 vs. 2110 +/- 384; p < 0.0001, respectively). In the same way, they were substantially lowered by both treatments in group II and group III. PLC and PLM were positively correlated with WBC and ESR (r : 0.44; p < 0.0001, r : 0.41; p = 0.001, r : 0.52; p < 0.0001, r : 0.41; p = 0.001), respectively) in AS patients. Additionally, MPV and PLM were positively correlated with BASDAI score (r : 0.41; p < 0.001, r = 0.29; p < 0.001 respectively). We have found that increased platelet activity reduced by therapy in AS patients. Additionally, it was correlated with inflammatory markers and disease activity. According to these results, it can be suggested that both anti-TNF-alpha and conventional therapy might contribute to a decrease in the risk of cardiovascular morbidity and mortality in AS patients. less...

The present study was designed to investigate the interaction between platelet indices, inflammatory markers and disease activity in rheumatoid arthritis (RA) subjects. The effects of anti-TNF-alpha therapy and conventional treatment on platelet indices were also compared. We studied 97 patients with RA (19 men, 78 women: mean age 51 years) and 33 age and sex-matched healthy subjects as a control group. All RA patients were administered conventional therapy. After 3 months of therapy, 35 subjects who had high disease activity score (DAS28 > 5.1) were grouped as non-responders and were administered infliximab as a TNF-alpha blocker at the standard intravenous dose. Responders to the conventional therapy and non-responders were also compared. At baseline white blood cell (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet count and mean platelet volume (MPV) were significantly higher in patients with RA. Mean platelet volume was positively correlated with DAS28 score (r = 0.27; p = 0.007). These markers of inflammation and platelet indices were substantially decreased after therapy. The reductions were similar in responders to conventional therapy and non-responders (TNF alpha group). In conclusion, we found that MPV was correlated with inflammatory markers and disease activity in patients with RA. Both anti-TNF-alpha and conventional therapy decreases markers of inflammation and platelet indices. MPV can reflect both disease activity and response to treatment. less...

Tumor necrosis factor alpha (TNF-alpha) is a cytokine, implicated in the pathogenesis of many inflammatory diseases, as well as in the immune-mediated response to infection, especially against intracellular pathogens. TNF-alpha antagonists have represented a revolution in the management of connective tissue diseases, such as rheumatoid arthritis. However, the use of these agents has been implicated with the emergence of a growing number of opportunistic infections. Here we report the case of a visceral Leishmaniasis in a 77-year-old woman who had been previously treated for rheumatoid arthritis with infliximab. The atypical presentation of this patient, previously treated with an anti-TNF-alpha biologic agent, where no splenomegaly or hepatomegaly was identified, is emphasized. less...

OBJECTIVE: To systematically review the general and comparative efficacy and safety of anakinra for rheumatoid arthritis. METHODS: We searched MEDLINE((R)), Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 to April 2009. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database. For efficacy we included randomized controlled trials (RCTs) comparing anakinra with placebo or other biologics For safety both experimental and observational studies were eligible. Two persons independently reviewed abstracts and full text articles and extracted relevant data. RESULTS: We included data from 3 RCTs comparing anakinra with placebo for rheumatoid arthritis (RA). The pooled relative risk (RR) of an ACR50 (American College of Rheumatology) response for anakinra compared with placebo is 2.28 (95% CI 1.41 to 3.67) Adjusted indirect comparisons of ACR50 response rates of anakinra and anti-TNF agents showed a RR of 0.67 (95% CI 0.38 to 1.17) favoring the anti-TNF drugs This result did not reach statistical significance. For safety, we included 9 experimental and observational studies of 24 weeks to 3 years duration. Up to 30% of patients withdrew from the studies due to adverse events. 67.2% (95% CI 38.7 to 95.7) of patients experienced an injection site reaction. CONCLUSIONS: Anakinra is an effective drug for treating RA. Indirect comparisons with adalimumab, etanercept and infliximab, however, showed a trend towards greater efficacy for the anti-TNF drugs. Anakinra also seems to be associated with comparably high rates of injection site reactions. These results should be taken into account when considering biologic therapy for patients with RA. less...

Juvenile Idiopathic Arthritis (JIA) is the most common autoimmune inflammatory disease in children; joint inflammation is the hallmark of the disease. Thirty five children with JIA were studied, of whom 26 had active disease and 14 were receiving anti-TNF therapy (5 with Infliximab, 9 with Etanercept) Sixteen healthy controls were also studied. Saliva samples were obtained for analysis of anti-oxidant status, MMP's and sialochemistry. The total antioxidant status was significantly higher in the saliva of all JIA patients, whether treated (p=0.014) or not treated (p=0.038) with anti-TNF agents. The increase in antioxidant status (TAS) in the saliva of the active patients was nearly 2 times higher than that of non-active patients (p=0.01). MMP levels were significantly lower in JIA patients than in controls. MMP-9, MMP-3, and MMP-2 were lower in JIA patients without anti-TNF treatment by 36.7% (p=0.01), 30.0% (p=0.0001), and 10.7% (p=0.0001), respectively. A greater reduction in MMP levels was observed in the group of patients treated with anti-TNF drugs: MMP-9, MMP-3, and MMP-2 were lower than in controls by 51.1% (p=0.0001), 61.5% (p=0.0001), and 55.4% (p=0.0001), respectively. Children with JIA exhibited a significantly higher salivary antioxidant activity and significantly lower MMP levels. Anti-TNF treatment was associated with a further decrease in MMP levels in the saliva of JIA patients while active state of the JIA was associated with further increase in the salivary antioxidant activity. Anti-TNF treatment may modulate the degradation process during the course of arthritis by inhibition of the activity of MMP. less...

Uveitis is one of the major features of behcet's disease with relapse and remission pattern. Severe presentation can be resistant to the conventional treatment. Steroid has been used in the treatment of acute behcet's uveitis, although it especially has its own ocular complications when used in large doses. We describe to patients presented with acute uveitis while on treatment, uveitis was controlled by adding anti-tumor necrosis factor (TNF) and Infliximab. less...

After over 10 years of use of tumor necrosis factor-alpha (TNF-alpha) inhibitors, their side effects and complications are reasonably well documented. Recently, however, granulomatous reactions and cases of complete sarcoidosis have been reported, especially in patients treated with the TNF-alpha receptor protein, etanercept This is intriguing because the TNF-alpha antibody drugs infliximab and adalimumab are reportedly used to treat sarcoidosis. We present three patients who developed sarcoidosis while on etanercept treatment, and discuss if possible differences in cytokine profiles and T regulatory cell function in patients taking different TNF-alpha inhibitors may explain this paradox less...