TNF-α Inhibitors In Patients Research Articles

Analysis of associations between polymorphisms within genes coding for tumour necrosis factor (TNF)-alpha and TNF receptors and responsiveness to TNF-alpha blockers in patients with rheumatoid arthritis

IntroductionDespite the fact that therapy with TNF-α inhibitors constitutes a breakthrough in rheumatoid arthritis management, no improvement is still achieved in approximately 30% of cases. The aim of the study was to evaluate whether single nucleotide polymorphisms (SNPs) within the TNF-α and TNF receptor encoding genes affect the efficacy of therapy with TNF-α inhibitors in patients with RA. MethodsFive SNPs within the TNF-α and TNF receptor encoding genes (TNFA: G-308A, G-238A, C-857T; TNFR1A G36A; TNFR1B T676G) were determined in 280 RA patients who had been treated with TNF-α inhibitors for at least 6 months or they stop therapy because of adverse events. The association between the relative change in DAS28 and SNP genotypes was tested by linear regression. ResultsAt week 24, low disease activity or remission was achieved by 45% of the patients. After 6 months remission of the disease or low disease activity were more frequently observed among patients homozygous for the TNFR1A 36A allele than among those who were GG homozygotes (52% vs. 34%, P=0.04). At week 24 DAS28 was significantly lower in the subgroup of patients homozygous for the TNFA-857T variant compared to the C allele carriers (P=0.045). The other polymorphisms were not found to be significantly associated with EULAR response at week 12 and 24 of the anti-TNF treatment. ConclusionsHomozygosity for the TNFR1A 36A allele and the TNFA-875T variant could act as a genetic factor associated with better response to anti-TNF treatment.

SAT0360 Combined Therapy with Rituximab and NSAIDS in Treatment of Active Ankylosing Spondylitis: Better than NSAIDS Alone, Worse than Combination of Tnf-Inhibitors and Nsaids

BackgroundSeveral reports have shown that rituximab may have some efficacy in patients with active ankylosing spondylitis (AS), mainly in tumor necrosis factor alpha (TNF-α) inhibitor naïve. No direct comparisons of...

AB0660 Predictive Factors of Treatment Response to A Second Tnf-α Inhibitor in Patients with Ankylosing Spondylitis - Results from the Portuguese Register Reuma.Pt

BackgroundApproximately one-third of patients with ankylosing spondylitis (AS) treated with tumor necrosis factor inhibitors (TNFi) need to switch their biological therapy. However, a significant clinical response only occurs in half...

Potential use of TNF-α inhibitors in systemic sclerosis.

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. TNF-α has a central role in initial host response to infections and in the pathogenesis of various systemic immune-mediated diseases. Serum levels of TNF-α are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension. Inflammatory arthritis can occur in patients with SSc. Infliximab and etanercept may improve the inflammatory arthritis and disability in SSc. TNF-α inhibitors reduce the systemic inflammation, improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and/or cerebrovascular events. Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections. Randomized controlled trials with TNF-α inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc.

Impact of smoking on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis or Crohn's disease

#These authors contributed equally as co-first authors Cigarette smoking may be associated with the augmentation of pro-inflammatory cytokines including Tumor Necrosis Factor-alpha (TNF-α), which may affect the outcomes of pharmacological agents such as TNF-α inhibitors. The purpose of this study was to investigate the impact of smok ing on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis (RA) or Crohn’s disease (CD). We used systematic literature review methods. A total of 1,147 articles were selected after exclusion of duplicates through a database search. Among them, 28 articles were finally se lected through a review of titles and abstracts and a subsequent review of full articles. The effective ness of TNF-α inhibitors in patients with RA or CD among the selected articles was summarized by their smoking status. Meta-analysis was performed with random effect model. When current smokers were compared with non-smokers for response after adjustments through meta-analysis among patients with RA, current smokers had 59% less response than non-smokers with statistical significance (Pooled adjusted OR=0.41, 95% CI=0.17-0.95). In patients with CD, current smokers tended to have lower clinical response than non-smokers, but statistical significance was not shown. In subgroup analyses for luminar CD or fistulizing CD, current smokers tended to have a lower re sponse in luminar CD (Pooled OR=0.62, 95% CI=0.34-1.14), but smoking status was not associated with drug response in fistulizing CD. This study raises awareness of the adverse effects of smoking in terms of clinical response in patients treated with TNF-α inhibitors.

FRI0053 Analysis of associations between tumor necrosis factor-alpha (TNFA -308 g>a, tnfa -238 g>a, tnfa -857 c>t) and tnf receptors (TNFRA 36 a>g, tnfrb 676 t>g) gene polymorphisms status and responsiveness to tnf-a blockers in rheumatoid arthritis.

BackgroundDespite the fact that therapy with TNF-α inhibitors constitutes a breakthrough in rheumatoid arthritis (RA) management, no improvement is still achieved in approximately 30% of casess.There is ongoing search for...

Chronic Administration of Infliximab (TNF‐α Inhibitor) Decreases Depression and Anxiety‐like Behaviour in Rat Model of Chronic Mild Stress

Pro-inflammatory cytokines have been proposed to be associated with the pathogenesis of depression. Consistent with this notion, several clinical observations have suggested the antidepressant efficacy of TNF-α inhibitors in patients with chronic inflammatory diseases. In this study, we evaluated the antidepressant and anxiolytic effects of chronic TNF-α inhibitor (infliximab, 5 mg/kg, i.p., weekly) administration in the chronic mild stress (CMS) model of depression. Rats were divided into three groups: saline-control (no stress), saline-CMS, and infliximab-CMS. Rats in the latter two groups were exposed to CMS for 8 weeks. Saline (former two groups) or infliximab was injected weekly during this period. After CMS, total locomotor activity, anxiety-like behaviour and depression-like behaviours were evaluated using automated locomotor activity cage, elevated plus maze (EPM), and sucrose preference (SPT) and forced swimming (FS) tests, respectively. As expected, the saline-CMS group exhibited higher depression-like behaviours in FS and SPT tests compared with the saline-control group. There were no differences between these two groups in terms of the anxiety-like behaviour or total locomotor activity. Infliximab reduced the depression-like behaviour of CMS rats compared with saline-CMS group, and anxiety-like behaviour of CMS rats compared with saline-CMS and saline-control groups. Our findings suggest that chronic and systemic TNF-α inhibition reduced depression and anxiety-like behaviour in the CMS model of depression in rats.

Tumor necrosis factor-α inhibitors and chronic hepatitis C: A comprehensive literature review

Tumor necrosis factor-α (TNF-α) inhibitors are known to increase reactivation of concurrent chronic hepatitis B, but their impact on the hepatitis C virus (HCV) is controversial. Some conditions of immunosuppression, such as liver transplantation, typically cause an increase in the rate of HCV evolution. Inhibition of TNF-α, a cytokine involved in the apoptotic signaling pathway of hepatocytes infected by HCV, could potentially increase viral replication. Currently available clinical data appear to contradict this hypothesis. A review of medical literature revealed that a total of 216 patients with HCV were exposed to one or more treatments with TNF-α inhibitors, with a median observation time of 1.2 years and 260 cumulative patient-years of exposure. Only three cases of drug withdrawal due to suspected HCV liver disease recrudescence were reported. Treatment with TNF-α inhibitors in patients with HCV infection appears to be safe in the short term, but there are insufficient data to assess their long-term safety. Universal screening for HCV before beginning treatment with TNF-α inhibitors is currently controversial. The presence of HCV is not a contraindication to therapy with TNF-α inhibitors, with the exception of cirrhotic patients. In cases of cirrhosis, the benefit/risk ratio should be evaluated at the individual level. Prior to treatment with TNF-α inhibitors, patients with HCV should be referred to a hepatologist to determine the necessity of hepatic disease assessment, using liver biopsy or non-invasive methods, and the potential indication for antiviral therapy. In patients with HCV infection who are treated with TNF-α inhibitors, liver function monitoring every three months is advised.

Linking systemic angiogenic factors (VEGF, angiogenin, TIMP-2) and Doppler ultrasound to anti-inflammatory treatment in rheumatoid arthritis

ObjectiveTo evaluate an association between synovial Doppler flow and serum levels of vascular endothelial growth factor (VEGF), angiogenin and TIMP-2 in patients with rheumatoid arthritis during anti-inflammatory treatment with glucocorticoids and TNF-α inhibitors. MethodsInflamed wrists of 15 patients with rheumatoid arthritis (RA) were examined by two independent ultrasound investigators prior to and at days 3, 7, 14 and 42 after the initiation of treatment with glucocorticoids in therapy-naïve patients or after the beginning of a therapy with a TNF-α inhibitor in patients with DMARD failure. Quantitative three-dimensional power Doppler ultrasonographic assessment of synovial vascularization was compared at each visit with serum levels of VEGF, angiogenin and TIMP-2. ResultsIn the glucocorticoid group, synovial Doppler signals decreased significantly at day 3 (−44%; P=0.003) in comparison to a delayed decrease in the TNF-α inhibitor group after 6 weeks (−46%; P=0.001). A significant reduction of serum VEGF levels could be determined with a delay of 1 week after the decrease of Doppler activity but no correlation was found between both parameters (rho: P=0.7; r=−0.03). Angiogenin concentrations decreased in the TNF group and increased in the GC group. Levels of TIMP-2 did not change significantly in both groups. ConclusionThe decrease of serum VEGF levels under treatment with glucocorticoids or TNF-α inhibitors followed the reduction of the intra-articular synovial Doppler flow. This result supports the idea that the reduction of synovial perfusion due to anti-inflammatory treatment is not regulated by systemic VEGF, but that the inflamed joints are the source for circulating VEGF.

Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.

CD6 and syntaxin binding protein 6 variants and response to tumor necrosis factor alpha inhibitors in Danish patients with rheumatoid arthritis.

BackgroundTNFα inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNFα inhibitors in patients with rheumatoid arthritis (RA).Methodology and Principal FindingsIn the DANBIO Registry we identified 237 TNFα inhibitor naïve patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n = 160), adalimumab (n = 56) or etanercept (n = 21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fisher’s exact test. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR = 4.43, 95% CI: 1.99–10.09, p = 7.211×10−5) and with EULAR good response vs. moderate/no response (OR = 4.54, 95% CI: 2.29–8.99, p = 3.336×10−6). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR = 4.01, 95% CI: 1.92–8.49, p = 5.067×10−5).ConclusionGenetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA.

Relations of Serum COMP to Cardiovascular Risk Factors and Endothelial Function in Patients with Rheumatoid Arthritis Treated with Methotrexate and TNF-α Inhibitors

To examine whether serum level of cartilage oligomeric matrix protein (S-COMP) is related to methotrexate (MTX) or to MTX and tumor necrosis factor-α (TNF-α) combination treatment for rheumatoid arthritis (RA); and to investigate whether S-COMP is related to cardiovascular risk factors including endothelial dysfunction and level of anticitrullinated protein antibodies (ACPA) in patients with RA. Clinical and laboratory measures, including S-COMP and reactive hyperemic index (RHI), were examined in 55 consecutive patients with RA starting with either MTX (n = 34) or MTX and anti-TNF-α treatment (n = 21) at baseline, and after 6 weeks and 6 months. S-COMP was similar in the 2 treatment regimens during followup. We found a positive relationship between S-COMP at baseline and the use of disease-modifying antirheumatic drugs the last year preceding the study (p = 0.001), and a negative relation to current use of systemic glucocorticosteroids (p = 0.044). The nonsignificant change in S-COMP between baseline and the 6-month followup was positively and independently related to change in ACPA level (p = 0.009). There was no significant association between RHI and level of S-COMP at baseline. The cartilage turnover marker S-COMP did not change significantly after 6 months' treatment with MTX with or without a TNF-α inhibitor in patients with RA. The positive association between S-COMP and ACPA suggests that these factors might interact, and could both be contributors to an unknown link between inflammation and cartilage destruction in patients with RA. S-COMP was not related to endothelial function in patients with RA, or to other cardiovascular risk factors studied. Clinical Trials registration number NCT00902005.

Responsiveness of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and clinical and MRI measures of disease activity in a 1-year follow-up study of patients with axial spondyloarthritis treated with tumour necrosis factor α inhibitors

ObjectivesTo investigate construct validity and responsiveness of the novel ankylosing spondylitis (AS) disease activity score (ASDAS) in patients with spondyloarthritis (SpA).MethodsIn a 46-week prospective longitudinal multicentre study of 60 patients...

Atopic dermatitis: Therapeutic concepts evolving from new pathophysiologic insights

Recent insights into the relevance of the epidermal barrier function and its interaction with components of the innate and adaptive immune responses in patients with atopic dermatitis (AD) give rise to a number of novel potential treatment options. In particular, the identification of loss-of-function mutations in the barrier protein filaggrin and of a diminished expression of certain antimicrobial peptides in AD skin stimulates new concepts to think beyond the T(H)1/T(H)2 paradigm. This review will focus on these most recent discoveries and will discuss new and corresponding proof-of-concept trials in patients with AD. It will further speculate on novel ways to restore the homeostasis among the 3 major components in AD skin suspected to be clinically relevant.

Psoriasis and Pustular Dermatitis Triggered by TNF-α Inhibitors in Patients With Rheumatologic Conditions

Psoriasis and Pustular Dermatitis Triggered by TNF-α Inhibitors in Patients With Rheumatologic Conditions

Psoriasis and Pustular Dermatitis Triggered by TNF-α Inhibitors in Patients With Rheumatologic Conditions

New onset or worsening of psoriasis has been reported in patients treated with tumor necrosis factor alpha (TNF-alpha) inhibitors for a variety of rheumatologic conditions. There is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease, including psoriasis, involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. We present herein a case series with clinical and histopathologic evidence of psoriasis in patients with rheumatologic disease treated with TNF-alpha inhibitors. We propose that the cross regulation between TNF-alpha and IFN may have a role in the pathogenesis of this reaction. We observed new-onset psoriasis (n = 13) or severe exacerbation of psoriasis (n = 2) in 15 patients with a variety of rheumatologic conditions-rheumatoid arthritis (n = 13), psoriatic arthritis (n = 1), and seronegative arthritis (n = 1)-during treatment with etanercept (n = 6), infliximab (n = 5), and adalimumab (n = 4). Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (MxA, a surrogate marker for lesional type 1 IFN activity) showed increased staining in TNF-alpha inhibitor-induced psoriasis compared with psoriasis vulgaris. New onset or severe exacerbation of psoriasis is a rare complication of TNF-alpha inhibitor therapy. The finding of increased production of IFN-alpha in TNF-alpha inhibitor-induced psoriasis is a possible pathophysiologic explanation for this reaction.