anti-TNF Therapy For Rheumatoid Arthritis Research Articles

Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis.

BackgroundFaced with an increasing number of choices for biologic therapies, rheumatologists have a critical need for better tools to inform rheumatoid arthritis (RA) disease management. The ability to identify patients who are unlikely to respond to first-line biologic anti-TNF therapies prior to their treatment would allow these patients to seek alternative therapies, providing faster relief and avoiding complications of disease.MethodsWe identified a gene expression classifier to predict, pre-treatment, which RA patients are unlikely to respond to the anti-TNF infliximab. The classifier was trained and independently evaluated using four published whole blood gene expression data sets, in which RA patients (n = 116 = 44 + 15 + 30 + 27) were treated with infliximab, and their response assessed 14–16 months post treatment according to the European League Against Rheumatism (EULAR) response criteria. For each patient, prior knowledge was used to group gene expression measurements into disease-relevant biological signaling mechanisms that were used as the input features for regularized logistic regression.ResultsThe classifier produced a substantial enrichment of non-responders (59 %, given by the cross validated test precision) compared to the full population (27 % non-responders), while identifying nearly a third of non-responders. Given this classifier performance, treatment of predicted non-responders with alternative biologics would decrease their chance of non-response by between a third and a half, substantially improving their odds of effective treatment and stemming further disease progression. The classifier consisted of 18 signaling mechanisms, which together indicated that higher inflammatory signaling mediated by TNF and other cytokines was present pre-treatment in the blood of patients who responded to infliximab treatment. In contrast, non-responders were classified by relatively higher levels of specific metabolic activities in the blood prior to treatment.ConclusionsWe were able to successfully produce a classifier to identify a population of RA patients significantly enriched in anti-TNF non-responders across four different patient cohorts. Additional prospective studies are needed to validate and refine the classifier for clinical use.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0100-6) contains supplementary material, which is available to authorized users.

A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis.

ObjectiveAnti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25–30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response.MethodsA total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy.ResultsWe found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042).ConclusionsIn the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.

Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern?

There are now five anti-TNF drugs available for clinical use, and it will not be long before they are joined by biosimilar drugs. Some patients treated with selective TNF drugs may develop adverse events such as infections, malignancies, acute infusion and injection reactions, autoimmunity and cardiovascular effects. Registry data consistently show that, particularly during the first 6 months, anti-TNF drugs slightly increase the risk of serious infections of the skin, soft tissues and joints, but it does not seem to increase the risk of cancer other than nonmelanoma skin cancers. A number of studies have shown that the administration of biological agents can lead to the formation of neutralizing and nonneutralizing antibodies. Lipid levels increase, but the atherogenic index remains stable and qualitative changes to lipid particles may reduce the risk of cardiovascular diseases. Patients treated with anti-TNF drugs therefore need to be monitored regularly.

Continuation of Anti-TNF Therapy for Rheumatoid Arthritis in Patients with Active Tuberculosis Reactivated during Anti-TNF Medication is more Beneficial than its Cessation

Objective: To evaluate the safety and efficacy of continuous anti-Tumor Necrosis Factor (TNF) therapy in rheumatoid arthritis (RA) patients with activated tuberculosis (TB) during anti-TNF therapy. Methods: We evaluated a total of 20 cases of RA with active TB, which were treated with TNF inhibitors including infliximab, adalimumab, and etanercept during TB therapy. Seven patients received re-administration of the same inhibitor after missing several administrations (Group A), while seven patients were treated on a continuous basis (Group B). Six RA patients who developed TB without pre-treatment with TNF biologics received infliximab or etanercept 0 to 10 months after initiation of the anti-TB treatment (Group C). During anti-TB therapy, we evaluated the influence of anti-TNF therapy on the disease activity of RA, paradoxical response, clinical symptoms related to TB, and the sputum culture positive period as the sputum culture conversion period. Results: Anti-TB medications were initiated after patients were diagnosed with TB in all groups. All tubercle bacilli were susceptible to the anti-TB drugs used. No TB exacerbation occurred, following the initiation of anti-TB therapy, in any of the patients and despite anti-TNF therapy. The sputum culture positive period, after initiation of anti-TB treatment, was not prolonged but shortened by anti-TNF therapy in Group B. Three patients in Group A developed a paradoxical response after cessation of anti-TNF biologics, whereas there were no paradoxical responses in Group B. Conclusion: Treatment with TNF inhibitors had beneficial effects on all RA patients with activated TB.

Overview of biologic treatments in the elderly

As life expectancies rise, the number of elderly people with inflammatory rheumatic diseases will continue to grow. Treatment of this frail population, whose clinical features differ from those of younger subjects, poses new challenges to healthcare systems. However, this issue is rarely addressed in the current literature. Thanks to their targeted mechanism of action, biologics represent one of the major therapeutic advances of the last 15 years, but their use in the elderly has been slow in developing. Published data, derived mainly from cohorts, focus on the use of TNF inhibitors in rheumatoid arthritis and show that these treatments are effective and generally well tolerated. Nevertheless, the risk of infection and cancer, particularly skin and lymphoid malignancies, must not be neglected. The use of these biologics as second-line treatment improves patient outcomes and comfort, while reducing consumption of the widely used and more deleterious drugs such as glucocorticoids and non-steroidal anti-inflammatory drugs. Additional studies on biologics, focusing on the longer term and in indications apart from anti-TNF therapies in rheumatoid arthritis should help overcome some of the reluctance and promote the rational use of these drugs in the elderly.

PDE3A-SLCO1C1 locus is associated with response to anti-tumor necrosis factor therapy in psoriatic arthritis.

Aim: Variation at PDE3A-SLCO1C1 locus has been recently associated with the response to anti-TNF therapy in rheumatoid arthritis. We undertook the present study to determine whether PDE3A-SLCO1C1 is also associated with the response to anti-TNF therapy in psoriatic arthritis. Patients & methods: Genomic DNA was obtained from 81 psoriatic arthritis patients that had been treated with anti-TNF therapy. PDE3A-SLCO1C1 SNP rs3794271 was genotyped using Taqman realt-time PCR. The clinical response to anti-TNF therapy was measured as the change from baseline in the level of disease activity according to the DAS28 score. Results: A significant association between rs3794271 and anti-TNF response in psoriatic arthritis was found (beta = -0.71; p = 0.0036). Conclusion: PDE3A-SLCO1C1 locus is also associated with response to anti-TNF therapy in psoriatic arthritis. Original submitted 12 May 2014; Revision submitted 18 August 2014.

OP0257 Differential DNA Methylation Related to Response to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis

BackgroundAnti-TNF therapies have proved a huge advance for the treatment of rheumatoid arthritis (RA), however very good disease control or remission is achieved in just 30% of patients. This makes...

AB0119 Fully Human Monoclonal Antibodies to Phosphorylcholine Inhibit Basal and Tnf-Induced IL-6 and ICAM-1 in Synovial-Like Fibroblasts from A Rheumatoid Arthritis

BackgroundRecently, we described that non-responders to anti-TNF therapy in rheumatoid arthritis (RA) had significantly lower levels of antibodies targeting phsphorylcholine (anti-PC)Since we had observed anti-inflammatory properties of human polyclonal anti-PC...

THU0183 Cardiovascular Serious Adverse Events of Anti-TNF Therapies in Rheumatoid Arthritis: A Systematic Literature Review

BackgroundResearch has shown increased TNF levels in heart failure (HF). Randomized controlled trials (RCT) have evaluated the effects of TNF inhibitors (TNFi) in these patients and failed to show benefit,...

AB0290 Serum protein biomarkers for response of rheumatoid arthritis to infliximab

BackgroundBiological therapies have been a great advance in Rheumatoid Arthritis (RA) treatment. However, up to a third of the RA patients do not respond to a given biologic and a...

Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores

ObjectivesTo identify the clinical factors predicting a good clinical response to anti-TNF therapy in rheumatoid arthritis (RA) patients entered in the LORHEN registry after 5years of treatment with anti-TNF agents and divided into two groups on the basis of their baseline DAS28 scores (moderate>3.2–5.1 [MDA] and high>5.1 [HDA]). MethodsDisease activity at baseline and after 12months was assessed using the DAS28, and response was evaluated using the EULAR improvement criteria. ResultsThe study involved 1300 patients with established RA: 975 with HDA and 325 with MDA. After a mean 36-month, 29.6% of the patients had a DAS28 score of less or equal to 2.6 (HDA 25.8% vs. MDA 43.0%; P<0.001) and were considered to be in remission. A higher probability of a good EULAR response in patients with HDA was associated with male gender (F vs. M – OR 0.45, 95% CI 0.26–0.78; P: 0.004), lower age at the start of treatment (OR 0.98, 95% CI 0.96–0.99; P: 0.002), the absence of comorbidities (OR 0.18, 95% CI 0.06–0.52; P: 0.002) or no previous use of corticosteroids (OR 1.92, 95% CI 1.14–3.22; P: 0.015) and the use of adalimumab vs. infliximab (OR 2.21, 95% CI 1.37–3.57; P 0.001); in patients with MDA, the probability of a good EULAR response was associated with male gender (F vs. M – OR 0.39, 95% CI 0.17–0.90; P: 0.027). ConclusionsWith the exception of male gender, the factors predicting a good EULAR response are different in patients with MDA and those with HDA.

FRI0088 Effect of body mass index on clinical response to anti-tnf therapy in rheumatoid arthritis

BackgroundRheumatoid Arthritis is the commonest inflammatory arthritis. Improved understanding of its pathogenesis has led to targeted therapies like TNF inhibitors. With more emphasis on personalised treatment of RA, a better...

Association between tumor necrosis factor-α (TNF-α) promoter −308 G/A and response to TNF-α blockers in rheumatoid arthritis: a meta-analysis

Objectives Tumor necrosis factor (TNF)-α promoter −308G/A polymorphism has been shown to be associated with high TNF-α production and poor response to anti-TNF-α treatment. However, not all patients show a good response to TNF-α antagonists, so this association remains controversial. This study was designed to investigate whether TNF-α promoter −308 G/A polymorphism is associated with responsiveness to anti-TNF therapy in rheumatoid arthritis (RA) patients. The 28-joint count Disease Activity Score (DAS) 28 or the American College of Rheumatology (ACR) improvement criteria 20 were used to measure patient response.Methods A meta-analysis was performed. Pooled ORs and 95 % CIs were calculated by both dominant and recessive genetic models.Results Fifteen studies with a total of 2127 patients were included in this meta-analysis. The results showed that patients with the G allele responded better to the treatment (OR = 1.87, 95 % CI 1.26–2.79). A subanalysis showed similar results.Conclusions Based on the results of this meta-analysis, RA patients with the TNF-α promoter −308 G allele respond better to TNF-α antagonist treatment, suggesting that this allele plays a major role in anti-TNF-alpha treatment response.

Tumor Necrosis Factor-associated Palmoplantar Pustular Psoriasis Treated with Interleukin 6 Blocker

To the Editor: Anti-tumor necrosis factor (anti-TNF) compounds are regarded as some of the most potent agents available for treatment of psoriasis vulgaris, with 80% of patients achieving at least a 75% reduction of their baseline skin lesions after 10 weeks of therapy1. Palmoplantar pustular psoriasis (PPP) is a chronic inflammatory skin condition characterized by recurrent eruptions of sterile pustules on erythematous skin, hyperkeratosis, and fissures on the palms and soles. Successful treatment options are usually limited. PPP has long been regarded as a localized variant of pustular psoriasis. Some authors have proffered that this pathological condition may not represent so much a subtype of psoriasis as a drug hypersensitivity reaction, as in acute generalized exanthematous pustulosis2,3. Increased expression of TNF has been identified as an important pathophysiological mechanism in different types of chronic inflammation, including psoriasis and psoriatic arthritis. Despite the evident efficacy of anti-TNF therapies in this setting, many have described pustular psoriasis occurring as an adverse event of these agents in patients without prior psoriasis, such as those receiving anti-TNF therapy for rheumatoid arthritis (RA)2,3,4 … Address correspondence to Prof. I. Rosner, Rheumatology, Bnai Zion Medical Center, PO Box 4940, Haifa, 31048 Israel. E-mail: rosneri{at}tx.technion.ac.il

Association between tumor necrosis factor-α (TNF-α) promoter −308 G/A and response to TNF-α blockers in rheumatoid arthritis: a meta-analysis

Tumor necrosis factor (TNF)-α promoter -308G/A polymorphism has been shown to be associated with high TNF-α production and poor response to anti-TNF-α treatment. However, not all patients show a good response to TNF-α antagonists, so this association remains controversial. This study was designed to investigate whether TNF-α promoter -308 G/A polymorphism is associated with responsiveness to anti-TNF therapy in rheumatoid arthritis (RA) patients. The 28-joint count Disease Activity Score (DAS) 28 or the American College of Rheumatology (ACR) improvement criteria 20 were used to measure patient response. A meta-analysis was performed. Pooled ORs and 95 % CIs were calculated by both dominant and recessive genetic models. Fifteen studies with a total of 2127 patients were included in this meta-analysis. The results showed that patients with the G allele responded better to the treatment (OR = 1.87, 95 % CI 1.26-2.79). A subanalysis showed similar results. Based on the results of this meta-analysis, RA patients with the TNF-α promoter -308 G allele respond better to TNF-α antagonist treatment, suggesting that this allele plays a major role in anti-TNF-alpha treatment response.

Evidence-based rather than habit-based treatment options

Accumulating data from clinical practice hint that an alternative class of biologic agent may be the best choice when anti-TNF therapy for rheumatoid arthritis fails to produce the desired effect. Furthermore, evidence suggests that non-anti-TNF biologic agents should perhaps also be considered as the initial choice of biologic agent.

Influence on Effectiveness of Early Treatment with Anti-TNF Therapy in Rheumatoid Arthritis

To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28 DAS28 < 2.6. Also the response related to criteria of the European League Against Rheumatism (EULAR) was evaluated. Therapeutic spacing was defined as the use of a lower dose or a higher interval according to label doses. The main endpoint was to assess the association between the effectiveness and the moment when the anti-TNF therapy begins. The secondary target was to evaluate the association between RA activity at the beginning of treatment with anti-TNF and dose used. Results. 82 patients were included. The prescription profile was: ADA (48.8%), ETN (31.7%) and IFX (19.5%). 71.4% of patients treated with anti-TNF during the first year since diagnosis, 57.1% of those who started after 1-5 years and 30.6% of patients who started after 5 years were in remission when the study ended. De-escalation strategy was performed in 25.6% of patients: ETN (38.5%), ADA (20.0%) and IFX (18.8%). The patients treated with a higher dose according to label doses were: IFX (81%), ADA, (12.5%) and ETN (7.7%). Results suggest that early treatment with anti-TNF can achieve a higher percentage of remissions. Therapeutic spacing is established as a strategy that improves the efficiency in those patients in remission, being the ETN the anti-TNF most susceptible for spacing, although a relation between the early beginning with anti-TNF and the used dose was not found.

Interleukin-1 measurement in stimulated whole blood cultures is useful to predict response to anti-TNF therapies in rheumatoid arthritis

In RA, response to TNF blockers may be associated with a profile of cytokine production unique to each patient. This study sought to predict the response to biologic agents by examining pro-inflammatory cytokine synthesis in stimulated whole blood cultures (WBCs). We measured the concentration of TNF-α, IL-1β and IL-6 in supernatants of lipopolysaccharide (LPS)-stimulated WBCs obtained from RA patients (n = 41) before anti-TNF therapy (infliximab, 13; etanercept, 26; and adalimumab, 2) and from healthy controls (n = 12). At 24 weeks after biologics, whole bloods were again drawn from 14 of 41 patients. Response was defined by the European League Against Rheumatism response criteria after 24 weeks of therapy. Among 41 patients, 32 were responders (good 14/moderate 18), while 9 were non-responders. All cytokines measured were significantly lower in RA patients than in controls. In RA, IL-1β production was lower in non-responders than in responders [median (interquartile range): 3.5 (1.5-9.4) vs 10.0 (5.1-93.1) pg/ml, P = 0.048]. The area under the curve from a receiver operating characteristic curve analysis for the prediction of response using IL-1β was 0.717 (95% CI 0.520, 0.914). The sensitivity and specificity of IL-1β (cut-off value 4.84 pg/ml) was 78.1 and 77.8%, respectively. All cytokines were significantly higher 6 months later compared with their respective baseline. IL-1β measurement in LPS-stimulated WBC is useful to predict responsiveness to anti-TNF agents. Cytokine production capacities in LPS-stimulated WBCs are up-regulated by biologics.

Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register

IntroductionAnti-tumour necrosis factor (TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). In 2001, BSRBR was established to evaluate the safety of these agents. This paper addresses the...