Anti-tumor Necrosis Factor Drugs Research Articles

Ustekinumab for the Treatment of Refractory Crohn's Disease: The Spanish Experience in a Large Multicentre Open-label Cohort.

Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice. Consecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up. One hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5-21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal. Subcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.

Three cases of anti-TNF induced myositis and literature review

Anti-tumor necrosis factor drugs are frequently preferred in the treatment of rheumatologic diseases and other inflammatory diseases. The development of myositis after using anti-tumor necrosis factor drugs is a rare clinical condition. Here we aimed to report cases who developed myositis after using anti-tumor necrosis factor drugs and review the current literature. We report two cases of rheumatoid arthritis and a case of ankylosing spondylitis developed idiopathic inflammatory myopathy following anti-tumor necrosis factor therapy. In conclusion, myositis could develop during anti-tumor necrosis factor therapy, so these patients should be evaluated carefully initially for myositis and should be closely monitored due to the potential for developing myositis in treatment process.

New molecules in the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a disorder of unknown aetiology that provokes chronic inflammation of the gastrointestinal tract. Anti-tumor necrosis factor drugs have represented a major advance in the treatment of IBD patients in the last few years and also have a good safety profile. Nevertheless, these treatments are not effective in all patients and, in initial responders, there can be a loss of response in the long-term. Consequently, new treatments are needed for IBD, aimed at distinct therapeutic targets. In the last few years, new molecules have been incorporated into the therapeutic armamentarium of IBD patients. Golimumab is an anti-tumor necrosis factor monoclonal antibody with demonstrated effectiveness in the treatment of ulcerative colitis. The use of CT-P13 (biosimilar infliximab) has been approved in Europe for the same indications as the original infliximab. More recently, vedolizumab, an anti-α4β7 integrin monoclonal antibody, has been approved for the treatment of Crohn's disease and ulcerative colitis. A large number of molecules are currently under development, some of which will, in the future, broaden the therapeutic options available in the treatment of IBD patients. Finally, in the next few years, studies should aim to identify factors predictive of response to the distinct biological agents for IBD in order to allow personalized selection of the best therapeutic alternative for each patient.

Longterm Clinical Outcomes in 420 Patients with Psoriatic Arthritis Taking Anti-tumor Necrosis Factor Drugs in Real-world Settings.

An observational study to evaluate the longterm clinical outcomes of adalimumab (ADA), etanercept (ETN), and infliximab (IFX) in patients with psoriatic arthritis (PsA), in real-world settings. From a prospective cohort we studied 420 biologic-naive patients with PsA who had peripheral arthritis and were beginning a treatment with ADA, ETN, or IFX. Drug survival was evaluated by Kaplan-Meier life analysis, and baseline predictors of drug discontinuation were assessed by Cox regression analysis. The frequency of concomitant glucocorticoids and the daily mean dosage were compared by chi-square test and ANOVA repeated measures across 4 years. After 4 years the overall survival of the first anti-tumor necrosis factor-α (anti-TNF) was 51.0%, but significantly higher for ETN (58.9%) than ADA (43.9%) or IFX (44.0%; p = 0.003). Patients taking ETN also had the lowest HR of drug discontinuation (HR 0.57, 95% CI 0.34-0.93, p = 0.02). The strongest predictor of drug interruption was female sex (HR 2.02, 95% CI 1.28-3.20, p = 0.002). The disease duration was inversely correlated with drug discontinuation (HR 0.96, 95% CI 0.93-0.99, p = 0.02). The average daily dose of prednisone significantly decreased from baseline: 5.6 ± 2.5 to 4.7 ± 1.9 at 1 year (p = 0.01) to 4.0 ± 1.8 at 4 years (p = 0.001). Additionally, compared to baseline (49.6%), a significant reduction of patients taking glucocorticoids was detected at 2 years (36.5%, p < 0.05), 3 years (29.9%, p < 0.01), and 4 years (22.6%, p < 0.01). In real-world settings, TNF inhibitors showed a high rate of drug survival at 4 years. Further, the need for glucocorticoids for controlling active PsA was lowered with time.

Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan.

Background/AimsAnti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines.MethodsThis cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines.ResultsThirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037).ConclusionsExposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion.

Cytomegalovirus and ulcerative colitis: Place of antiviral therapy.

The link between cytomegalovirus (CMV) infection and inflammatory bowel diseases remains an important subject of debate. CMV infection is frequent in ulcerative colitis (UC) and has been shown to be potentially harmful. CMV reactivation needs to be diagnosed using methods that include in situ detection of viral markers by immunohistochemistry or by nucleic acid amplification techniques. Determination of the density of infection using quantitative tools (numbers of infected cells or copies of the genome) is particularly important. Although CMV reactivation can be considered as an innocent bystander in active flare-ups of refractory UC, an increasing number of studies suggest a deleterious role of CMV in this situation. The presence of colonic CMV infection is possibly linked to a decreased response to steroids and other immunosuppressive agents. Some treatments, notably steroids and cyclosporine A, have been shown to favor CMV reactivation, which seems not to be the case for therapies using anti-tumor necrosis factor drugs. According to these findings, in flare-ups of refractory UC, it is now recommended to look for the presence of CMV reactivation by using quantitative tools in colonic biopsies and to treat them with ganciclovir in cases of high viral load or severe disease.

Effect of Anti-TNF Antibodies on Clinical Response in Rheumatoid Arthritis Patients: A Meta-Analysis.

Background. Antitumor necrosis factor (anti-TNF) drugs have been applied for rheumatoid arthritis (RA) treatment; however, patients having anti-drug antibodies (ADAbs) do not benefit from these drugs. The meta-analysis aims to comprehensively assess the relationship between ADAb positive (ADAb+) and anti-TNF response in RA patients. Methods. Observational studies comparing different clinical response between ADAb+ and ADAb negative groups were included. Odds ratio (OR) with its corresponding 95% confidence interval (CI) was used as effect size. Subgroup analyses stratified by TNF inhibitor types and assay methods for ADAb detection were performed. Results. Totally, 10 eligible studies containing 1806 subjects were included. ADAb+ was significantly associated with reduced anti-TNF response to RA at all the time points after follow-up (P < 0.001). Subgroup analysis also supported this significant association (P < 0.05), except for enzyme-linked immunosorbent assay (ELISA) group at 3 months, infliximab (INF) and enzyme-linked immunosorbent assay (ELISA) groups at 6 months, and Immunological Multi-Parameter Chip Technology (IMPACT) group at 12 months. Conclusion. ADAb+ was significantly associated with reduced clinical response in RA patients, and other alternatives should be considered in RA patients presenting ADAb+.

Nuevas moléculas en el tratamiento de la enfermedad inflamatoria intestinal

Inflammatory bowel disease (IBD) is a disorder of unknown aetiology that provokes chronic inflammation of the gastrointestinal tract. Anti-tumor necrosis factor drugs have represented a major advance in the treatment of IBD patients in the last few years and also have a good safety profile. Nevertheless, these treatments are not effective in all patients and, in initial responders, there can be a loss of response in the long-term. Consequently, new treatments are needed for IBD, aimed at distinct therapeutic targets.In the last few years, new molecules have been incorporated into the therapeutic armamentarium of IBD patients. Golimumab is an anti-tumor necrosis factor monoclonal antibody with demonstrated effectiveness in the treatment of ulcerative colitis. The use of CT-P13 (biosimilar infliximab) has been approved in Europe for the same indications as the original infliximab. More recently, vedolizumab, an anti-α4β7 integrin monoclonal antibody, has been approved for the treatment of Crohn's disease and ulcerative colitis. A large number of molecules are currently under development, some of which will, in the future, broaden the therapeutic options available in the treatment of IBD patients.Finally, in the next few years, studies should aim to identify factors predictive of response to the distinct biological agents for IBD in order to allow personalized selection of the best therapeutic alternative for each patient.

Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.

Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs

Recent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case-control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs. The study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria. We found that carriers of the TNFRSF1Brs3397C allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1Brs1061622 SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (PDOM=0.67 and PREC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1Brs3397C/C, TNFRSF1Brs1061622G/G, and TNFRSF1Brs1061631A/A genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1Brs3397C or TNFRSF1Brs1061622G alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1Brs1061622 SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (PDOM=0.12). Our results suggest that the TNFRSF1Brs3397 variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.

In antisynthetase syndrome, ACPA are associated with severe and erosive arthritis: an overlapping rheumatoid arthritis and antisynthetase syndrome.

Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case–control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P < 0.0001). The number of swollen joints was significantly higher (7.0 ± 5.0 vs 2.9 ± 3.9, P < 0.005), with a distribution resembling that of RA. Radiographic damages were also more frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a significantly higher transfer factor for carbon monoxide in ACPA–ASS patients, lung, muscle, and skin involvements had similar incidences, patterns, and severity in both groups. Although Nonbiologic treatments were similarly used in both groups, ACPA-positive patients received biologics more frequently (59% vs 12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) with good efficacy and tolerance, whereas 2 of the 5 patients treated with antitumor necrosis factor drugs had worsened myositis and/or interstitial lung disease. After a >7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA–ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements.

Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis.

ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.

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.

Response to Tocilizumab in Rheumatoid Arthritis Is Not Influenced by the Body Mass Index of the Patient

To assess the relationship between the body mass index (BMI) and the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). We conducted a retrospective study in 222 patients with RA followed by 5 centers. The European League Against Rheumatism response was evaluated at 6 months. Univariate and multivariate logistic regressions were performed. No significant association between the BMI and the response to TCZ at 6 months was found after adjustment for potential confounding factors (adjusted OR 0.45, 95% CI 0.16-1.24, p = 0.13 and OR 1.19, 95% CI 0.31-4.48, p = 0.78 for BMI 25-30 kg/m(2) and BMI > 30 kg/m(2), respectively, compared to BMI < 25 kg/m(2)). Response to TCZ in patients with RA is not influenced by the baseline BMI, in contrast to anti-tumor necrosis factor drugs.

Long-term real-life experience with rituximab in adult Finnish patients with rheumatoid arthritis refractory or with contraindication to anti-tumor necrosis factor drugs.

The objective of this study was to evaluate the long-term safety and efficacy of repeated rituximab (RTX) infusions in the treatment of rheumatoid arthritis in daily clinical practice in Finland. Data were collected from the medical records of a total of 151 patients with rheumatoid arthritis treated with RTX and followed up for at least 12 months after the treatment onset. Change in the 28-joint Disease Activity Score (DAS28), European League Against Rheumatism response criteria and proportions of patients reaching disease remission (DAS28 < 2.6) or low disease activity (DAS28 < 3.2) were used to assess the clinical response. Of the 151 patients 128 received 2 courses, 76 received 3 courses, and 42 received 4 courses of RTX. The mean time to retreatment for the first 4 courses varied between 11 and 13 months. Median DAS28 decreased from 5.4 (0.5-8.6) to 3.3 (0.6-6.6) after the first course. After the second treatment course, the DAS28 was 3.1 (range, 0.1-6.5). The median precourse baseline DAS28 before the second and third courses were 4.6 (range, 1.7-7.8) and 4.24 (range, 1.7-7.2), respectively. The number of previously failed tumor necrosis factor inhibitors did not predict response to RTX in this patient cohort with extensive use of previous disease-modifying antirheumatic drugs (median = 6). The treatment as-needed regimen used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. A regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity.

Pregnancy outcomes in women with inflammatory bowel disease following exposure to thiopurines and antitumor necrosis factor drugs: a systematic review with meta-analysis.

Several studies have indicated the harmful effect of flare-up periods in pregnant women with inflammatory bowel disease (IBD) on their newborns. Therefore, an effective and safe medical treatment during pregnancy is of great concern in IBD patients. The aim of this study was to perform a meta-analysis on the outcomes of thiopurines use and a systematic review of antitumor necrosis factor (anti-TNF) drugs used during pregnancy in women with IBD. The results of cohorts evaluating the safety of anti-TNF drugs during pregnancy up to July 2013 were collected and analyzed. In the meta-analysis, a total of 312 pregnant women with IBD who used thiopurines were compared with 1149 controls (women with IBD who were not treated with any medication and women who were exposed to drugs other than thiopurines) to evaluate the drug effect on different pregnancy outcomes, including prematurity, low birth weight, congenital abnormalities, spontaneous abortion, and neonatal adverse outcomes. Results of statistical analysis demonstrated that congenital abnormalities were increased significantly in thiopurine-exposed group in comparison with control group who did not receive any medicine for IBD treatment. The summary odds ratio was 2.95 with 95% confidence interval = 1.03-8.43 (p = 0.04). We observed no significant differences in occurrence of other adverse pregnancy outcomes between compared groups. The results of cohorts evaluated the safety of anti-TNF drugs during pregnancy demonstrated no increase in occurrence of adverse pregnancy outcomes in comparison with controls except for the significant decrease in gestational age of newborns of drug-exposed mothers in one trial. In conclusion, a benefit-risk ratio should be considered in prescribing or continuing medicinal therapy during pregnancy of IBD patients.

Pregnancy Outcomes in Women with Inflammatory Bowel Syndrome Following Exposure to Thiopurines and Anti-Tumor Necrosis Factor Drugs: A Meta-Analysis and Systematic Review.

Pregnancy Outcomes in Women with Inflammatory Bowel Syndrome Following Exposure to Thiopurines and Anti-Tumor Necrosis Factor Drugs: A Meta-Analysis and Systematic Review.

Disease activity measurements and monitoring in psoriatic arthritis and axial spondyloarthritis.

In addition to the critical need of measuring tools for drug development of spondyloarthritis (SpA), these tools are also valuable for patient management. An early diagnosis, determination of early therapeutic response, and monitoring therapeutic response have now become increasingly important because effective therapies are available, and therapies such as anti-tumor necrosis factor (TNF) drugs are even more effective if used in early disease stages. In this review, we focus on disease activity measurements and monitoring in axial SpA and psoriatic arthritis (PsA). Both axial SpA and PsA have heterogeneous clinical manifestations. Therefore, in addition to the measurement of each clinical domain, composite measures inclusive of all clinical domains can be very helpful and are more likely to give complete and reliable information about the disease activity. A major focus of this review is to describe the recently developed composite measures for axial SpA and PsA.

47: TRAF2 regulates NFkB transcription factors to inhibit cell death and inflammation in the skin

Tumor Necrosis Factor (TNF) is an important factor in initiation and development of inflammation, and anti TNF therapy is well established for treatment of inflammatory diseases such as psoriasis, rheumatoid arthritis and Crohn’s disease.1 However, anti TNF drugs are not always efficient and developing new effective anti-inflammatory drugs is in the interest of many pharmaceutical companies.1 Therefore, We think that better understanding of TNF signalling pathway helps to discover new targets and design more effective drugs for inflammatory diseases. We have previously showed that Lymphotoxin? signals similar to TNF and suggested to be an alternative factor to induce inflammation in the absent of TNF 2 and both TNF and Lymphotoxin are not blockable by newly proposed inhibitor called Progranulin 3. These results encouraged us to investigate downstream regulator of TNF signalling pathway. Surprisingly, after 30 years of research on TNF, role of many components of TNF pathway are still unclear. TNF Receptor Associated Factor-2 (TRAF2) is one of those molecules which its role is controversial and not well defined yet 4. Since TRAF2 knock-out mice are lethal at birth, we have established various conditional and tissue specific TRAF2 knock-out to study the role of TRAF2 in different tissues. Interestingly, we found that loss of TRAF2 in keratinocytes disrupts TNF signalling and causes cell death, epidermal hyperplasia and skin inflammation. Surprisingly and contradictory to other models, additional loss of TNF did not completely rescue this phonotype. We have found that constitutive activation of non-canonical NF κ B and excessive production of TNF and other cytokines are responsible for this TNF independent inflammation. We propose that this novel model of skin inflammation could be a better model and targeting non-canonical NF κ B signalling might be a more effective target for treatment of inflammatory diseases.

Neutrophil lymphocyte ratio can be a valuable marker in defining disease activity in patients who have started anti-tumor necrosis factor (TNF) drugs for ankylosing spondylitis.

Neutrophil lymphocyte ratio (NLR) has emerged as a valuable and reliable method for follow-up of systemic inflammatory disease. We herein aimed to evaluate the role of NLR in the clinical follow-up of inflammation and also to compare its relationship with other measures, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). A total of 35 active ankylosing spondylitis (AS) and 38 healthy volunteers were included in the study. The patient group was enrolled for treatment with one anti-tumor necrosis factor (TNF) drug. Total blood count, ESR, CRP, and BASDAI score were obtained before and 3 months following the treatment. NLR was found with a mathematical calculation of the ratio of neutrophils with lymphocytes. The mean NLR value of the control group and patients was 1.90±0.89 and 2.67±1.17, respectively (p<0.05). After a 3-month course of treatment, the patient group had a mean NLR value of 1.8±0.7, which was significantly lower than pretreatment values (p<0.001). The post-treatment mean ESR, CRP, and BASDAI scores were significantly lower than mean baseline scores (p<0.001, p=0.007, p<0.001, respectively). Also, NLR was found to be correlated with BASDAI, ESR, and CRP (r=0.388, p<0.001; r=0.455, p<0.0001; and r=0.3389, p<0.005, respectively). Neutrophil lymphocyte ratio could be a reliable and easily accessible method for follow-up of patients with AS.