Response To Tumor Necrosis Factor Inhibitors Research Articles

Uveitis treatment in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry: response to tumour necrosis factor inhibitors.

Treatment with tumour necrosis factor inhibitors (TNFi) has significantly improved outcomes in uveitis associated with juvenile idiopathic arthritis (JIA-U). This study examines a CARRA Registry cohort of JIA-U patients on TNFi to analyse utilisation patterns and identify factors associated with response. This retrospective cohort study used CARRA Registry data for subjects aged 0-25 with JIA-U who had uveitis onset before the age of 19, and ever used TNFi. We collected data about demographics, uveitis courses, and treatment. We defined TNFi response and identified associated characteristics. As appropriate, comparisons between factors were tested using t-test, Chi-square, and Fisher's exact test. Multivariable logistic regression was used to model TNFi response. Among 871 JIA-U subjects, 616 (70.7%) used TNFi; 558 met inclusion criteria; 418 (74.9%) had successful treatment under TNFi. Among the 140 (25.1%) TNFi non-responders, 117 remained on TNFi and 23 discontinued. Multivariate analysis found significant TNFi success associations with White race (OR=2.08, p=0.005) and non-oligoarticular JIA (OR=1.58, p=0.044). In this CARRA Registry cohort of patients with JIA-U, a large proportion used a TNFi for uveitis. The percentage successfully treated with TNFi is consistent with the current literature. White race and non-oligoarticular JIA were associated with a successful response to TNFi.

Longitudinal variation of serum PCSK9 in ulcerative colitis: association with disease activity, T helper 1/2/17 cells, and clinical response of tumor necrosis factor inhibitor.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates CD4+ T cell differentiation and inflammatory response, the latter ones mediate ulcerative colitis (UC) initiation. This study intended to explore the correlation of serum PCSK9 with disease activity, T helper (h)1/Th2/Th17 cells, and clinical response of tumor necrosis factor inhibitor (TNFi) in UC patients. In 65 UC patients underwent TNFi treatment, serum PCSK9 was evaluated at baseline (W0), week (W)2, W6, and W12 by enzyme-linked immunosorbent assays; meanwhile, Th1/Th2/Th17 cells were determined at W0 by flow cytometry. Besides, serum PCSK9 was detected in 65 healthy controls (HCs). Serum PCSK9 was increased in UC patients compared to HCs (P<0.001), which also positively correlated with C-reactive protein (P=0.009), total Mayo score (P=0.018), Mayo-defined disease activity (P=0.020), Th1 (P=0.033), and Th17 (P=0.003) cells, but not Th2 cells (P=0.086) in UC patients. Interestingly, serum PCSK9 was steadily declined from W0 to W12 (P<0.001). W2-W0, W6-W0, and W12-W0 serum PCSK9 change (PCSK9 at W2, W6, or W12 minus PCSK9 at W0, respectively) was gradually becoming greater during TNFi treatment (P<0.001). Furthermore, forty-five (69.2%) patients achieved clinical response at W12, whose serum PCSK9 at W6 (P=0.041) and W12 (P=0.001) was lower, and W6-W0 (P=0.043), W12-W0 (P=0.019) serum PCSK9 change was more obvious compared to patients without clinical response at W12. Serum PCSK9 is positively related to disease activity, Th1, and Th17 cells in UC patients; further, its decline correlates with TNFi response achievement in these patients.

P136 T-cell-Specific Biomarkers of Early Treatment Response in Patients with Rheumatoid Arthritis Treated with a Tumour Necrosis Factor Inhibitor

Abstract Background/Aims The use of tumour necrosis factor inhibitors (TNFi) has advanced the clinical management of rheumatoid arthritis (RA). However, only 30-40% of patients who receive initial treatment with a TNFi experience a beneficial response. The discovery of reliable biomarkers of TNFi response is, therefore, a priority. Whilst T-cell dysfunction is documented in RA pathophysiology, T-cell involvement in TNFi treatment response is unclear. We aimed to phenotype peripheral blood-derived T-cells in RA patients over a number of time-points through the first 12-weeks of TNFi treatment; and to apply a cluster-free association testing method developed on single-cell CITE-seq data—co-varying neighbourhood analysis (CNA)—to high-dimensional single-cell CyTOF data. Methods 16 TNFi-naïve RA patients commenced treatment with a TNFi (10 on Adalimumab, 6 on Etanercept) and peripheral blood samples were collected at 6-7 time-points between pre-treatment and 12-weeks. Peripheral blood mononuclear cells were extracted, and stained with a 35-marker CyTOF panel. Treatment response was classified using the EULAR response criteria, and patients were characterised as good, moderate or non-responders. Data were cleaned in FlowJo and analysed using both i) a cluster-based approach, where data were clustered into 12 populations, and linear mixed models were fitted per cluster to test for significant differences in population abundance and ii) a cluster-free approach called CNA where association testing is purely data-driven. Both analyses controlled for age, sex, type of TNFi and TNFi concentration. Results Cluster-based analysis showed at 12-weeks, 1 of the 12 clusters (CD4+CD39+HLA-DR+) significantly increased in abundance in the non-responder cohort compared to the good and moderate responders (adjusted p = 0.037). Interestingly, HLA-DR and CD39 genetic effects have previously been associated with TNFi response. No significant differences were observed with CNA. Conclusion These results demonstrate that significant differences in T-cell abundance can be seen as early as 12-weeks after commencing treatment with a TNFi. Validation of these findings is required before the predictive value of this T-cell population can be tested. Disclosure M.A. Sutcliffe: None. S. Ling: None. A. Banyard: None. L. Rumker: None. S. Viatte: None. A. Morris: None. A. Barton: None. S. Raychaudhuri: None. D. Plant: None.

Tumor necrosis factor inhibitor (TNFi) persistence and reasons for discontinuation in a predominantly male cohort with axial spondyloarthritis

Although tumor necrosis factor inhibitors (TNFi) have favorably altered the treatment landscape for patients with axial spondyloarthritis (axSpA), there is limited data regarding TNFi persistence and reasons for discontinuation. This is an observational time-to-event study utilizing data collected for a prospective multiple-disease registry of US Veterans with axSpA treated with TNFi therapies and recruited over a 10year period. Clinical, serological, and comorbid parameters were collected. Corporate Data Warehouse Pharmacy files provided courses of the 5 TNFi agents, and response to treatment was documented. Individual TNFi persistence was established utilizing univariate and multivariate Cox proportional models, and reasons for discontinuation were obtained by physician chart review. Two-hundred and fifty-five axSpA patients received 731 TNFi courses. A majority of patients (84.3%) had TNFi persistence at 12months; 63.5% and 47.1% at 24 and 36months, respectively. Compared to adalimumab, infliximab demonstrated greater persistence, certolizumab the least. Age, smoking status, BMI, comorbidity burden, inflammatory markers and HLA-B27 did not predict TNFi persistence or discontinuation. Stroke and peripheral arterial disease increased the probability of TNFi discontinuation. Secondary non-response (SNR) was the most common reason for discontinuation (46% of all courses); non-adherence (6%) and clinical remission (2%) were uncommon. Pain score at enrollment, myocardial infarction, African American race and inflammatory bowel disease (IBD) predicted TNFi response. While initial persistence of TNFi treatment was high, a large proportion of the patients discontinued initial TNFi therapy by 3years, primarily due to loss of efficacy. While further research identifying potential predictors of TNFi discontinuation in axSpA is warranted, access to alternate disease-modifying therapies is needed.

POS0357 MiRNAs CORRELATE WITH IMPROVEMENT IN DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS ON TUMOUR NECROSIS FACTOR INHIBITORS

Background:Tumour necrosis factor inhibitors (TNFi) although effective in the treatment of rheumatoid arthritis (RA), show a variable response rate. Therefore, there is a need to identify treatment response predictors to inform therapy selection in order to practise precision medicine. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs that can alter gene expression by regulating messenger RNA translation. There is evidence for miRNA involvement in RA pathogenesis and they may serve as a useful biomarker of treatment response.Objectives:To identify miRNAs associated with response to TNFi in RA.Methods:Biologic naïve patients were selected from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), a prospective multi-center UK study investigating treatment response biomarkers to TNFi with a primary outcome measure of change in DAS28 scores. Patients were stratified into European League Against Rheumatism (EULAR) good or non-responders based on their 3 or 6-month DAS28-CRP score.Pre-treatment and 3-month post-treatment serum samples were substrates for miRNA profiling, which was conducted by FIRALIS using the HTG EdgeSeq miRNA whole transcriptome V2 targeted sequencing assay. Linear modelling using R package limma compared miRNA expression at (i) pre-treatment and at three-months, in EULAR good-responders and non-responders (ii) longitudinal change in expression from pre-treatment to three-months in EULAR good and non-responders.A literature search was conducted to identify miRNAs associated with RA as a diagnostic and/or treatment response predictor. Data on these miRNAs were extracted from the miRNAs identified in the serum samples. A correction for multiple testing was applied to statistical tests.Results:A total of 54 patients were analysed; of these, 35 (65%) were female, median disease duration [inter-quartile range] was 6 years [2 – 14] (n=51), and 44/51 (86%) patients were on a concomitant disease modifying anti-rheumatic drug. Of the 54 patients, 39 (72%) were classified as EULAR good-responders and 15 (28%) as non-responders. 1880 miRNAs were detected in the serum samples. 64 miRNAs were identified to be associated with RA from the literature, of which, 26 were identified in the serum samples tested.No difference in pre-treatment or three-month miRNA levels was seen comparing EULAR good-responders and non-responders (FDR p&lt;0.05). There was a significant differential expression of four miRNAs at 3-months in good-responders compared with pre-treatment levels; miR-125a-3p (downregulated, p-value 0.002), miR-149-3p (upregulated, p-value 0.004), miR-766-3p (downregulated, p-value 0.008), miR-146b-5p (upregulated, p-value 0.006). No significant differences were observed between 3-months and baseline in non-responders.Conclusion:Although no pre-treatment miRNAs were associated with TNFi response, changes in the levels of four miRNAs were detected at 3-months compared to baseline in EULAR good-responders. Future work involves validation of these samples in a larger patient cohort and analysing miRNA levels at 6 and 12 months. Replication and validation of these results in larger studies are required to analyse the role of miRNAs in stratifying EULAR good-responders from non-responders at three-months, and as treatment response predictors to TNFi in RA.Acknowledgements:Joint last-author: Dr. Darren PlantDisclosure of Interests:Trixy David: None declared, Nisha Nair: None declared, James Oliver: None declared, Eric Schordan: None declared, Hüseyin Firat: None declared, Kimme Hyrich Consultant of: consultancy/honoraria from AbbVie, Grant/research support from: Pfizer, UCB, BMS, Ann Morgan: None declared, Anthony G Wilson: None declared, John D Isaacs Speakers bureau: consultancy/speaker fees from AbbVie, Gilead, Roche, UCB, Consultant of: consultancy/speaker fees from AbbVie, Gilead, Roche, UCB, Grant/research support from: Pfizer, Darren Plant: None declared, Anne Barton: None declared

Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis

Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein–protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.

OP0220 ASSESSING THE EFFECT OF INCREASED BODY MASS INDEX ON RESPONSE TO TNF INHIBITORS IN ESTABLISHED RHEUMATOID ARTHRITIS: RESULTS FROM THE METEOR DATABASE

Background:Rheumatoid arthritis (RA) is associated with increased body mass index (BMI)- 60% of patients are either overweight or obese. Obesity in RA has been shown to predict reduced response to biologic therapy including tumour-necrosis-factor inhibitors (TNFi) [1]. However, it is not clear whether increased BMI influences response to all TNFi drugs in RA.Objectives:1.To explore whether BMI is associated with response to TNFi in patients with established rheumatoid arthritis (estRA), including those newly-starting on these drugs.Methods:Participants with estRA (&gt;1year since diagnosis) taking biologic medications, registered on METEOR (international database of RA patients), 2008-2013, were included. EULAR response, DAS28 remission (including components), and treatment regimens were recorded at baseline, 6, and 12 months. WHO definitions of overweight (BMI≥ 25) and obese (BMI≥30) were explored as predictors of TNFi response (good EULAR response and DAS28 remission) using normal BMI as comparator. Logistic and linear regression models (controlling for age, gender, smoking, and baseline outcomes) and sensitivity analyses were performed. Subgroup analyses were performed for grouped TNFi and individual TNFi (infliximab, IFX; adalimumab, ADA; etanercept, ETN).Results:247 patients with estRA were taking a biologic at 6 months, and 231 patients were taking a biologic at 12 months. Obese patients taking any biologic were significantly less likely to achieve DAS28 remission (OR 0.33 [95%CI 0.12-0.80]) or good EULAR response (OR 0.37 [95%CI 0.16-0.81]) after 6 months, compared to those of normal BMI; this was also demonstrated in those co-prescribed methotrexate (DAS28 remission: OR 0.23 [95%CI 0.07-0.62]; good EULAR response: OR 0.39 [95%CI 0.15-0.92]). These associations did not remain statistically significant at the 12 months assessment.Regarding specific anti-TNF therapies, RA patients treated with monoclonal antibody (-mab) TNFis (IFX/ADA/ GOL) were significantly less likely to achieve good EULAR response at 6 months if they were obese RA (n=38), compared to those of normal weight (n=44) (OR 0.17 [95%CI 0.03-0.59]). A similar non-significant difference was demonstrated for DAS28 remission, and 12-month remission. Specifically, obese individuals were significantly less likely to achieve good EULAR response at 6 months with IFX (OR 0.09 [95%CI 0.00-0.61]; n=20), and significantly less likely to achieve DAS28 remission at 6 months when newly-starting ADA (OR 0.14 [95%CI 0.01-0.96]; n=17), compared to those of normal weight. There were no significant differences in remission outcomes between individuals of different BMI taking ETN. A small number of individuals stopped taking their respective biologic after 6months; reason for cessation was not recorded.Similar outcomes were seen in patients already established on anti-TNF therapy, with overweight and obese individuals less likely overall to be in DAS28 remission at all time points.Conclusion:In established RA, obesity is associated with reduced treatment response to -mab TNFi. No association between increased BMI and response to ETA was observed. Using BMI to direct biologic drug choice could prove to be a simple and cost-effective personalised-medicine approach to prescribing.

Ankylosing Spondylitis versus Nonradiographic Axial Spondyloarthritis: Comparison of Tumor Necrosis Factor Inhibitor Effectiveness and Effect of HLA-B27 Status. An Observational Cohort Study from the Nationwide DANBIO Registry.

To compare baseline disease activity and treatment effectiveness in biologic-naive patients with nonradiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) who initiate tumor necrosis factor inhibitor (TNFi) treatment and to study the role of potential confounders (e.g., HLA-B27 status). Observational cohort study based on prospectively registered data in the nationwide DANBIO registry. We used Kaplan-Meier plots, Cox, and logistic regression analyses to study the effect of diagnosis (nr-axSpA vs AS) and potential confounders (sex/age/start yr/HLA-B27/disease duration/TNFi-type/smoking/baseline disease activity) on TNFi adherence and response [e.g., Bath Ankylosing Spondylitis Activity Index (BASDAI) 50%/20 mm]. The study included 1250 TNFi-naive patients with axSpA (29% nr-axSpA, 50% AS, 21% lacked radiographs of sacroiliac joints). Patients with nr-axSpA were more frequently women (50%/27%) and HLA-B27-negative (85/338 = 25%), compared to AS (81/476 = 17%; p < 0.01). At TNFi start patients with nr-axSpA had higher visual analog scale scores [median (quartiles)] for pain: 72 mm (55-84)/65 mm (48-77); global: 76 mm (62-88)/68 mm (50-80); fatigue: 74 mm (55-85)/67 mm (50-80); and BASDAI: 64 (54-77)/59 (46-71); all p < 0.01. However, patients with nr-axSpA had lower C-reactive protein: 7 mg/l (3-17)/11 mg/l (5-22); and BAS Metrology Index: 20 (10-40)/40 (20-50); all p < 0.01. Median (95% CI) treatment adherence was poorer in nr-axSpA than in AS: 1.59 years (1.15-2.02) versus 3.67 years (2.86-4.49), p < 0.0001; but only in univariate and not confounder-adjusted analyses (p > 0.05). Response rates were similar in AS and nr-axSpA (p > 0.05). HLA-B27 negativity was associated with poorer treatment adherence [HLA-B27 negative/positive, nr-axSpA: HR 1.74 (1.29-2.36), AS: HR 2.04 (1.53-2.71), both p < 0.0001]; and lower response rates (nr-axSpA: 18/61 = 30% vs 93/168 = 55%; AS: 17/59 = 29% vs 157/291 = 54%, both p < 0.05). In this nationwide cohort, patients with nr-axSpA had higher subjective disease activity at start of first TNFi treatment, but similar outcomes to patients with AS after confounder adjustment. HLA-B27 positivity was associated with better outcomes irrespective of axSpA subdiagnosis.

Older age at rheumatoid arthritis onset and comorbidities correlate with less Health Assessment Questionnaire-Disability Index and Clinical Disease Activity Index response to etanercept in the RADIUS 2 registry.

Controversy exists in understanding the effects of age at onset and comorbidities in predicting rheumatoid arthritis (RA) response to biologic therapy. The objective of this study was to investigate the influence of age at onset and number of comorbidities on Health Assessment Questionnaire-Disability Index (HAQ-DI) and Clinical Disease Activity Index (CDAI) responses in active RA patients after 6 months of treatment with etanercept. One thousand eight hundred ninety-nine RA patients were assessed after 6 months of etanercept therapy. Patients met the following inclusion criteria: initiated etanercept, continued therapy for at least 6 months, and were not in CDAI low disease activity (LDA) at baseline (CDAI ≤10.0). Changes in HAQ-DI and CDAI scores over 6 months were analyzed across age of onset quintiles. Multivariate regression models evaluated the independent association between both age at onset and number of comorbidities with change in HAQ-DI/CDAI scores or achieving LDA, while accounting for other covariates. Significant improvements in HAQ-DI and CDAI scores were observed in all age-onset groups, although HAQ-DI improvements were less in older-onset patients. Results of multiple linear regression demonstrated that younger age at onset, higher baseline HAQ-DI/CDAI score, rheumatoid factor positivity, shorter disease duration, and fewer comorbidities at baseline were independently associated with improvement in both HAQ-DI and CDAI scores. Similarly, achieving CDAI LDA after 6 or more months of etanercept was associated with younger age at onset, higher baseline CDAI, shorter disease duration, and fewer comorbidities. These patients with older-onset RA and more comorbidities clinically improved with etanercept, but had lower odds of achieving CDAI LDA. Age of onset and number of comorbidities may be important in determining RA tumor necrosis factor inhibitor response.

Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis

ObjectivesPharmacogenetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores, such as disease activity score...

Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: Observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts

To determine whether cigarette smoking influences the response to treatment in patients with early rheumatoid arthritis (RA). We retrieved clinical information about patients entering the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) early RA cohort from 1996 to 2006 (n=1,998) who were also in the Swedish Rheumatology Register (until 2007). Overall, 1,430 of the 1,621 registered patients were followed up from the time of inclusion in the EIRA cohort. Of these, 873 started methotrexate (MTX) monotherapy at inclusion, and 535 later started treatment with a tumor necrosis factor (TNF) inhibitor as the first biologic agent. The primary outcome was a good response according to the European League Against Rheumatism criteria at the 3-month visit. The influence of cigarette smoking (current or past) on the response to therapy was evaluated by logistic regression, with never smokers as the referent group. Compared with never smokers, current smokers were less likely to achieve a good response at 3 months following the start of MTX (27% versus 36%; P=0.05) and at 3 months following the start of TNF inhibitors (29% versus 43%; P=0.03). In multivariate analyses in which clinical, serologic, and genetic factors were considered, the inverse associations between current smoking and good response remained (adjusted odds ratio [OR] for MTX response 0.60 [95% CI 0.39-0.94]; adjusted OR for TNF inhibitor response 0.52 [95% CI 0.29-0.96]). The lower likelihood of a good response remained at later followup visits. Evaluating remission or joint counts yielded similar findings. Past smoking did not affect the chance of response to MTX or TNF inhibitors. Evaluating the overall cohort, which reflects all treatments used, current smoking was similarly associated with a lower chance of a good response (adjusted ORs for the 3-month, 6-month, 1-year, and 5-year visits 0.61, 0.65, 0.78, 0.66, and 0.61, respectively). Among patients with early RA, current cigarette smokers are less likely to respond to MTX and TNF inhibitors.