TNFi Therapy Research Articles

FRI0555 DO TNF INHIBITORS DECREASE RISK OF INCIDENT PSORIATIC ARTHRITIS IN PSORIASIS PATIENTS COMPARED TO THOSE TREATED WITH METHOTREXATE ALONE?

Background:Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterized by joint and entheseal inflammation seen in 30% patients with psoriasis (Pso). In 90% of patients, Pso precedes PsA. Inhibitors of tumor necrosis factor (TNFi) are efficacious treatment options for both, though whether they prevent development of incident PsA in Pso patients is unknown.Objectives:To determine if the use of TNFi reduces the risk of developing psoriatic arthritis in Pso patients compared to those treated with methotrexate alone.Methods:Records on all Pso patients seen at dermatology clinic at our University from January 2006 - June 2019 were reviewed. Patients with any musculoskeletal symptoms were referred to rheumatology and were considered to have PsA if they were diagnosed by a rheumatologist. We used Student’s t-test to compare continuous covariates and Pearson’s chi-squared test or Fisher’s exact test to compare categorical covariates. Variables that were found to be significantly associated with PsA diagnosis were included as potential confounders in the multivariate model. We used Cox proportional hazards models to compare the risk of incident PsA diagnosis for those who initiated TNFi compared to those who initiated methotrexate. A propensity score of TNFi therapy compared to methotrexate therapy was calculated using variables associated with treatment choice and adjusted for in the model. Variables that were associated with both treatment choice and PsA risk were not included in the propensity score. We used backwards stepwise variable selection to build the final model.Results:Out of 154 Pso patients who did not have PsA at baseline, and were started exclusively on a TNFi or methotrexate during the study period,, 85 (55.2%) initiated methotrexate and 69 (44.8%) initiated a TNFi. Mean duration of therapy for those on TNFi was 3.95 (standard error: 0.50) years while mean duration of therapy for those on methotrexate was 1.93 years (standard error: 0.28). Mean follow-up time for those on TNFi was 5.18 years (standard error: 0.49) and for those on methotrexate was 2.71 years (standard error: 0.37) Seventy nine (51.3%) of the cohort were women. Thirty five (22.7%) of subjects developed PsA over the course of the study. After adjusting for propensity score, nail pitting, body surface area (BSA) involved in psoriasis, and depression, TNFi did not significantly reduce the risk of PsA as compared to methotrexate (HR: 0.68 [95% CI: 0.32, 1.41]).Conclusion:Use ofTNFi was not associated with a statistically significant decreased risk of incident PsA compared to methotrexate in this study, but a larger cohort with longer follow up will have better power to estimate the true association.Table 1.Characteristics of the psoriasis cohort starting exclusively TNFi or methotrexateIncident PsAn = 35PsA negativen = 119p-valueTreatment [n (%)]0.37TNFi18 (51.4)51 (42.9)Methotrexate17 (48.6)68 (57.1)Sex [n (%)]0.24Female21 (60.0)58 (48.7)Male14 (40.0)61 (51.3)Age [median (IQR)]47.0 (39.4, 59.7)48.9 (35.3, 61.7)0.71Pso manifestations [n (%)]Nail pitting27 (77.1)51 (42.9)<0.01Scalp psoriasis31 (88.6)105 (89.0)0.95Inverse psoriasis14 (40.0)37 (31.09)0.33BSA [median (IQR)]6 (3, 15)12 (5, 22)0.06BMI [median (IQR)]31.7 (25.9, 40.4)29.1 (26.3, 34.7)0.30Therapy duration (years)TNFi [median (IQR)]4.38 (1.34, 8.13)2.26 (0.76, 5.82)0.29Methotrexate [median (IQR)]2.44 (0.06, 3.44)0.94 (0.27, 2.39)0.43Disclosure of Interests:Noah Lininger: None declared, Sarah Siegel: None declared, Sonam Kiwalkar: None declared, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Alex Ortega Loayza Consultant of: Adviser board for Janssen, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB

Elevated CRP even at the first visit to a rheumatologist is associated with long-term poor outcomes in patients with psoriatic arthritis.

Little is known about the long-term association of CRP levels during psoriatic arthritis (PsA) disease course. In this study, we examined whether raised CRP over the disease course is associated with worse outcome measures in a well-characterised PsA cohort with a long-term follow up. A cohort of 283 PsA patients (fulfilling CASPAR criteria) was evaluated. All underwent detailed skin and rheumatologic assessments. Moreover, we documented the presence/absence of comorbidities using Charlson Comorbidity Index (CCI). CRP at first visit to a rheumatologist was documented. Cumulative inflammation over time was represented by the cumulative averages of CRP (ca-CRP). Multiple linear regression modelling CRP was used. Two hundred eighty-three PsA patients attended for detailed assessments. A total of 56.5% (n = 160) of the cohort had raised CRP at their first visit to our rheumatology department, and this was significantly associated with long-term erosions, sacroiliitis, PsA requiring TNFi, and high comorbidity Index, on logistic regression analysis. Moreover, 24% (n = 69) of the cohort never had raised CRP during their long-term follow-up, and on logistic regression analysis, such patients had significantly milder disease with fewer erosions, less sacroiliitis and fewer patients requiring TNFi therapy. The median (IQR) and mean (SD) Ca-CRP was 8.8 (4.6-14.8) and 11.72 (10.52), respectively. On multiple linear regression, erosions, sacroiliitis and CCI were most significantly associated with ca-CRP [(F = 77.6, p < 0.001), 72% (R-square)]. Elevated CRP is associated with radiographic damage, disease more resistant to treatment and also having higher number of significant comorbidities. Raised CRP can help stratify patients with a more severe PsA phenotype. Key Points • Raised CRP can provide important future prognostic information among patients with PsA. • PsA patients with raised CRP at first visit to a rheumatologist had significantly more destructive and refractory disease. • PsA patients with consistently normal CRP had significantly milder disease.

P282 Outcome for PsA biologic switchers following primary inefficacy of TNFi therapy in a secondary care cohort: sequential TNFi versus switching mode of action

Abstract Background TNFi are the most used first line of biologic disease modifying anti-rheumatic drugs (bDMARDs) in PsA. In primary loss of response (PLR) to TNFi, there is no current evidence that directs the choice of second line bDMARDs. Our aim in this work was to compare drug survival for those who switched to a second TNFi versus alternative agents in real life. Methods Data was analysed retrospectively from a cohort of 400 PsA patients followed through from 2002-2019. Statistical analysis was carried out with descriptive statistics and t-test analysis using SPSS version 22. Results Out of 400 patients, 220 (55.0%) were started on bDMARD treatment. Of these 220, 212 (96.5%) were started on TNFi as initial therapy. PLR was seen in 42 of these patients (19.8%). The median drug survival of initial TNFi therapy was 7.1 months (interquartile range [IQR] 3.6 - 53.4 months). Of the 42 patients with PLR: 32 (76.2%) were switched to a second TNFi; 6 (14.3%) were switched to ustekinumab and 4 (9.5%) were switched to secukinumab. 21 of the 32 patients switched to a second TNFi were subsequently switched onto a third biologic due to treatment failure (65.6%). The median drug survival of the second TNFi in this group was 7.7 months (IQR 3.0 - 26.3 months). 3 out of the 6 (50%) patients who were switched to ustekinumab were then subsequently switched, this was due to primary inefficacy in 66.7% and adverse events in 33.3%. The median drug survival of ustekinumab in this group was 10.0 months (IQR 0.0 - 16.0 months). All 4 patients switched to secukinumab continue on this treatment with no drop outs, giving a median drug survival 12.3 months (IQR 6.5 - 19.5 months). Conclusion Our data suggests that patients with PLR to TNFi in PsA who switched mode of action to IL-17 inhibitor appeared to have better drug survival than subsequent TNFi or IL-12/23 inhibitors. Exploring the clinical biomarkers for those with successful switch to non-TNFi bDMARD in a larger cohort would help with targeting the most appropriate individuals and early disease control. Disclosures M. Naja None. L. R. Santos None. M. Shipa None. G. Mandy None. M. Castelino None.

P218 Interrogation of transcriptome data in RA for identifying disease susceptibility loci and predictors of treatment response

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the Caucasian population worldwide causing significant morbidity. The genetics of disease pathogenesis remains poorly understood despite recent advances in high throughput genotyping and sequencing. Biological agents (e.g. TNF inhibitors, TNFi) have significantly impacted on disease management, however 30-40% of RA patients do not respond to this therapy. The aim of this study was to use transcriptome sequencing (RNA sequencing) data from human neutrophils to identify variants in RA that may underpin disease pathogenesis and predict response to biologic therapy. Methods RNA sequencing (RNA-seq) data from peripheral blood neutrophils isolated pre-TNFi treatment was analysed from 27 RA patients and 6 healthy controls. 21 RA patients subsequently responded to TNFi therapy (change in DAS28 &amp;gt;1.2). RNA-seq reads were mapped to the human genome (hg19) using TopHat2 and annotated using Cufflinks. Data was combined, calibrated and filtered using the Genome Analysis Tool Kit (GATK) to create a file of identified variants. These variants were subsequently interrogated using the VCFtools program package. Quality control parameters were applied in accordance with guidance and available literature, excluding variants that were: PHRED &amp;lt; 30, Minimum read depth &amp;lt; 4 and a loci sequencing success rate &amp;lt; 80%, with SNP clusters and indels also removed. Tajima D was used as a statistic for identifying regions of interest within the RNA-seq data. Identified variants were annotated and interrogated using the UCSC bioinformatics platform and pathway analysis of identified genes predicted through Ingenuity Pathway Analysis (IPA). Results GATK analysis identified 536,668 variants, which were refined to 5230 variants following application of QC parameters as specified with over 99% of variants excluded. RA patients had a mean Tajima-D score of 0.51 vs -0.19 in the controls (p &amp;lt; 0.0001) and furthermore had significantly more regions of transcriptome with extreme positive Tajima-D values (p &amp;lt; 0.0001). Bioinformatics analysis identified the variants with high Tajima-D scores to be within a number of biologically relevant loci, including NCF1, which has been associated with autoimmune diseases including SLE and is predictor of RA severity in rat models. IPA revealed that a number of the highest scoring variants were within loci that were linked via a gene network regulated by activation of Fcgamma receptors (FCGR1A/B/C, FCGR2A/B, FCGR3B) and p38 MAPK. Conclusion This study suggests that interrogation of transcriptome data has a role in elucidating the components underpinning RA pathogenesis, identifying a number of interesting loci that may contribute towards its missing heritability. However, such preliminary data will require validation through direct sequencing of variants and investigation in independent data sets as well sub-group analysis of treatment response to biological therapy. Disclosures R. Smith None. N. Goodson None. R.J. Moots None. H.L. Wright None.

Characteristics of coexisting localized scleroderma and inflammatory arthritis.

Localized scleroderma (LS), including morphea and linear scleroderma, is an autoimmune disease where excessive subcutaneous collagen deposits lead to thickening, scarring, and fibrosis of the tissues. LS coexisting with inflammatory arthritis is less well-described but has been reported in as many as 20% of 53 LS patients in a recent cohort. Herein, we describe a cohort of 8 children with both LS and inflammatory arthritis. The objective of this study is to determine the characteristics of inflammatory arthritis in children with LS and their response to treatment regimens. A retrospective chart review was completed on patients less than 19 years of age who were diagnosed with either morphea or linear scleroderma at the Children of Alabama center from 2004-2018. Patients were identified using ICD-9 and ICD-10 diagnostic codes. Records were reviewed for additional diagnostic codes, exams, and laboratory findings confirming coexisting inflammatory arthritis and LS. A total of 87 patients with a diagnosis of either morphea or linear scleroderma were identified. Eight (9%) had coexisting inflammatory arthritis according to the diagnostic codes with documented active arthritis. Median age of initial rheumatic disease diagnosis was 7.5 years. A majority of patients with both LS and inflammatory arthritis were female (62.5%). Half of the patients (n=4, 50%) had LS lesions over arthritic joints. All of the identified patients were diagnosed with a form of juvenile idiopathic arthritis (JIA). The JIA diagnoses varied widely in 3 (37.5%) patients with rheumatoid factor (RF) negative polyarticular JIA, 2 (25%) with oligoarticular JIA, 2 (25%) with psoriatic JIA, and 1 (12.5%) with enthesitis-related JIA. The timing of onset of LS and inflammatory arthritis varied widely. Three (37.5%) patients had LS lesions preceding clinical arthritis, and three (37.5%) had arthritis before the appearance of LS. Two (25%) patients had both LS and arthritis at the time of diagnosis. All patients received methotrexate (MTX) during their disease course with only 3 (37.5%) receiving systemic steroids during treatment. All 8 patients showed resolution of LS lesions. However, 6 of the 8 patients demonstrated active arthritis on combination MTX and TNFi therapy. In this cohort of pediatric LS, 9% of patients had coexisting inflammatory arthritis. The characteristics of this cohort varied widely. All patients received MTX initially and showed a resolution of LS lesions. However, in the majority of patients, the arthritis failed to respond to MTX and TNFi combination therapy. These results suggest that inflammatory arthritis coexisting with LS may be less likely to respond to traditional inflammatory arthritis or JIA therapies.

The Effect of TNF Inhibition on Bone Density and Fracture Risk and of IL17 Inhibition on Radiographic Progression and Bone Density in Patients with Axial Spondyloarthritis: a Systematic Literature Review.

Osteoporosis in axial spondyloarthritis may be modified by therapy. The purpose of this systematic review is to describe (i) the effect of TNFi on BMD, (ii) the effect of secukinumab on BMD, and (iii) the effect of secukinumab on radiographic disease progression in axSpA. We searched PubMed, Embase, and Cochrane using the following retrieval languages: spondyloarthritis, ankylosing spondylitis, TNF, IL-17, x-rays, and osteoporosis. Twenty-nine studies were included; 27 re: TNFi and BMD, and 2 re: IL-17 blockers and x-ray progression. TNFi over 2-4years increased BMD of the lumbar spine (3.2-14.9%) and hip (2.26-4.7%) without reducing vertebral fractures. Secukinumab reduced radiographic progression; none (73%) and minimal (79%) at 4years. No data on IL-17 blockade and bone were found. TNFi therapy improves bone density but not vertebral fracture rates. Secukinumab improves symptoms and may slow radiographic progression. Data is lacking regarding the effects of secukinumab on BMD and fractures. These are important questions which may impact the choice of therapy.

3521 Distinct single cell gene expression in peripheral blood monocytes correlates with treatment response groups to TNF-alpha inhibition in rheumatoid arthritis

OBJECTIVES/SPECIFIC AIMS: The cellular mechanisms that underlie the IFNβ/α ratio that predicts response are not known. Effects of IFN on single immune cells may be masked in whole blood or mixed cell populations. By studying the effect of IFNβ/α activity ratio on individual monocytes, we can determine the functional impact of the IFN ratio and suggest the cellular mechanisms that underlie response/non-response to TNFi therapy in RA. METHODS/STUDY POPULATION: We used single cell analysis to investigate whether monocyte gene expression differs significantly between RA patients according to their pre-TNFi serum IFN-β/α ratio. Single classical (CL) and non-classical (NC) blood-derived monocytes were isolated from 15 seropositive RA subjects prior to biologic therapy. Subjects were grouped by pre-TNFi serum IFN-β/α ratio into two groups, those with a high IFN-β/α ratio (≥1.3, n = 6) and those with a low IFN-β/α ratio (&lt;1.3, n = 9). 87 target genes were analyzed. Genes that varied significantly between the groups by categorical analyses were tested in multivariate logistic regression models. RESULTS/ANTICIPATED RESULTS: Every participant was seropositive for rheumatoid factor and antibodies to cyclic citrullinated peptide. Among the participants in the groups, there were no significant differences in age or DAS scores (P&gt;0.05). The treatments were comparable and none were being treated with biologic therapy. There were striking differences in monocyte gene expression between patients with pre-treatment blood IFNβ/α activity &lt;1.3 and ≥1.3. Expression of (1) key type I IFN pathway genes (JAK1, STAT2, IFIT2, IFIH1, PRDM1); (2) IL12; (3) CD36; and (4) CTLA4 were the strongest differentiators between groups (p&lt;0.0001 for each, corrected for multiple comparisons). DISCUSSION/SIGNIFICANCE OF IMPACT: In this study we were able to measure gene expression in single monocytes from seropositive RA patients prior to biologic treatment. Within-cell co-expression patterns demonstrate biological differences in monocytes of RA patients with an IFNβ/α ≥1.3, the ratio of type I IFNs which predicts non-response to TNFi. The data suggest that there may be differential IFN production and pathway activation in patients who do not respond to TNFi. The increased expression of CD36 in monocytes from RA patients with high IFN β/α activity may be a reflection of increased “foam cells” in the inflamed tissue of patients who do not respond to TNFi. Enrichment of CTLA4 in those with high serum IFNβ/α suggests that CTLA4-Ig may be less likely to be an effective alternative for someone who is not likely to respond to TNFi. Current work includes determining whether the peripheral blood findings reflect altered cellular composition, type I IFN production and signaling in the synovium. Significance: This work will help to develop a more individualized approach to therapy in RA and determine an immunological basis of response/non-response to TNFi.

Malignancy risk in Australian rheumatoid arthritis patients treated with anti-tumour necrosis factor therapy: an update from the Australian Rheumatology Association Database (ARAD) prospective cohort study

BackgroundTumour necrosis factor inhibitor (TNFi) therapy has been available for rheumatoid arthritis (RA) patients for several decades but data on the long-term risk of malignancy associated with its use is limited. Our aims were to assess malignancy risk in a cohort of Australian RA patients relative to the Australian population and to compare cancer risk for patients exposed to TNFi therapy versus a biologic-naïve group.MethodsDemographic data for RA participants enrolled in the Australian Rheumatology Association Database (ARAD) before 31 Dec 2012 were matched to national cancer records in May 2016 (linkage complete to 2012). Standardised incidence ratios (SIRs) were used to compare malignancy incidence in TNFi-exposed and biologic-naïve ARAD participants with the Australian general population using site-, age- and sex-specific rates by calendar year. Malignancy incidence in TNFi-exposed participants and biologic-naïve RA patients, were compared using rate ratios (RRs), adjusted for age, sex, smoking, methotrexate use and prior malignancy.ResultsThere were 107 malignancies reported after 10,120 person-years in the TNFi-exposed group (N = 2451) and 49 malignancies after 2232 person-years in the biologic-naïve group (N = 574). Compared with the general population, biologic-naïve RA patients showed an increased risk for overall malignancy (SIR 1.52 (95% confidence interval (CI) 1.16, 2.02) prostate cancer (SIR 2.10, 95% CI 1.18, 4.12). The risk of lung cancer was increased for both biologic naïve and TNFi-exposed patients compared with the general population (SIR 2.69 (95% CI 1.43 to 5.68) and SIR 1.69 (95% CI 1.05 to 2.90) respectively). For the TNFi-exposed patients there was an increased risk of lymphoid cancers (SIR 1.82, 95% CI 1.12, 3.18). There were no differences between the exposure groups in the risk of cancer for any of the specific sites examined.ConclusionsOverall malignancy incidence was elevated for biologic-naïve RA patients but not for those exposed to TNFi. TNFi exposure did not increase malignancy risk beyond that experienced by biologic-naïve patients. Lung cancer risk was increased for both TNFi-treated and biologic-naïve RA patients compared with the general population suggesting that RA status or RA treatments other than TNFi may be responsible in some way.

The Effect of Prednisone on Tuberculin Skin Test Reaction in Patients with Rheumatoid Arthritis.

Objectives To assess the correlation between prednisone and methotrexate (MTX) treatment duration and dosage with the TST induration diameter of the TST reaction among rheumatoid arthritis (RA) patients. Method We retrospectively analyzed consecutive cases of RA patients who were TNF-i therapy candidates. TST measurements, prednisone and methotrexate dosages, and treatment durations were recorded. A control group was randomly selected from healthy subjects. We compared TST reaction size between the following three groups: RA patients with current prednisone treatment, RA prednisone naïve patients, and healthy individuals. Results Our study sample comprised 43 RA patients with prednisone treatment, 22 prednisone naïve patients, and 195 healthy subjects. There was no significant difference in mean TST between the groups (5.3±6.6, 7.8±6.2, and 7.6±7.0, respectively, p=0.149). No correlation was noted between TST size and prednisone u-y (r=0.229, p=0.140) or methotrexate u-y in patients with and without prednisone therapy (r=0.219, p=0.158; and r=−0.293, p=0.186, respectively). Conclusions Our results show that the TST reaction size among RA patients may not be affected by prednisone therapy. In addition, the TST reaction of RA patients may present similarly to that of healthy individuals. Therefore, we suggest that the criterion of a TST reaction of 5 mm to define latent TB infection in our population should be reevaluated.

Risk of post-operative surgical site infections after vedolizumab vs anti-tumour necrosis factor therapy: a propensity score matching analysis in inflammatory bowel disease.

Perioperative vedolizumab (VDZ) and anti-tumour necrosis factor (TNFi) therapies are implicated in causing post-operative complications in inflammatory bowel disease (IBD). To compare the risk of surgical site infections (SSIs) between VDZ- and TNFi-treated IBD patients in propensity-matched cohorts. The Optum Research Database was used to identify IBD patients who received VDZ or TNFi within 30days prior to abdominal surgery between January 2015 and December 2016. The date of IBD-related abdominal surgery was defined as the index date. SSIs were determined by ICD-9/10 and CPT codes related to superficial wound infections or deep organ space infections after surgery. Propensity score 1:1 matching established comparable cohorts based on VDZ or TNFi exposure before surgery based on evidence-based risk modifiers. The propensity-matched sample included 186 patients who received pre-operative biologic therapy (VDZ, n=94; TNFi, n=92). VDZ and TNFi cohorts were similar based on age, gender, IBD type, concomitant immunomodulator exposure, chronic opioid or corticosteroid therapy, Charlson Comorbidity Index and malnutrition. VDZ patients were more likely to undergo an open bowel resection with ostomy. After propensity score matching, there was no significant difference in post-operative SSIs (TNFi 12.0% vs VDZ 14.9%, P=0.56). Multivariable analysis indicated that malnutrition was the sole risk factor for developing SSI (OR 3.1, 95% CI 1.11-8.71) regardless of the type of biologic exposure. In the largest, risk-adjusted cohort analysis to date, perioperative exposure to VDZ therapy was not associated with a significantly higher risk of developing an SSI compared to TNFi therapy.

Manage cutaneous adverse effects associated with tumour necrosis factor inhibitors with topical corticosteroids and oral antibiotics

Cutaneous adverse effects (CAEs), such as eczema, psoriasis, and skin infections, are common in patients receiving tumour necrosis factor inhibitors (TNFIs; e.g. adalimumab, etanercept and infliximab). Once a CAE is diagnosed, patients should receive appropriate dermatological care, as this may avoid cessation of TNFI therapy. Topical corticosteroids are the mainstay of therapy for numerous skin lesions, while oral antibiotics are effective in the treatment of superinfections.

PMS6 - Secukinumab shows Higher Symptomatic improvement Versus Etanercept in Psoriatic Arthritis: Comparative Effectiveness Up To 24 Weeks Assessed by Matching-Adjusted Indirect Comparison

When populations across different trials are heterogeneous, Matching-Adjusted Indirect Comparison (MAIC) can be used to assess comparative effectiveness; it is supported by NICE DSU methodological guidance. The objective of this MAIC was to assess the comparative effectiveness of secukinumab 150mg (SEC; fully human anti-interleukin-17A) and etanercept 25mg twice weekly (ETN; tumor necrosis factor inhibitor [TNFi]) up to 24 weeks in biologic-naïve patients with psoriatic arthritis (PsA). In this MAIC, individual patient data from the pooled SEC arms of FUTURE 1 (F1) and FUTURE 2 (F2; n=302) were weighted to match baseline characteristics of the ETN arm of NCT00317499 (n=101); placebo arms were also matched. Before matching, one notable difference was the proportion of biologic-naïve patients (67.2% [F1/F2] versus 100% [NCT00317499]). Logistic regression was used to determine weights for age, body weight, sex, race, PsA disease duration, presence of psoriasis (≥3% body surface area), mean HAQ-DI score, swollen joint count (SJC), CRP, methotrexate use and previous TNFi therapy failure. Recalculated outcomes from F1/F2 (SEC, effective sample size [ESS]=79; placebo, ESS=94) were compared with NCT00317499. Pairwise comparisons using odds ratios (ORs) were performed for American College of Rheumatology (ACR) 20, 50 and 70 responses at week 12 (placebo-adjusted) and week 24 (non-placebo-adjusted). Placebo-adjustment at week 24 was not possible as patients could receive active treatment from week 16. At week 12, no differences in placebo-adjusted ACR 20, 50 and 70 responses between SEC and ETN were observed. At week 24 (non-placebo-adjusted), ACR 70 responses were higher with SEC than ETN (OR [95% CI]: 3.06 [1.30–7.19], p= 0.010). A sensitivity analysis excluding PsA disease duration, SJC and CRP from the matching confirmed these results. In this MAIC, secukinumab showed evidence of superiority for symptomatic improvement (non-placebo-adjusted ACR 70) over etanercept for active PsA at 24 weeks.

Time to rebound in joint symptoms following discontinuation of TNFi therapy after achieving low disease activity in psoriatic arthritis patients enrolled in the US Corrona Registry

Time to rebound in joint symptoms following discontinuation of TNFi therapy after achieving low disease activity in psoriatic arthritis patients enrolled in the US Corrona Registry

Costs associated with failure to respond to treatment among patients with rheumatoid arthritis initiating TNFi therapy: a retrospective claims analysis

BackgroundTumor necrosis factor inhibitors (TNFi) are common second-line treatments for rheumatoid arthritis (RA). This study was designed to compare the real-world clinical and economic outcomes between patients with RA who responded to TNFi therapy and those who did not.MethodsFor this retrospective cohort analysis we used medical and pharmacy claims from members of 14 large U.S. commercial health plans represented in the HealthCore Integrated Research Database. Adult patients (aged ≥18 years) diagnosed with RA and initiating TNFi therapy (index date) between 1 January 2007 and 30 April 2014 were included in the study. Treatment response was assessed using a previously developed and validated claims-based algorithm. Patients classified as treatment responders in the 12 months postindex were matched 1:1 to nonresponders on important baseline characteristics, including sex, age, index TNFi agent, and comorbidities. The matched cohorts were then compared on their all-cause and RA-related healthcare resource use, and costs were assessed from a payer perspective during the first, second, and third years postindex using parametric tests, regressions, and a nonparametric bootstrap.ResultsA total of 7797 patients met the study inclusion criteria, among whom 2337 (30%) were classified as treatment responders. The responders had significantly lower all-cause hospitalizations, emergency department visits, and physical/occupational therapy visits than matched nonresponders during the first-year postindex. Mean total all-cause medical costs were $5737 higher for matched nonresponders, largely driven by outpatient visits and hospitalizations. Mean all-cause pharmacy costs (excluding costs of biologics) were $354 higher for matched nonresponders. Mean RA-related pharmacy costs (conventional synthetic and biologic drugs), however, were $8579 higher in the responder cohort, driven by higher adherence to their index TNFi agent (p < 0.01 for all comparisons). A similar pattern of cost differentiation was observed over years 2 and 3 of follow-up.ConclusionsIn this real-world study we found that, compared with matched nonresponders, patients who responded to TNFi treatments had lower all-cause medical, pharmacy, and total costs (excluding biologics) up to 3 years from initiation of TNFi therapy. These cost differences between the two cohorts provide a considerable offset to the cost of RA medications and should encourage close monitoring of treatment response to minimize disease progression with appropriate therapy choices.

Disease activity-guided TNFi therapy cost saving for RA

Disease activity-guided TNFi therapy cost saving for RA

Rheumatoid Arthritis — Anti-TNF

This review will focus on the recent information and strategies now informing best use of TNF inhibitor therapy in RA. These issues include the role of TNFi therapy in early RA management, anti-drug antibodies in TNFi therapy, updates on safety and optimal dosage regimens in long term management.

Response to Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis for Function and Pain is Affected by Rheumatoid Factor.

Objectives : To investigate differences in response to tumor necrosis factor inhibitor treatment (TNFi) in seropositive (rheumatoid factor positive; RF+) versus seronegative (RF-) patients with established RA as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain.Methods : RA patients from an established RA cohort were studied according to rheumatoid factor (RF) status for change in HAQ-DI and pain (0-3 VAS) one year after starting treatment with a TNFi.Results : There were 238 patients treated with TNFi who had follow-up data (178 RF+ and 60 RF-). Disease duration was longer in RF+ vs RF- (12+8 vs 8+8 years) but the proportion of females (82% vs 72%, P=0.7), baseline HAQ-DI (1.44+0.63 vs 1.41+0.63, P=0.8) and pain (1.92+0.67 vs 1.93+0.67, P=0.9) were not different. The mean duration of treatment of first TNFi was 2.8 vs 2.3 years, P=0.1 and 68% of RF+ vs 62% of RF- were still receiving first TNFi at last visit (P=0.5). For patients with data at baseline and one year, the one-year HAQ-DI change was significantly greater in 90 RF+ patients (-0.356) versus 38 RF- patients (-0.126; P=0.04). The mean pain improvement was also greater in 77 RF+ vs 32 RF- patients (-0.725 vs -0.332 respectively; P=0.03). Numbers are small, data are missing and comorbidities, DAS28 and anti-CCP were not collected.Conclusion : Despite limitations in the data, in established RA after failure of DMARDs, RF+ patients may be more responsive to TNFi therapy as measured by changes in HAQ-DI and pain.Innovation : There may be a better response to TNFi in RA if RF positive for function and pain.

AB0469 Patient-Oriented Decision of Early Treatment of Rheumatoid Arthritis with Combination of Triple Conventional Disease Modifying Anti-Rheumatic Drugs or Tumor Necrosis Factor Inhibitors and Methotrexate (Prospective, Open-Label Clinical Trial)

BackgroundEarly optimization of conventional disease modifying anti-rheumatic drugs (cDMARD) treatment is imperative as delay of biologics in certain patients potentially leads to irreversible functional disability. Bucillamine (BUC) is a unique...

222. Current Management of Ankylosing Spondylitis in the UK: The Patient Perspective

3rd TNFi drug and 2 switching to a 4th TNFi drug. Secondary failure was the main cause of switching, with 26 switching for this reason after the first TNFi (mean duration 28 months). Adverse events were the cause of switching in 6 patients receiving the first TNFi. Primary failure (mean duration 5 months) was the reason in 4 patients receiving their first TNFi. Responses to the first switch were that 25/39 (64%) continued on the second TNFi (mean duration on therapy of 43 months). Of the 14 patients who subsequently switched to a 3rd TNFi therapy, 9 had secondary failure (mean duration 14 months on 2nd TNFi), 2 had primary failure and 3 had adverse events. 10/14 (71%) patients continue on a 3rd TNFi, with 3 switched due to secondary failure and 1 primary failure. 3 patients received and responded to a 4th TNFi drug. Conclusion: These data support previous studies that people with PsA receiving TNFi therapy have a lower rate of secondary failure to TNFi therapy compared with RA. Our data show that after switching most people remain on the second TNFi for a substantial time, suggesting efficacy is maintained. Disclosure statement: L.B. has received honoraria from Roche, MSD, Pfizer and BMS. B.K. has received honoraria from AbbVie, BMS, MSD, Novartis, Pfizer, Roche and UCB. S.M. has received honoraria from BMS.

232. Interferons Alter the Response of Neutrophils to Inflammatory Cytokines in vitro

Background: Neutrophils are central to the initiation, progression and resolution of inflammatory diseases such as RA. We have previously shown that neutrophils from RA patients have a gene expression signature indicating activation in vivo by interferons (IFNs), and higher expression of IFN-response genes is associated with a good response to TNFi therapy. The aim of this work was to investigate the functional effects of IFNs on neutrophils in vitro both (i) alone, and (ii) in combination with inflammatory cytokines. Methods: Neutrophils were isolated from peripheral blood of healthy controls and incubated with Type-I IFN (IFNa) or Type-II IFN (IFNg) at a range of concentrations in the absence or presence of GM-CSF and TNFa. Apoptosis was measured at 18h by flow cytometry using annexin V/PI; respiratory burst was measured at hourly intervals up to 5h using luminol-enhanced chemiluminescence after stimulation with fMLP or PMA; changes in protein expression and phosphorylation were measured by Western blotting; changes in gene expression were measured by RNA-Seq (Illumina). Results: Neutrophils stimulated with IFNs in vitro underwent rapid phosphorylation of STAT proteins (5–30 min), activation of IFNresponse genes (1h), and priming of the respiratory burst (3h), but only Type-II IFN delayed apoptosis, measured at 18h (unstimulated 58.6% 0.6, IFNg 41.4% 4.1, P<0.05). Addition of IFNs to neutrophil suspensions containing GM-CSF or TNFa had a profound dose-dependent effect on the function of the inflammatory cytokines. Type-I IFNs abrogated the protective effect of GM-CSF on neutrophil apoptosis at 18h (GM-CSF 25.6% 2.7, GM-CSFþ IFNa 49.5% 1.2, P<0.01), whereas Type-II IFNs enhanced the anti-apoptotic effect of TNFa (TNFa 42.3% 3.3, TNFaþ IFNg 27.4% 1.2, P< 0.05) and sustained the TNFa priming effect on the respiratory burst for up to 4h (P<0.01). Type-I and Type-II IFNs enhanced STAT3 phosphorylation by GM-CSF, and altered the activation kinetics of ERK and AKT by GM-CSF. Type-I IFN enhanced AKT phosphorylation in TNFa stimulated neutrophils. Conclusion: IFNs profoundly alter the functional effects of inflammatory cytokines on neutrophils in vitro. This may have important consequences in vivo during therapy with biologic drugs such as TNFi. The complexity and heterogeneity of inflammatory diseases such as RA, where different cytokines dominate or act synergistically to perpetuate systemic inflammation, may explain why some patients respond better to certain biologic therapies than others. We are currently investigating the consequences of TNFi (Infliximab) and JAKi (Tofacitinib) on neutrophils stimulated in vitro with IFNs, GM-CSF and TNFa. Disclosure statement: The authors have declared no conflicts of interest.