Baseline DAS28 Research Articles

OA13 Comprehensive genetic and functional analyses of Fc gamma receptors explain response to rituximab therapy for autoimmune rheumatic diseases

Abstract Background/Aims Rituximab is widely used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) but clinical response varies. Efficacy is determined by the efficiency of depletion, which may depend on a variety of Fc gamma receptor (FcγR)-dependent mechanisms. Previous research was limited by complexity of the FCGR locus, not integrating copy number variation with functional SNP, and small sample size. Here, we aimed to assess the effect of the full range of FcγRs variants on depletion, clinical response and functional effect on NK-cell-mediated killing in two rheumatic diseases with a view to personalised B-cell depleting therapies. Methods A prospective longitudinal study was conducted in 873 patients (RA = 611; SLE=262) from four cohorts (BSRBR-RA, BILAG-BR, Leeds RA and Leeds SLE Biologics). For RA, the outcome measures were 3C-DAS28CRP and 2C-DAS28CRP at 6 (+/-3) months post-rituximab (adjusted for baseline DAS28). For SLE, major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using a commercial multiplex ligation-dependent probe amplification. Median NK cell FcγRIIIa expression (CD3-CD56+CD16+) and NK-cell degranulation (CD107a) in the presence of rituximab-coated Daudi/Raji B-cell lines were assessed using flow cytometry. Results In RA, for FCGR3A, carriage of V allele (coefficient -0.25 [SE 0.11]; p = 0.02) and increased copies of V allele (-0.20 [0.09]; p = 0.02) were associated with better 2C-DAS28 response. Irrespective of FCGR3A genotype, increased gene copies were associated with a better response. In SLE, 177/262 (67.6%) achieved BILAG response (MCR=34.4%; Partial=33.2%). MCR was associated with increased copies of FCGR3A-158V allele, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). Of patients with B-cells data in the combined cohort, 236/413 (57%) achieved complete depletion post-rituximab. Only homozygosity for V allele and higher copies of FCGR3A V allele were associated with increased odds of depletion. Patients with complete depletion had higher NK cell FcγRIIIa expression at rituximab initiation than those with incomplete depletion (p = 0.04) and this higher expression was associated with improved EULAR response in RA. Moreover, for FCGR3A, degranulation activity was increased in V allele carriers vs FF genotype in the combined cohort; p = 0.02. Conclusion FcγRIIIa is the major low affinity FcγR and increased copies of the FCGR3A-158V allele, encoding the allotype with a higher affinity for IgG1, was associated with clinical and biological responses to rituximab in two autoimmune diseases. This was supported by functional data on NK cell-mediated cytotoxicity. In SLE, increased copies of the FCGR2C-ORF allele was also associated with improved response. Our findings indicate that enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping could stratify patients for optimal treatment protocols. Disclosure M. Md Yusof: None. J. Robinson: None. V. Davies: None. D. Wild: None. M. Morgan: None. J. Taylor: None. Y. El-Sherbiny: None. D. Morris: None. L. Liu: None. A. Rawstron: None. M. Buch: None. D. Plant: None. H. Cordell: None. J. Isaacs: None. I. Bruce: None. P. Emery: Grants/research support; PE has received consultancy fees and funding for research from Roche within the last 3 years. A. Barton: None. T. Vyse: None. J. Barrett: None. E. Vital: Grants/research support; EMV has received consultancy fees and funding for research from Roche within the last 3 years. A. Morgan: None.

OA04 COVID-19 admissions and mortality in patients with early inflammatory arthritis: results from a national cohort

Abstract Background/Aims Patients with inflammatory arthritis were identified as a potentially vulnerable group during the COVID-19 pandemic, with recommendations from the UK government to shield. We set out to describe the risks of COVID-19 according to initial treatment strategy amongst patients recruited to the National Early Inflammatory Arthritis Audit (NEIAA). Methods NEIAA is an observational cohort design. It includes adults in England with a new diagnosis of inflammatory arthritis between May 2018 and March 2021. The outcomes of interest were death due to COVID-19 (COVID-19 stated on a death certificate) and hospitalisation due to COVID-19 (primary admission reason or nosocomial acquisition), identified using NHS Digital linkage. Cox proportional hazards models were used to calculate hazard ratios, with adjustment for patient factors (age, gender, smoking status, comorbidity) and disease factors (seropositivity, disease severity (DAS28), patient-reported disability (HAQ) and functional impact (MSK-HQ)) recorded at baseline. Individuals were considered at risk from February 2020 or date of diagnosis (whichever was later) and censored at a COVID-19 event, May 2021 or death (whichever was sooner). Results 14,127 patients were included. Mean age was 57 (+/-16); 62% were female. Smoking status: 19% current; 29% ex-smokers. Comorbidities: 19% hypertension; 9% diabetes; and 9% lung disease. Overall, 20% had two or more comorbidities. Rheumatoid Factor or CCP antibodies were positive in 56%. At presentation, mean scores were 4.6 (+/-1.5) for DAS28, 1.1 (+/-0.7) for HAQ and 25 (+/-11) for MSK-HQ. Initial DMARD therapy was known for 13,682/14,127 patients; methotrexate was most common (54%), then hydroxychloroquine (23%) and sulfasalazine (11%). There were 143 COVID-19 hospital admissions and 47 deaths, corresponding to incidence rates per 100 person-years for hospitalisation: 0.94 (95% CI: 0.79-1.10) and death: 0.31 (95% CI: 0.23-0.41). Increasing age, male gender, diabetes, hypertension, lung disease and smoking status all predicted COVID-19 events. Higher baseline DAS28 predicted COVID-19 admission (HR 1.24 (95% CI: 1.10-1.39)) and mortality (HR 1.33 (95% CI: 1.09-1.63)). Higher HAQ predicted both COVID-19 admission and death. Seropositivity was not a significant predictor of any COVID-19 event, nor was MSK-HQ. Unadjusted, corticosteroids associated with COVID-19 death (HR 2.29 (95% CI: 1.02-5.13)), and sulfasalazine monotherapy associated with COVID-19 admission (HR 1.93 (95% CI: 1.04-3.56)). In adjusted models, associations for corticosteroids and sulfasalazine were no longer significant. Only age, smoking status, and comorbidities independently predicted COVID-19 events. Conclusion The burden of COVID-19 amongst early arthritis patients was substantial during the pandemic. Patient characteristics and rheumatoid disease severity at diagnosis appear to be the more important predictors of COVID-19 events than initial treatment strategy. An important limitation is that we have not looked at treatment changes over time, and must acknowledge that many patients, especially those recruited in 2019, may have changed therapy prior to the pandemic. Disclosure M.A. Adas: None. M.D. Russell: Grants/research support; has received speaker fees and educational grants from Janssen, Lilly, Menarini, Pfizer and UCB. E. Cook: None. E. Alveyn: None. S. Oyebanjo: None. P. Amlani-Hatcher: None. J. Ledingham: Other; is a BSR trustee. J.B. Galloway: Honoraria; has received honoraria from AbbVie, Celgene, Chugai, Gilead, Janssen, Eli Lilly, Pfizer, Roche and UCB.

Toward Individualized Prediction of Response to Methotrexate in Early Rheumatoid Arthritis: A Pharmacogenomics-Driven Machine Learning Approach.

To test the ability of machine learning (ML) approaches with clinical and genomic biomarkers to predict methotrexate treatment response in patients with early rheumatoid arthritis (RA). Demographic, clinical, and genomic data from 643 patients of European ancestry with early RA (mean age 54 years; 70% female) subdivided into a training (n = 336) and validation cohort (n = 307) were used. The genomic data comprised 160 single-nucleotide polymorphisms (SNPs) previously associated with RA or methotrexate metabolism. Response to methotrexate monotherapy was defined as good or moderate by the European Alliance of Associations for Rheumatology (EULAR) response criteria at the 3-month follow-up. Supervised ML methods were trained with 5 repeats and 10-fold cross-validation using the training cohort. Prediction performance was validated in the independent validation cohort. Supervised ML methods combining age, sex, smoking, rheumatoid factor, baseline Disease Activity Score in 28 joints (DAS28) scores and 160 SNPs predicted EULAR response at 3 months with the area under the receiver operating curve of 0.84 (P = 0.05) in the training cohort and achieved a prediction accuracy of 76% (P = 0.05) in the validation cohort (sensitivity 72%, specificity 77%). Intergenic SNPs rs12446816, rs13385025, rs113798271, and ATIC (rs2372536) had variable importance above 60.0 and along with baseline DAS28 scores were among the top predictors of methotrexate response. Pharmacogenomic biomarkers combined with baseline DAS28 scores can be useful in predicting response to methotrexate in patients with early RA. Applying ML to predict treatment response holds promise for guiding effective RA treatment choices, including timely escalation of RA therapies.

Use of tacrolimus for managing csDMARD-failed rheumatoid arthritis: A real- time experience from a single tertiary care centre

Aim: To evaluate the efficacy of tacrolimus in achieving disease activity score-28-c-reactive protein 3 [DAS28-CRP (3)] remission in patients managed with tacrolimus at the end of 24 week in a tertiary setting. Methodology: The retrospective study included RA patients who fulfilled American College of Rheumatology (ACR) 2010 criteria and managed by tacrolimus as an add-on to the background DMARD or as a substitute to conventional synthetic DMARD. Apart from demographic data, TJC, SJC, ESR and CRP were recorded at each visit. Subjects were grouped as those who achieved remission (DAS28-CRP (3) <2.6) and not under remission (DAS28-CRP (3)>2.6). Descriptive analysis was carried out for different variables in the classified groups, chi-square test for categorical variables and ANOVA and t-test to compare the continuous variables. Results: The study selected 100 patients who fulfilled the criteria for analysis. The corresponding number of subjects who received 4 mg, 3 mg, 2 mg, 1.5 mg and 1 mg of tacrolimus were 3, 23, 57, 2 and 15 respectively. The corresponding number of patients evaluated at 3, 6, 9 and 12 months were 100, 86, 71 and 56. Around 20% of the patients reached a state of remission by the end of 12 months. The DAS28-CRP (3) remission (<2.6) was achieved in 7 (7%) out of 100 at the end of 3 months, which increased to 17 (20%) out of 86 by 6th month. Around 9 out of 57 maintained the remission till the end of 12 months and 11 (20%) out of 57, who were followed till 12th month, had moderate response. Discriminate function analysis showed that the age and duration of disease were strong predictors of achieving remission. Baseline DAS score and duration of illness at the time of introduction of tacrolimus negatively predicted the patients achieving remission.

Ultrasound-detected tenosynovitis as a risk factor for flares in rheumatoid arthritis patients in clinical remission.

Our objective was to investigate the value of ultrasound (US) detected synovitis and tenosynovitis as risk factors for short term flare in rheumatoid arthritis (RA) patients in clinical remission. Consecutive RA patients in clinical remission (DAS28 ERS < 2.6) for at least 3months underwent Power Doppler ultrasound (PDUS) examination of 1st to 6th extensor compartments at the wrist, 2nd to 5th finger flexor, posterior tibial tendon, and peroneal tendons. To assess synovitis, carpal joints, 1st to 5th metacarpophalangeal (MCP) joints, and 2nd to 5th interphalangeal proximal (IPP) joints were bilaterally examined. Synovitis and tenosynovitis were defined according to OMERACT. Patients were followed for 1year. Disease flare was defined as an increase in disease activity generating the need for a change in therapy by the attending rheumatologist. Ninety patients were included. After 1year of follow-up, 26 patients (29%) experienced a flare. At baseline 39%, 23% and 8% had US-detected synovitis, tenosynovitis or both, respectively. In the 1-year period after the baseline US examination, US-detected tenosynovitis (RR: 4.9; 95% CI: 2.2-10.8) was associated with an increased risk of exacerbation. This association was not shown with US-detected synovitis (RR: 1.3; 95% CI: 0.76-2.2). In the multivariate analysis, only subclinical tenosynovitis (OR: 9.8; 95% CI: 2.5-39.1; p = 0.001) and baseline DAS28 (OR: 5.7; 95% CI: 1.1-31.6; p = 0.047) were significantly associated with an increased risk of having a flare. In our study, subclinical tenosynovitis was associated with disease flare in patients with RA in clinical remission. • Synovitis and tenosynovitis are risk factors for short term flare in RA patients in clinical remission. • Subclinical tenosynovitis, but not synovitis, was associated with disease flare in patients with unstable remission. • Ultrasound-detected tenosynovitis could be useful to predict relapses in RA patients in clinical remission.

Differences in trajectory of disease activity according to biologic and targeted synthetic disease-modifying anti-rheumatic drug treatment in patients with rheumatoid arthritis

BackgroundThe purpose of this study was to stratify patients with rheumatoid arthritis (RA) according to the trend of disease activity by trajectory-based clustering and to identify contributing factors for treatment response to biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) according to trajectory groups.MethodsWe analyzed the data from a nationwide RA cohort from the Korean College of Rheumatology Biologics and Targeted Therapy registry. Patients treated with second-line biologic and targeted synthetic DMARDs were included. Trajectory modeling for clustering was used to group the disease activity trend. The contributing factors using the machine learning model of SHAP (SHapley Additive exPlanations) values for each trajectory were investigated.ResultsThe trends in the disease activity of 688 RA patients were clustered into 4 groups: rapid decrease and stable disease activity (group 1, n = 319), rapid decrease followed by an increase (group 2, n = 36), slow and continued decrease (group 3, n = 290), and no decrease in disease activity (group 4, n = 43). SHAP plots indicated that the most important features of group 2 compared to group 1 were the baseline erythrocyte sedimentation rate (ESR), prednisolone dose, and disease activity score with 28-joint assessment (DAS28) (SHAP value 0.308, 0.157, and 0.103, respectively). The most important features of group 3 compared to group 1 were the baseline ESR, DAS28, and estimated glomerular filtration rate (eGFR) (SHAP value 0.175, 0.164, 0.042, respectively). The most important features of group 4 compared to group 1 were the baseline DAS28, ESR, and blood urea nitrogen (BUN) (SHAP value 0.387, 0.153, 0.144, respectively).ConclusionsThe trajectory-based approach was useful for clustering the treatment response of biologic and targeted synthetic DMARDs in patients with RA. In addition, baseline DAS28, ESR, prednisolone dose, eGFR, and BUN were important contributing factors for 4-year trajectories.

Predictors of response to TNF inhibitors in rheumatoid arthritis: an individual patient data pooled analysis of randomised controlled trials

ObjectiveTo identify patient characteristics associated with responsiveness to tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA).Materials and methodsIndividual patient data from 29 randomised controlled trials (RCTs) evaluating the efficacy...

The susceptibility of attaining and maintaining DMARD-free remission in different (rheumatoid) arthritis phenotypes.

To compare (sustained) DMARD-free remission rates((S)DFR), defined as respectively ≥6 months and >1 year, after 2 and 5 years between three clinical arthritis phenotypes; undifferentiated arthritis(UA), autoantibody-negative(RA-) and positive rheumatoid arthritis(RA+). All UA(n = 130), RA-(n = 176) and RA + (n = 331) patients from the tREACH trial, a stratified single-blinded trial with a treat-to-target approach, were used. (S)DFR comparisons between phenotypes after 2 and 5 years were performed with Logistic regression. Medication use and early and late flares(DAS ≥ 2.4), respectively defined as < 12 and >12 months after reaching DFR, were also compared. Cox proportional hazard models were used to evaluate potential predictors for (S)DFR. Within 2 and 5 years less DFR was seen in RA + (17.2-25.7%), followed by RA-(28.4-42.1%) and UA patients(43.1-58.5%). This also applied for SDFR within 2 and 5 years (respectively 7.6% and 21.4%; 20.5% and 38.1%; and 35.4% and 55.4%). A flare during tapering was seen in 22.7% of patients. Of the patients in DFR 7.5% had an early flare and 3.4% a late flare. Also more treatment intensifications occurred in RA+ compared with RA- and UA. We found that higher baseline DAS, ACPA positivity, BMI and smoking were negatively associated with (S)DFR, while clinical phenotype(reference RA+), short symptom duration(<6 months) and remission within 6 months were positively associated. (Long-term) clinical outcomes differ between undifferentiated arthritis, autoantibody-negative and positive rheumatoid arthritis(RA). These data reconfirm that RA can be subdivided into aforementioned clinical phenotypes and that treatment might be stratified upon these phenotypes, although validation is needed. ISRCTN, https://www.isrctn.com/, ISRCTN26791028.

Patterns of T and B cell responses to Mycobacterium tuberculosis membrane-associated antigens and their relationship with disease activity in rheumatoid arthritis patients with latent tuberculosis infection.

This study was aimed at exploring whether latent tuberculosis infection (LTBI) contributes to the pathogenesis of immune-mediated inflammatory diseases in a TB endemic setting. We screened 198 rheumatoid arthritis (RA) patients with tuberculin skin test (TST) and studied 61 (median DAS28-ESR = 6.3) who were positive. Whole blood T cell proliferative responses to Mycobacterium tuberculosis (Mtb) membrane (MtM) antigens, including the latency-induced protein alpha crystallin (Acr), were determined by flow cytometry using Ki67 expression as the marker for nuclear proliferation. Serum antibody levels were determined by ELISA. Follow-up investigations (at 3-6, 9-12 and 15-18 months after baseline) were performed in 41 patients who were classified empirically as 'high' (HR-T/HR-B) or 'low' (LR-T/LR-B) responders based on their dynamic T cell or antibody responses. Significant correlations were seen between baseline T cell responses to MtM and Acr, and between IgG, IgA and IgM antibody responses to MtM. However, no correlation was seen between T and B cell responses. At all time points during the follow-up, T cell responses to both antigens (except for MtM at one point) were significantly higher in HR-T (n = 25) than LR-T (n = 16) patients. Levels of IgA and IgM (but not IgG) antibodies to MtM were also significantly higher in HR-B (n = 13) than LR-B (n = 28) at all time points. Importantly, HR-T patients exhibited significantly higher baseline and follow-up DAS28 scores than LR-T. Ten (of 61) patients had a history of TB and developed RA 6 years (median) after contracting TB. Three new TB cases (1 from TST-positive and 2 from TST-negative groups) emerged during the follow-up. Our results suggest that persistently elevated T cell responses to Mtb antigens may contribute to disease activity in RA.

Clinical, Radiologic, and Functional Outcomes Following Methotrexate Withdrawal in Etanercept-Treated Patients with Active Early Rheumatoid Arthritis: A Subanalysis of COMET Year 2 by Week 52 DAS28 Status

Introduction: This post-hoc analysis explored Methotrexate (MTX) withdrawal on clinical, radiographic, and functional outcomes in patients with early rheumatoid arthritis who previously received 52 weeks of Etanercept (ETN) + MTX treatment in the COMET study. Methods: Response at week 104 was analyzed based on the attainment of remission (28-joint disease activity score [DAS28] &lt;2.6; Boolean); low disease activity (LDA; 2.6 ≤DAS28 ≤3.2); normal Health Assessment Questionnaire-Disability Index (HAQ-DI) score (≤0.5); or radiographic non-progression (change in modified Total Sharp Score ≤0.5). Results: Of 208 patients with baseline DAS28 scores at week 52, 105 received ETN + MTX and 103 received ETN over weeks 52-104 (Period 2). At week 104, rates of LDA (70% vs 67%), remission (59% vs 52%), and normal HAQ-DI (63% vs 61%) were similar in both arms; week 52 responders also had a higher response rate at week 104 irrespective of treatment during Period 2. Overall rates of radiographic non-progression were higher for ETN + MTX (90%) vs ETN (74%) at week 104; week 52 non-responders in the Period 2 ETN + MTX arm had a 21-27% higher rate vs ETN, while the treatment difference was 11-12% for week 52 responders. Conclusion: The data suggest that for responders to ETN + MTX at week 52, MTX may be safely withdrawn. For non-responders where de-escalation would not be considered, the continuation of the combination is advisable. Radiological outcome was numerically worse, but of uncertain clinical significance.

Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (β = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (β = 0.56. P = 0.01) and did not carry the shared epitope (β = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.

POS0446 FILGOTINIB-TREATED RHEUMATOID ARTHRITIS PATIENTS WITH HIGH BASELINE NEUTROPHIL-TO-LYMPHOCYTE RATIO SHOW BETTER CLINICAL RESPONSE RATES AND PATIENT-REPORTED OUTCOMES

Background:Rheumatoid arthritis (RA) is a systemic inflammatory disease which includes increased innate and myeloid immune cell activation. Filgotinib (FIL), an oral JAK1 inhibitor, has shown safety and efficacy in three phase 3 studies (FINCH1-3) in adults with moderately-to-severely active RA. The baseline (BL) neutrophil-to-lymphocyte ratio (NLR) in RA has been associated with a positive response to anti-tumor necrosis factor (TNF) therapy1 and a negative response to DMARD triple therapy2. We previously reported a BL signature of clinical response in the FINCH2 (bDMARD-IR) population which included a neutrophil component3.Objectives:We conducted a post-hoc analysis to explore whether the BL NLR was associated with response to treatment in the FINCH studies.Methods:Clinical data of 3273 RA patients (pts) enrolled in the FINCH clinical trials (FINCH3, methotrexate (MTX)-naïve: NCT02886728; FINCH1, MTX-Inadequate Responder (IR): NCT02889796; FINCH2, bDMARD-IR: NCT02873936) were retrospectively analyzed for a relationship between the BL NLR and composite clinical endpoints (ACR-N, DAS28CRP, or CDAI) or PROs (Pain VAS, FACIT Fatigue, HAQ-DI) through week 24. Pts were classified as High or Low BL NLR using a cutpoint (2.7) identified as an independent predictor of treatment failure in a published RA study2. Adjusted clinical outcomes were estimated based on mixed effects linear regression models including geographic region and demographics covariates.Results:57% of pts enrolled in the FINCH trials were classified as BL NLR-High (Table 1) and FINCH3 NLR-High pts showed higher BL DAS28(CRP). FINCH1 and FINCH3 FIL+MTX-arm NLR-High pts demonstrated significantly better DAS28(CRP) response compared to NLR-Low pts (Figure 1). DAS28(CRP) differences between NLR-High and NLR-Low were detectable as early as Week 2 for FIL200mg + MTX and were sustained through Week 24. FINCH1 and FINCH3 FIL200mg + MTX NLR-High pts also demonstrated sustained clinical and PRO improvements over NLR-Low, including CDAI, ACR-N, Pain VAS, FACIT Fatigue, and HAQ-DI. The strength of these associations was dose-dependent; pts that received FIL100mg + MTX demonstrated weaker but directionally consistent trends in both populations. No significant association between NLR subgroup and clinical efficacy was observed in FINCH2 FIL+MTX-arm pts, FIL-monotherapy (FINCH3) pts, or adalimumab+MTX (FINCH1) pts.Conclusion:In FINCH1 (MTX-IR) and FINCH3 (MTX-naïve), FIL200mg + MTX -arm NLR-High pts demonstrate better sustained clinical response and PRO scores compared to NLR-Low pts. These data are the first to report an association between the BL NLR and therapeutic response in large randomized RA clinical trials. Future studies on pathobiologies reflected by the NLR biomarker may clarify its potential to guide RA disease management.

P128 A subgroup analysis of the efficacy of filgotinib for patients with moderately active RA following an inadequate response to methotrexate

P128 A subgroup analysis of the efficacy of filgotinib for patients with moderately active RA following an inadequate response to methotrexate

P127 Treating rheumatoid arthritis patients with moderate disease activity: an analysis of the upadacitinib SELECT Phase III randomised studies

Abstract Background/Aims Some health systems restrict use of advanced therapies for rheumatoid arthritis (RA) to patients with high disease activity (DAS28&amp;gt;5.1). Upadacitinib (UPA), a selective JAK inhibitor, has demonstrated significant improvement in patients with moderate-to-severe RA. We aimed to explore the efficacy and safety of UPA in RA patients with moderate disease activity. Methods This was a post-hoc, subgroup analysis from three phase 3 registrational trials evaluating once daily UPA 15mg versus placebo (PBO) in patients with moderate (DAS28(CRP)&amp;gt;3.2, ≤5.1) and high (DAS28(CRP)&amp;gt;5.1) disease activity. Patients had prior inadequate response to csDMARDs (SELECT-COMPARE and SELECT-NEXT integrated analysis) or bDMARDs (SELECT-BEYOND). Clinical and functional outcomes were analysed at the studies primary endpoint (Week12). Missing data were handled using non-responder imputation for binary endpoints and mixed-effect model repeat measurement for continuous variables. Results Across all three studies mean baseline DAS28(CRP) was ∼4.5 and ∼6.2 in moderate and severe patients, respectively. At Week 12 significantly greater proportions of csDMARD-inadequate responder (IR) and bDMARD-IR patients receiving UPA 15 mg achieved ACR20, low disease activity (DAS28(CRP)≤3.2) and remission (DAS28(CRP)&amp;lt;2.6) compared to PBO in both disease severity subgroups (Table 1). Improvement in physical function assessed by Health Assessment Questionnaire for Rheumatoid Arthritis (HAQ-DI) and pain visual analogue scale (VAS) were significantly greater with UPA 15mg vs PBO for severe csDMARDs-IR and bDMARD-IR populations and numerically greater in moderate bDMARD-IR patients. Across all IR populations higher proportions of patients with moderate disease treated with UPA 15mg achieved DAS28(CRP)≤3.2 and DAS28(CRP)&amp;lt;2.6 compared to those with severe disease. The safety profile of UPA in moderate and severe patients was comparable and consistent with previously published data. Conclusion UPA 15mg was effective in improving clinical, functional, and patient reported outcomes in patients with either moderate or severe RA. P127 Table 1:Baseline characteristics and efficacy endpoints at week 12 from SELECT-NEXT, -COMPARE and -BEYONDTimepointKey EndpointscsDMARD IR (SELECT COMPARE and SELECT NEXT integrated)ModerateSevereUPA 15mg (n = 209)PBO (n = 195)UPA 15mg (n = 649)PBO (n = 671)BaselineAge (yrs; Mean ± SD)53.7 ± 12.654.5 ± 12.454.9 ± 11.654.1 ± 12.3Duration since diagnosis (yrs; Mean ± SD)7.5 ± 7.47.3 ± 6.78.0 ± 7.98.2 ± 8.2DAS28(CRP) (Mean ± SD)4.6 ± 0.44.6 ± 0.46.2 ± 0.76.1 ± 0.7HAQ-DI (Mean ± SD)1.2 ± 0.61.2 ± 0.61.7 ± 0.61.7 ± 0.6Pain VAS (0-100) (Mean ± SD)52.5 ± 21.448.4 ± 21.669.8 ± 18.268.9 ± 17.9Week 12ACR20 (% response, 95% CI)63.6 (57.1, 70.2)***33.8 (27.2, 40.5)71.2 (67.7, 74.7)***37.0 (33.3, 40.6)DAS28 (CRP) ≤3.2, (% response, 95% CI)61.7 (55.1, 68.3)***28.7 (22.4, 35.1)40.7 (36.9, 44.5)***10.3 (8.0, 12.6)DAS28 (CRP) ≤2.6, (% response, 95% CI)41.4 (34.5, 47.8)***14.9 (9.9, 19.9)25.1 (21.8, 28.5)***4.6 (3.0, 6.2)ΔHAQ-DI (mean, 95% CI)-0.43 (-0.51, -0.35)***-0.23 (-0.32, -0.15)-0.67 (-0.72, -0.61)***-0.31 (-0.36, -0.25)Δ Pain VAS (0-100) (% response, 95% CI)-25.0 (-28.6, -21.4)***-7.0, (-10.6, -3.2)-32.8 (-35.1, -30.5)***-16.1 (-18.4, -13.8)TimepointKey EndpointsbDMARD IR (SELECT-BEYOND)ModerateSevereUPA 15mg (n = 39)PBO (n = 38)UPA 15mg (n = 124)PBO (n = 128)BaselineAge (yrs; Mean ± SD)56.1 ± 11.157.7 ± 13.456.4 ± 11.557.6 ± 10.9Duration since diagnosis (yrs; Mean ± SD)13.6 ± 10.014.7 ± 9.411.9 ± 9.214.6 ± 9.3DAS28(CRP) (Mean ± SD)4.7 ± 0.34.4 ± 0.56.2 ± 0.86.2 ± 0.7HAQ-DI (Mean ± SD)1.4 ± 0.71.1 ± 0.51.8 ± 0.61.7 ± 0.6Pain VAS (0-100) (Mean ± SD)58.1 ± 22.449.8 ± 22.271.3 ±74.5 ±Week 12ACR20 (% response, 95% CI)61.5 (46.3, 76.8)*36.8 (21.5, 52.2)66.1 (57.8, 74.5)***26.6 (18.9, 34.2)DAS28 (CRP) ≤3.2, (% response, 95% CI)64.1 (49.0, 79.2)**28.9 (14.5, 43.4)36.3 (27.8, 44.8)***9.4 (4.3, 14.4)DAS28 (CRP) ≤2.6, (% response, 95% CI)43.6 (28.0, 59.2)*21.1 (8.1, 34.0)24.2 (16.7, 31.7)***6.3 (2.1, 10.4)ΔHAQ-DI (mean, 95% CI)-0.24 (-0.41, -0.07)-0.12 (-0.30, 0.05)-0.47 (-0.56, -0.37)***-0.18 (-0.28, -0.08)Δ Pain VAS (0-100) (% response, 95% CI)-16.8 (-25.4, -8.1)-5.4 (-14.3, 3.4)-28.7 (-33.5, -24.0)***-12.2 (-17.0, -7.3)*p ≤ 0.05;**p ≤ 0.01;***p ≤ 0.001 for comparison of UPA versus PBO. Disclosure P.G. Conaghan: Other; P.C. has been a consultant or speaker for AbbVie, BMS, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer. K. Pavelka: Other; K.P. has received honoraria for consultations and lectures from AbbVie, Roche, Pfizer, MSD, Sanofi, UCB and Amgen. S. Hsieh: None. T. Bonnington: Other; T.B. is an employee at AbbVie Limited. T.C. Kent: Other; T.C. is an employee at AbbVie Limited. C.J. Edwards: Other; C.E. has received honoraria, advisory boards, speakers bureau, research support from AbbVie, BMS, Biogen, Fresenius, Gilead Janssen, Lilly, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB.

Interactions between rheumatoid arthritis antibodies are associated with the response to anti-tumor necrosis factor therapy

BackgroundBlocking of the Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for 50–60% of rheumatoid arthritis (RA) patients. However, there are yet no biomarkers to stratify patients for anti-TNF therapy. Rheumatoid factor (RF) and anti-cyclic-citrullinated antibodies (anti-CCP) have been evaluated as biomarkers of response but the results have shown limited consistency. Anti-carbamylated protein (anti-CarP) and anti-peptidylarginine deiminase type 4 (anti-PAD4) antibodies have been much less studied. Despite being linked to common immune processes, the interaction between these markers has not been evaluated yet. Our aim was to analyze the interaction between these four antibodies in relation to the response to anti-TNF therapy.MethodsFor this objective, a prospective cohort of n = 80 RA patients starting anti-TNF therapy was recruited. Serum determinations at baseline were performed for RF, anti-CCP, anti-CarP and anti-PAD4 antibodies using enzyme-linked immunosorbent assays (ELISA). The clinical response to anti-TNF therapy was determined at week 12 using the change in DAS28 score. Association was performed using multivariate linear regression adjusting for baseline DAS28, sex and age.ResultsThe interaction between pairs of antibodies was tested by the addition of an interaction term. We found two highly significant antibody interactions associated with treatment response: anti-CarP with anti-PAD4 (p = 0.0062), and anti-CCP with RF (p = 0.00068). The latter antibody interaction was replicated in an independent retrospective cohort of RA patients (n = 199, p = 0.04).ConclusionsThe results of this study suggest that antibody interaction effects are important factors in the response to anti-TNF therapy in RA.

Cost-effectiveness of Triple Therapy vs. Biologic Treatment Sequence as First-line Therapy for Rheumatoid Arthritis Patients after Methotrexate Failure.

IntroductionA clinical trial (RACAT) reported the noninferiority of triple therapy compared to biologic agents (etanercept + methotrexate), and previous studies confirmed that biologic disease-modifying antirheumatic drugs (bDMARDs) are more expensive but less beneficial than triple therapy for patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) fails. However, from the perspective of the Chinese healthcare system, the cost-effectiveness of triple therapy versus bDMARD treatment sequences as a first-line therapy for patients with RA is still unclear.MethodsAn individual patient simulation model was used to extrapolate the lifetime cost and health outcomes by tracing patients from initial treatment through switches to further treatment lines in a sequence. Therapeutic efficacy and physical function were evaluated using the American College of Rheumatology (ACR) response, 28-Joint Disease Activity Score (DAS28), and Health Assessment Questionnaire score. All input parameters in the model were derived from published studies, national databases, local hospitals, and experts’ opinions. Both direct costs and indirect costs were taken into consideration. Probabilistic and one-way sensitivity analyses were performed to test the uncertainty of the model, as were multiple scenario analyses.ResultsThe lifetime analysis demonstrated that triple therapy was associated with lower costs and quality-adjusted life years (QALYs) than bDMARD sequences. These resulted in incremental cost-effectiveness ratios (ICERs) ranging from $87,090/QALY to $104,032/QALY, higher than the willingness-to-pay (WTP) threshold in China ($30,950/QALY). The baseline DAS28 impacted the model outcomes the most. Scenario analyses indicated that adding triple therapy to bDMARD sequences as a first-, second-, third-, or fourth-line therapy is very cost-effective, at a WTP of $10,316/QALY.ConclusionsFrom a Chinese payer perspective, triple therapy as first-line treatment in treatment sequence could be regarded as cost-effectiveness option for patients who failed MTX, compared to bDMARDs as first-line treatment, and instead of prescribing triple therapy as a substitute for bDMARDs as a first-line treatment, adding triple therapy to the bDMARD treatment sequence is likely to be very cost-effective for patients with active RA compared to bDMARD sequences.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00300-4.

Complex Machine-Learning Algorithms and Multivariable Logistic Regression on Par in the Prediction of Insufficient Clinical Response to Methotrexate in Rheumatoid Arthritis.

The goals of this study were to examine whether machine-learning algorithms outperform multivariable logistic regression in the prediction of insufficient response to methotrexate (MTX); secondly, to examine which features are essential for correct prediction; and finally, to investigate whether the best performing model specifically identifies insufficient responders to MTX (combination) therapy. The prediction of insufficient response (3-month Disease Activity Score 28-Erythrocyte-sedimentation rate (DAS28-ESR) > 3.2) was assessed using logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting (XGBoost). The baseline features of 355 rheumatoid arthritis (RA) patients from the “treatment in the Rotterdam Early Arthritis CoHort” (tREACH) and the U-Act-Early trial were combined for analyses. The model performances were compared using area under the curve (AUC) of receiver operating characteristic (ROC) curves, 95% confidence intervals (95% CI), and sensitivity and specificity. Finally, the best performing model following feature selection was tested on 101 RA patients starting tocilizumab (TCZ)-monotherapy. Logistic regression (AUC = 0.77 95% CI: 0.68–0.86) performed as well as LASSO (AUC = 0.76, 95% CI: 0.67–0.85), random forest (AUC = 0.71, 95% CI: 0.61 = 0.81), and XGBoost (AUC = 0.70, 95% CI: 0.61–0.81), yet logistic regression reached the highest sensitivity (81%). The most important features were baseline DAS28 (components). For all algorithms, models with six features performed similarly to those with 16. When applied to the TCZ-monotherapy group, logistic regression’s sensitivity significantly dropped from 83% to 69% (p = 0.03). In the current dataset, logistic regression performed equally well compared to machine-learning algorithms in the prediction of insufficient response to MTX. Models could be reduced to six features, which are more conducive for clinical implementation. Interestingly, the prediction model was specific to MTX (combination) therapy response.

Health Assessment Questionnaire at One Year Predicts All-Cause Mortality in Patients With Early Rheumatoid Arthritis.

Higher self-reported disability (high Health Assessment Questionnaire [HAQ] score) has been associated with hospitalizations and mortality in established rheumatoid arthritis (RA), but associations in early RA are unknown. Patients with early RA (symptom duration <1 year) enrolled in the Canadian Early Arthritis Cohort who initiated disease-modifying antirheumatic drugs and had completed HAQ data at baseline and 1 year were included in the study. Discrete-time proportional hazards models were used to estimate crude and multi-adjusted associations of baseline HAQ and HAQ at 1 year with all-cause mortality in each year of follow-up. A total of 1,724 patients with early RA were included. The mean age was 55 years, and 72% were women. Over 10 years, 62 deaths (3.6%) were recorded. Deceased patients had higher HAQ scores at baseline (mean ± SD 1.2 ± 0.7) and at 1 year (0.9 ± 0.7) than living patients (1.0 ± 0.7 and 0.5 ± 0.6, respectively; P < 0.001). Disease Activity Score in 28 joints (DAS28) was higher in deceased versus living patients at baseline (mean ± SD 5.4 ± 1.3 versus 4.9 ± 1.4) and at 1 year (mean ± SD 3.6 ± 1.4 versus 2.8 ± 1.4) (P < 0.001). Older age, male sex, lower education level, smoking, more comorbidities, higher baseline DAS28, and glucocorticoid use were associated with mortality. Contrary to HAQ score at baseline, the association between all-cause mortality and HAQ score at 1 year remained significant even after adjustment for confounders. For baseline HAQ score, the unadjusted hazard ratio (HR) was 1.46 (95% confidence interval [95% CI] 1.02-2.09), and the adjusted HR was 1.25 (95% CI 0.81-1.94). For HAQ score at 1 year, the unadjusted HR was 2.58 (95% CI 1.78-3.72), and the adjusted HR was 1.75 (95% CI 1.10-2.77). Our findings indicate that higher HAQ score and DAS28 at 1 year are significantly associated with all-cause mortality in a large early RA cohort.

The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis.

ObjectivesCardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA.MethodsMyography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT).Resultssgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol.ConclusionsIL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population.

Improvements in Fatigue Lag Behind Disease Remission in Early Rheumatoid Arthritis: Results From the Canadian Early Arthritis Cohort.

To examine the relationship between disease activity and fatigue over time in early rheumatoid arthritis (RA). Data were from patients with early RA (duration of symptoms ≤12 months) enrolled in the Canadian Early Arthritis Cohort (CATCH). Patients rated their fatigue over the past week using an 11-point numerical rating scale (NRS) for up to 5 years of follow-up. Fatigue severity was classified as low (≤2), moderate (>2 but <5), or high (≥5). Differences in fatigue ratings in patients who achieved a low disease state (Disease Activity Score in 28 joints [DAS28] <3.2) and those who did not within 3-months of cohort entry were compared. Of 1,864 patients included, 88% met RA criteria, and 72% were women. The mean ± SD baseline DAS28 was 4.9 ± 1.5. Nineteen percent of the patients reported moderate baseline fatigue, and 59% reported severe baseline fatigue. Fatigue was correlated with pain and patient global ratings (r = 0.56-0.67, P < 0.001), and was weakly correlated with DAS28, tender joint count, swollen joint count, physician global assessment of disease activity, erythrocyte sedimentation rate, and C-reactive protein level. Patients who reported low fatigue by 3 months had significantly lower fatigue throughout follow-up compared to those who had moderate or high fatigue at 3 months (P < 0.001). Patients who achieved a DAS28 <3.2 within 3 months had significantly lower fatigue ratings (mean ± SD 2.7 ± 2.6) than those with a DAS28 >3.2 (4.6 ± 3.0) (P < 0.001), with improvements in fatigue that persisted through 5 years of follow-up. Maximal improvements in fatigue lagged behind remission by 6 months. Fatigue is common in early RA, and improvements may occur after remission. Early treatment response within 3-months was associated with short-term and long-term benefits in fatigue over time.