Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study

This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan–Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.

Effectiveness and drug retention of biologic disease modifying antirheumatic drugs in Korean patients with late onset ankylosing spondylitis

The clinical data on the biologic disease-modifying antirheumatic drug (bDMARD) use in late-onset ankylosing spondylitis (LOAS) is limited. Thus, this study aimed to evaluate the drug efficacy and retention rate of bDMARDs in LOAS and compare it to young-onset ankylosing spondylitis (YOAS). Data of patients with AS receiving bDMARDs were extracted from the Korean College of Rheumatology Biologics and Targeted Therapy registry. Patients whose age of onset was > 50 years and ≤ 50 years were classified as having LOAS and YOAS, respectively. Their baseline characteristics and disease-associated parameters were evaluated. Drug efficacy [Ankylosing Spondylitis Disease Activity Score (ASDAS)-clinically important improvement (CII), ASDAS-major improvement (MI), Assessment of SpondyloArthritis International Society (ASAS) 20, and ASAS 40] at 1-year follow-up and drug retention rates were assessed. A total of 1708 patients (comprising 1472 patients with YOAS and 236 patients with LOAS) were included in this analysis. The LOAS group had a lower prevalence among males, lower HLA-B27 positivity and a higher prevalence of peripheral arthritis. Patients with LOAS were more likely to have higher disease-associated parameters (inflammatory reactants, patient global assessment, ASDAS-erythrocyte sedimentation rate, and ASDAS-C-reactive protein). LOAS was negatively associated with achieving ASDAS-CII, ASAS 20, and ASAS 40. The drug retention rate was lower in LOAS; however, the propensity score-matched and covariate-adjusted hazard ratios for bDMARD discontinuation were comparable to YOAS. There were no differences in the drug retention rates based on the type of bDMARD used in LOAS. Inferior clinical efficacy and shorter drug retention time were found in patients with LOAS receiving bDMARDs using real-world nationwide data. There were no differences among each bDMARD type.

Factors Affecting Drug Retention of Janus kinase Inhibitors in Patients with Rheumatoid Arthritis: The ANSWER Cohort Study

Background: This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) baricitinib (BAR) and tofacitinib (TOF) in patients with RA.Methods: Patients were included as follows: females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185) and concomitant glucocorticoid (prednisolone [PSL] equivalent) 5.3 mg/day (46.7%) or methotrexate (MTX) 8.9 mg/week (60.7%); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories: lack of effectiveness, toxic adverse events, non-toxic reasons and remission. The drug retention rate was estimated at 24 months using the Kaplan–Meier method and adjusted for potential confounders using multivariate Cox proportional hazards modelling.Results: Adjusted discontinuation rates for the corresponding reasons were as follows: lack of effectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior use of anti-interleukin-6 receptor antibody (aIL-6R) was significantly associated with discontinuation due to lack of effectiveness (P = 0.021). Ageing (P = 0.015), usage of PSL ≥5 mg/day (P = 0.017) and female sex (P = 0.041) were significantly associated with discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, different JAKi and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.Conclusions: Prior use of aIL-6R was associated with discontinuation due to lack of effectiveness, while ageing (≥75 years), PSL usage ≥5 mg/day, and female sex were associated with discontinuation due to toxic adverse events.

Comparison of Retention Rates Between Tumor Necrosis Factor-α Inhibitors in Patients With Ankylosing Spondylitis: Data From the Korean College of Rheumatology Biologics Registry

This study aimed to investigate drug retention rates for various TNF inhibitors (TNFis) commonly prescribed to Korean patients with ankylosing spondylitis (AS) in the Korean College of Rheumatology Biologics registry (KOBIO; December 2012–June 2016). Discontinuation was defined as switching or stopping the biologic agent. Kaplan–Meier curves and Cox's proportional hazard models were used for further analysis. The reasons for discontinuation of TNFis were also assessed. Univariate and multivariate analyses were used to identify possible predictors of discontinuation. Data from 1,005 patients with AS were analyzed with a median follow-up period of 14 months. Seventy-six percent of patients were first-line biologic users. Discontinuation of TNFis occurred in 24.2% (switching in 9.6%) of patients during follow-up. An estimate of the drug failure showed that the adjusted hazard ratio (HR) for golimumab compared to etanercept was 0.441 (95% confidence interval: 0.277–0.703, p < 0.001). Reasons for discontinuation included lack of efficacy (32.6%), adverse events (23.6%), clinical improvement (11.2%), and others (32.6%). Predictors of discontinuation using a multivariate analysis were a shorter disease duration (HR: 0.973, p = 0.044) and being negative for HLA-B27 (HR: 1.623, p = 0.0093). In conclusion, few Korean patients with AS switched to other TNFis during their treatment. The drug retention rate for golimumab was higher than for other agents.

Multicenter Study of Secukinumab Survival and Safety in Spondyloarthritis and Psoriatic Arthritis: SEcukinumab in Cantabria and ASTURias Study

Objectives: We aimed to evaluate the drug retention rate and safety of secukinumab (SEC) in patients with axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA) in a real clinical setting.Methods: This multicenter retrospective observational study included all AxSpA and PsA patients who received at least one dose of SEC. Adverse events (AE) and the drug retention rate were the main study outcomes. Drug survival was analyzed by Kaplan-Meier curves while predictive factors of discontinuation were evaluated using a Cox regression analysis. The weight of these associations was estimated by hazard ratio (HR) values.Results: We included 154 patients (59 PsA and 95 AxSpA). Mean disease duration was 6.5 years (IQR 2-8). Sixty-one percent of patients were treated with two or more biologics prior to SEC. The 1 and 2-year retention rates for SEC were 66 and 43%, respectively. The main causes of discontinuation were inefficacy (59%) and AE (36%). The factors associated with lower risk of discontinuation were male gender (HR 0.54, 95% CI 0.38-0.78 p = 0.001), obesity (HR 0.53, 95% CI 0.30-0.93 p = 0.027), hypertension (HR 0.55, 95% CI 0.30-0.93 p = 0.008), and diabetes (HR 0.42 95% CI 0.18-0.99 p = 0.047) while number of previous biologics and depression were predictors of discontinuation (HR 1.18, 95% CI 1.04-1.34 p = 0.011 and HR 2.53, 95% CI 1.61-3.96 p < 0.001).Conclusions: SEC showed a good retention rate in a population previously exposed to several biological therapies. As a novelty, cardiometabolic comorbidities were associated with better drug survival.

AB0466 RETENTION RATE AND EFFECTIVENESS OF SECUKINUMAB VERSUS TNF INHIBITOR SWITCHING IN ANKYLOSING SPONDYLITIS PATIENTS WITH A HISTORY OF TNF INHIBITOR TREATMENT: DATA FROM A KOREAN NATIONWIDE REGISTRY

Background:The choice of second-line biologics for ankylosing spondylitis (AS) patients previously treated with a tumour necrosis factor inhibitor (TNFi) remains unclearObjectives:Here, we compared drug retention and clinical efficacy between AS patients who switched biologics to secukinumab and those who switched to a different TNFi.Methods:AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were included. Patients with previous TNFi exposure were divided into the secukinumab group and the TNFi switching group. Drug retention and clinical efficacy (BASDAI50, ASAS20, ASAS40, ASDAS <2.1, ASDAS clinically important improvement, and ASDAS major improvement) were assessed at the 1 year follow-up. Propensity score (PS)-matched and covariate-adjusted logistic regression analyses were performed.Results:246 had available 1 year follow-up data. Secukinumab as third- or later-line biologics was more frequent than alternative TNFi (54% vs. 14%). PS-matched and multiple covariate-adjusted analyses showed that the odds ratio (OR) for drug discontinuation was comparable between the secukinumab and TNFi switching groups (OR=1.136; 95% CI, 0.843–1.531 and OR=1.000; 95% CI, 0.433–2.308, respectively). The proportion of patients who achieved BASDAI50 was also comparable between the two groups (OR=0.833; 95% CI, 0.481–1.441 in PS-matched analysis). Other clinical efficacy parameters were also comparable. In the subgroup analysis of AS patients with previous TNFi discontinuation due to ineffectiveness, all clinical efficacy parameters were comparable between the two groups.Conclusion:In AS patients with previous exposure to a TNFi, switching biologics to secukinumab and switching to an alternative TNFi resulted in comparable drug retention and clinical efficacy.References:[1]Micheroli R, Tellenbach C, Scherer A, et al. Effectiveness of secukinumab versus an alternative TNF inhibitor in patients with axial spondyloarthritis previously exposed to TNF inhibitors in the Swiss Clinical Quality Management cohort. Ann Rheum Dis 2020;79:1203-9.Disclosure of Interests:None declared.

AB0252 EFFICACY OF A SECOND JANUS KINASE INHIBITOR THAT WAS SWITCHED FOR DIFFICULT-TO-TREAT RA IN CLINICAL PRACTICE

Background:In clinical practice, when refractory rheumatoid arthritis (RA) is present, of which the definition implies previous use of at least two biologic disease-modifying antirheumatic drugs (bDMARDs) (generally tumour necrosis factor inhibitors (TNFis)), the next treatment choice often made is a bDMARD of another class (non-TNFis) [1]. However, patients who are inadequately responding to bDMARDs need new treatment options because subsequent bDMARDs treatment reduces their response [2]. Janus Kinase inhibitors (JAKis) are the first targeted synthetic DMARDs (tsDMARD) licensed for the treatment of RA with comparable efficacy to bDMARDs. Unlike the single cytokine targeting approach of bDMARDs, JAKis are specifically designed to inhibit intracellular signalling molecules common to the receptors of multiple inflammatory cytokines implicated in RA pathogenesis. The choice of therapeutic agents for refractory RA is increasing, and its efficacy is expected. On the other hand, it is also true that some patients discontinued JAKis at a rate that cannot be overlooked because of insufficient efficacy. Difficult-to-treat (D2T) RA is defined as refractory to two or more b/ts DMARDs with different mechanisms of action, with active and progressive disease, as published by Eular(3)Objectives:To evaluate real world efficacy of approved JAKis switching in patients with D2T RA who were unable to control their disease activity due to insufficient efficacy despite the sequential use of multiple bDMARDs and JAKis, focusing on the drug retention rate.Methods:In our hospital, RA was diagnosed according to the 1987 or 2010 classification criteria, and when two or more bDMARDs (including both TNFis and non-TNFis) were inadequately effective, it was defined as D2T RA. We retrospectively investigated patients who switched to JAKis for D2T RA. The drug retention rate was investigated by the Kaplan-Meier method, and the difference was tested by the Logrank test.Results:The 1-year retention rate of JAKis for D2T RA was 50.8% in TOF 38 cases [28 women, age average 70.2 years, disease duration average 12.4 years, past bDMARDs use average 3.5 drugs, MTX combination 9 cases, DAS28 ESR average 4.11] and 66.3% in BAR 35 cases [26 cases, 73.0 years old, 14.8 years, 4.17 agents, 9 cases, 3.68], and there was no significant difference (P = 0.30). Among them, there were 17 cases [11 cases, 70.6 years old, 13.5 years, 4.18 drugs, 2 cases, 3.65] of switching between JAKis, all of which were switching from TOF to BAR. The 1-year retention rate was 45.8% [reason for discontinuation: insufficient effect in 3 cases, adverse events in 6 cases], which was not significantly different but tended to be lower than 72.7% [reason for discontinuation: insufficient effect in 1 case, adverse event in 2 cases, patient’s convenience in 1 case] in 16 patients [13 cases, 76.3 years old, 17.1 years, 3.19 drugs, 7 cases, 3.69] who received BAR as the first JAKi for D2T RA patients (P = 0.089).Conclusion:Although the number of cases is small in the retrospective survey, it is suggested that the retention rate of BAR switched to D2T RA may be slightly lower in patients with a history of TOF discontinuation due to insufficient efficacy than in JAKi naive patients. It is expected that the number of new JAKi usage cases will increase in the future, and it is necessary to consider switching between other JAKis in addition to switching from BAR to TOF.References:[1]Smolen JS, Landewe R, Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960_77.[2]Rendas-Baum R, Wallenstein GV, Koncz T et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res Ther 2011;13:R25.[3]Nagy G, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80:31–35. doi:10.1136/annrheumdis-2020-217344.Disclosure of Interests:None declared

POS0663 SAFETY AND EFFICACY OF COMBINING METHOTREXATE AND LEFLUNOMIDE AMONG PATIENTS WITH INFLAMMATORY ARTHROPATHIES: FINDINGS FROM THE PRIME REGISTRY

Background:Currently, conventional synthetic DMARDs (csDMARDs) are the most commonly prescribed drugs as first-line treatment for peripheral arthritis. In resource-constrained settings where biologic agents are not widely available, there are limited therapeutic options for patients with rheumatoid arthritis (RA) and seronegative inflammatory arthropathies refractory to other csDMARD therapies. Hence, in our practice, we are inclined to use combination of potent DMARDs after MTX failure, prior to considering biologic therapies. We believe that combination of DMARDs, especially combining MTX and Leflunomide (LEF) provides a potent and valuable low-cost treatment option. Efficacy of MTX and LEF is very well established, but there have been lot of concern as regards their combination use due to potential risk of hepatotoxicity.Objectives:We aimed to review our inflammatory arthropathies cohort data especially examining the safety, efficacy and drug retention of the combination usage of MTX and Leflunomide. We addressed this question using real-world data from the PRIME registry.Methods:This was a cross-sectional study conducted using data collected at the time of patient enrolment in the PRIME registry. The PRIME Registry is a large, independent, prospective, observational cohort initiated in October 2019 that comprises patients diagnosed with RA, SLE, PsA or AS by a rheumatologist, and is being actively followed up. IRB approval and informed consent was obtained. A number of clinical variables were recorded. Detailed history was gathered from every patient regarding their present and past medications usage. Questions were asked directly about the usage or otherwise of all available DMARDs and biologics. The duration of usage, any adverse events, or the reasons for discontinuation were recorded. Evaluation of disease activity and severity was made as per internationally agreed definitions.Results:The data of 766 inflammatory arthritis patients (RA=663, PsA=103) was reviewed. Among them, 241 patients (RA=196, PsA=45) were using combination therapy of MTX and LEF (combo MTX+LEF) with mean age 42.3±6 years; 42% male]. These patients had failed MTX or LEF monotherapy. Among these 241 patients, 49 patients were also on concomitant hydroxychloroquine therapy. It was noted that median drug retention of combo MTX+LEF therapy has been 9.5 months (IQR 6-16). Regarding any adverse events of combo MTX+LEF therapy, hepatotoxicity (ALT ≤3 times the upper limit of normal) was noted among 15 (6.2%) patients, hepatotoxicity (ALT ≥3 times the upper limit of normal) was noted among 8 (3.3%) patients, and troublesome gastrointestinal upset (nausea, or vomiting, or diarrhoea) in 3 (1.2%). Overall, only 13 (5.4%) patients had to discontinue this combo MTX+LEF therapy due to adverse events. Disease activity among combo MTX+LEF users was as follows: 64% (n=29) of PsA patients had achieved MDA; 42% (n=83) of RA cohort were in DAS28 remission, 46% (n=91) of RA patients were having DAS low disease activity.Conclusion:Combination of MTX and LEF was well tolerated and had good drug retention time, with 94.6% of patients having ongoing treatment to date. In low-income countries, where bDMARD availability is limited, financial arguments significantly influence decision making process, and our data provides initial evidence that MTX and LEF combination therapy could be an effective treatment option.Disclosure of Interests:Muhammad Haroon Speakers bureau: Roche, Novartis, Grant/research support from: Abbvie, Pfizer, Arfa Ashraf: None declared, Hafiza Javeria Shaheen: None declared, Sadia Asif: None declared, Shabnam Batool: None declared, Farzana Hashmi: None declared, Saadat Ullah: None declared

AB0533 COMBINATION OF METHOTREXATE AND LEFLUNOMIDE IS SAFE AND HAS GOOD DRUG RETENTION AMONG PATIENTS WITH PSORIATIC ARTHRITIS

Background:Among patients with psoriatic arthritis (PsA), there remains a considerable confusion regarding the effectiveness of conventional synthetic DMARDs (csDMARDs), especially methotrexate (MTX). The availability of biologic DMARDs and targeted synthetic DMARDs have revolutionised the management of psoriatic disease; however, it comes with a significant cost burden. We believe that combination of DMARDs, especially combining MTX and Leflunomide (LEF) provides a valuable low-cost treatment option for patients with PsA after failure of MTX monotherapy. Hence, in our practice, we are inclined to use combination of potent DMARDs after MTX failure, prior to considering biologic therapies. Little is known about the combination use of LEF and MTX in PsA, especially in the context of drug retention time and tolerability.Objectives:We aimed to review our PsA cohort data especially examining the drug retention of first-line csDMARD monotherapy and combination csDMARDs.Methods:In our centre, MTX is a preferred first line csDMARD, unless contraindicated, and patients are followed up with a protocol on 4-6 weekly basis unless complete remission is achieved. MTX if needed is escalated to the maximum tolerated dose (up to 25mg/week), and if PsA is still active then preferably LEF is added (usual starting dose for add-on therapy is 10mg a day and if needed escalated to 20mg a day, without any loading dose). Other csDMARDs, such as sulphasalazine are used, if needed. For this study, after written-informed consent, only those adult patients were included who had a follow up of at least 6 months with our rheumatology services, and were fulfilling CASPAR criteria. Moreover, only patients who were DMARD-naïve (no prior DMARD therapy for any cause, including psoriasis), and initiated DMARD as monotherapy after 1 April 2018 were included. If any patient had already been on any DMARDs prior to attending our rheumatology services was excluded.Results:A total of 81 PsA patients [mean age 45.6±6 years; 52% male; mean PsA disease duration=9±4 years; 35% with dactylitis, 42% with enthesitis, 17% with sacroiliitis, median current PASI=2.6, median number of swollen joints=8.0, median number of tender joints= 11.0] fulfilled the inclusion and exclusion criteria. As regards first-line csDMARD monotherapy, 88% (n=71) of patients were commenced on MTX. In total, 79% (n=56 out of 71) of patients who were started on MTX as their first-line csDMARD therapy failed this monotherapy during follow-up (51=ineffective, 5=intolerance). After a median follow-up of 22 months, MTX median drug retention among all MTX monotherapy users (n=71) was only 7 months (IQR 5-7); and among MTX failures (n=56), MTX monotherapy median drug retention was 6.0 months (IQR 4-8). Eighty percent (n=45 out of 56) of the MTX monotherapy failure cohort was started on combination therapy of MTX and LEF (combo MTX+LEF); among them, only 7 patients needed escalation of therapy to bDMARDs, and the rest are still using combo MTX+LEF. It was noted that to date median drug retention time of combo MTX+LEF has been 8 months (IQR 7-11), and 84% (n=38 out of 45) of these patients are still using this combo therapy. Significantly more patients managed to continue the combo MTX+LEF therapy compared to MTX monotherapy (84% vs. 21%, p<0.001)Conclusion:Among csDMARD naïve PsA patients, 79% of patients failed MTX monotherapy with median drug retention time of only 6 months. Combination of MTX and LEF was well tolerated and had good drug retention time, with 84% of patients having ongoing treatment to date. Our data provides initial evidence that MTX and LEF combination therapy could be an effective treatment option for PsADisclosure of Interests:Muhammad Haroon Speakers bureau: Roche, Novartis, Grant/research support from: Abbvie, Pfizer, Shabnam Batool: None declared., Sadia Asif: None declared., Farzana Hashmi: None declared., Saadat Ullah: None declared.