Exploring drug cost and disease outcome in rheumatoid arthritis patients treated with biologic and targeted synthetic DMARDs in Norway in 2010–2019 – a country with a national tender system for prescription of costly drugs

Background In Norway, an annual tender system for the prescription of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has been used since 2007. This study aimed to explore annual b/tsDMARDs costs and disease outcomes in Norwegian rheumatoid arthritis (RA) patients between 2010 and 2019 under the influence of the tender system. Methods RA patients monitored in ordinary clinical practice were recruited from 10 Norwegian centers. Data files from each center for each year were collected to explore demographics, disease outcomes, and the prescribed treatment. The cost of b/tsDMARDs was calculated based on the drug price given in the annual tender process. Results The number of registered RA patients increased from 4909 in 2010 to 9335 in 2019. The percentage of patients receiving a b/tsDMARD was 39% in 2010 and 45% in 2019. The proportion of b/tsDMARDs treated patients achieving DAS28 remission increased from 42 to 67%. The estimated mean annual cost to treat a patient on b/tsDMARDs fell by 47%, from 13.1 thousand euros (EUR) in 2010 to 6.9 thousand EUR in 2019. The mean annual cost to treat b/tsDMARDs naïve patients was reduced by 75% (13.0 thousand EUR in 2010 and 3.2 thousand EUR in 2019). Conclusions In the period 2010–2019, b/tsDMARD treatment costs for Norwegian RA patients were significantly reduced, whereas DAS28 remission rates increased. Our data may indicate that the health authorities’ intention to reduce treatment costs by implementing a tender system has been successful.

Exploring Drug Cost and Disease Outcome in Rheumatoid Arthritis Patients Treated With Biologic and Targeted Synthetic DMARDs in Norway in 2010-2019 – a Country With a National Tender System for Prescription of Costly Drugs

BACKGROUND: In Norway, an annual tender system for the prescription of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has been used since 2007. This study aimed to explore annual b/tsDMARDs costs and disease outcomes in Norwegian rheumatoid arthritis (RA) patients between 2010 and 2019 under the influence of the tender system.METHODS: RA patients monitored in ordinary clinical practice were recruited from ten Norwegian centers. Data files from each center for each year were collected to explore demographics, disease outcomes, and the prescribed treatment. The cost of b/tsDMARDs was calculated based on the drug price given in the annual tender process.RESULTS: The number of registered RA patients increased from 4909 in 2010 to 9335 in 2019. The percentage of patients receiving a b/tsDMARD was 39.4% in 2010 and 44.5% in 2019. The proportion of b/tsDMARDs treated patients achieving DAS28 remission increased from 34.8% to 61.3%. The estimated mean annual cost to treat a patient on b/tsDMARDs fell by 47.3%, from 13,1 thousand euros (EUR) in 2010 to 6.9 thousand EUR in 2019. The mean annual cost to treat b/tsDMARDs naïve patients was reduced by 75.4% (13,0 thousand EUR in 2010 and 3.2 thousand EUR in 2019).CONCLUSIONS: In the period 2010-2019, b/tsDMARD treatment costs for Norwegian RA patients were significantly reduced, whereas DAS28 remission rates increased. Our data may indicate that the health authorities’ intention to reduce treatment costs by implementing a tender system has been successful.

Higher levels of anti-phosphorylcholine autoantibodies in early rheumatoid arthritis indicate lower risk of incident cardiovascular events

Background The increased risk of cardiovascular events (CVE) in rheumatoid arthritis (RA) is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. It has been suggested that anti-phosphorylcholine antibodies (anti-PC) of the IgM subclass may have atheroprotective effects. Here, we aimed to investigate the association between levels of IgM anti-PC antibodies with CVE in patients with early RA. Methods The study population was derived from the BARFOT early RA cohort, recruited in 1994–1999. The outcome of incident CVE (AMI, angina pectoris, coronary intervention, ischemic stroke, TIA) was tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM. The Kaplan-Meier estimates and Cox proportional hazards regression models were used to compare CV outcome in the groups categorized by baseline median level of IgM anti-PC. Results In all, 653 patients with early RA, 68% women, mean (SD) age 54.8 (14.7) years, DAS28 5.2 (1.3), 68% seropositive, and without prevalent CVD, were included. During the follow-up of mean 11.7 years, 141 incident CVE were recorded. Baseline IgM anti-PC above median was associated with a reduction in risk of incident CVE in patients aged below 55 years at inclusion, HR 0.360 (95% CI, 0.142–0.916); in males, HR 0.558 (0.325–0.958); in patients with BMI above 30 kg/m2, HR 0.235 (0.065–0.842); and in those who did not achieve DAS28 remission at 1 year, HR 0.592 (0.379–0.924). The pattern of associations was confirmed in the models with AUC IgM anti-PC over 2 years. Conclusion Protective effects of higher levels of innate IgM anti-PC autoantibodies on CVE were detected in younger patients with RA and those at high risk of CVE: males, presence of obesity, and non-remission at 1 year.

The association between increased body mass index and response to conventional synthetic DMARD treatment in rheumatoid arthritis: Results from the METEOR database

Background Few data exist on the association between increased BMI and response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). We aimed to explore the association between increased (overweight or obese) BMI on csDMARD-prescribing, methotrexate-dose and disease activity over 12-months. Methods Participants in an international RA database were stratified into early (<1year post-diagnosis) and established RA. EULAR response, DAS28 remission and treatments were recorded at baseline, 6-months and 12-months. Increased BMI was explored in early and established RA, as predictors of good EULAR response, DAS28 remission, number of csDMARDs and methotrexate-dose, using logistic and linear regression. Results Data from 1313 patients, 44.3% with early RA, were examined. In early RA, increased BMI was not significantly associated with remission. In established RA, obese patients on monotherapy were significantly less likely to achieve good EULAR response or DAS28 remission at 6 months and more likely to be treated with combination csDMARDs, compared with normal BMI. In patients taking methotrexate, overweight and obese patients with early and established RA were exposed to higher methotrexate doses (mono- and combination-therapy), with a mean dose of 20mg/week, compared to 15mg/week in those of normal BMI. Conclusion We observed, compared to patients with normal BMI, overweight and obese individuals experienced more intensive csDMARD exposures. Similar response rates were observed in early RA but increased BMI was associated with reduced response in established RA. Optimisation of targeted RA treatment remains important, particularly in those with increased BMI where response in established disease may be attenuated.

Preliminary Results of first Belgian Cohort of Juvenile Idiopathic Arthritis: Where Do we Stand in Terms of Quality of Care and Remission?

IntroductionJuvenile idiopathic arthritis (JIA) represents a very heterogeneous disease. As such, it has been a challenge to describe the disease activity of JIA cohorts. Our objective was to describe the first Belgian cohort of children with JIA by assessing their disease characteristics, outcomes, and potential markers of prognosis.MethodsThe CAP48 cohort is a multicentric observational study of children with recent or well-established diagnosis of JIA (naïve or not to treatment at baseline), evaluated every 3 to 6 months during a follow-up of 10 years.ResultsThere were 125 children included, composing of 25 naïve and 100 established patients. Their median age at onset was 6.2 and 4.2 years in the naïve and established cohort respectively, with a predominance of female. All subtypes of JIA were represented in both cohorts. The mean DAS28-CRP and JADAS10-CRP at baseline in naïve patients was 2.52 and 6.0 respectively. Uveitis occurred in 19% of patients and was strongly associated with presence of antinuclear antibodies (odds ratio of 6). Among naïve patients, 55% were in remission at 12 months according to ACR criteria and JADAS10 scores, in contrast with 100% achieving DAS28 remission. ConclusionThis first cohort study in Belgium allowed to compare its data to other existing cohorts and to evaluate quality of care in Belgian French-speaking hospitals. Additionally, it highlighted a superiority of JADAS10 over DAS28 to monitor and evaluate remission in JIA. This study also underlined a need for more accurate markers of prognosis to improve treatment and long-term outcomes.

Using a DAS28-CRP-steered treat-to-target strategy does not eliminate subclinical inflammation as assessed by ultrasonography in rheumatoid arthritis patients in longstanding clinical remission

Background Subclinical synovitis by ultrasound is a frequent finding in rheumatoid arthritis (RA) patients in remission and has been shown to be related to erosive progression, risk of flare and unsuccessful drug tapering, but it has not been investigated how a DAS28 T2T-steered strategy in routine care affects the presence of subclinical synovitis in RA patients in remission. The aim of the current study was to investigate the presence of ultrasound-detected subclinical inflammation in RA patients in long-term remission receiving either biological or conventional disease-modifying anti-rheumatic drugs (bDMARD/csDMARD) and, finally, to investigate the presence of ultrasound remission using different ultrasound remission criteria. Methods Eighty-seven RA patients (42 patients receiving bDMARD and 45 csDMARD) received DAS28-CRP-steered treatment in routine care and had achieved DAS28-CRP-remission for > 1 year without radiographic progression. Twenty-four joints were scored 0–3 by ultrasound (elbows, wrists, knees, ankles, metacarpophalangeal and metatarsophalangeal joints 2–5) for grey-scale synovial hypertrophy (GS) and colour Doppler activity (CD) using the OMERACT scoring system. Ultrasound remission was defined as strict (GS score = 0 and CD score = 0), semi-strict (GS score < 1 and Doppler score = 0) and Doppler remission (Doppler score = 0). Results No differences between treatment groups were found for GS sum score and Doppler sum score (median (range) 6 (0–19) and 0 (0–12), respectively). A Doppler score > 0 in at least 1 joint was seen in 44%, a GS score > 1 in at least 1 joint in 93% and a GS score > 2 in at least 1 joint in 54% of patients. Strict ultrasound remission was only observed in bDMARD patients (7%; p = 0.01). Thirty-seven per cent were in semi-strict ultrasound remission and 56% in Doppler remission (no significant difference between groups) with similar results across the subgroups of patients who also fulfilled the ACR-EULAR Boolean-, CDAI- and SDAI-remission criteria. Conclusions Ultrasound frequently detected subclinical synovitis in RA patients in longstanding DAS28-remission obtained through a DAS28-CRP-steered strategy. This was independent of treatment and applied ultrasound remission criteria. Strict ultrasound remission was rare.

Preliminary Results of first Belgian Cohort of Juvenile Idiopathic Arthritis: Where Do we Stand in Terms of Quality of Care and Remission?

BackgroundJuvenile idiopathic arthritis (JIA) represents a very heterogeneous disease, and our objectives were to describe the first Belgian cohort of children with JIA, assess their disease characteristics and outcome and identify potential markers of prognosis.MethodsThe CAP48 cohort is a multicentric observational study of children with a recent or well-established diagnosis of JIA (naïve or not to treatment at baseline), evaluated every 6 months during a follow-up of 5 to 10 years.ResultsThere were 125 children included in the cohort, composed of 25 naïve and 100 established patients. The patients had a median age of 6.2 and 4.2 years at onset in the naïve and established cohort respectively, with a predominance of female. All subtypes of JIA were represented in both cohorts. The mean DAS28-CRP and JADAS10-CRP at baseline in naïve patients was 2.52 and 6.0 respectively. Uveitis occurred in 19% of patients and was strongly associated with presence of antinuclear antibodies (odds ratio of 6). Fifty-five percent of naïve patients were in remission at 12 months of follow-up according to the ACR criteria and JADAS10 scores, in contrast with 100% achieving DAS28 remission. ConclusionThis first cohort study in Belgium allowed to compare its data to other existing cohorts and to evaluate quality of care in Belgian French-speaking hospitals. Additionally, it highlighted a superiority of JADAS10 over DAS28 to monitor and evaluate remission in JIA. This study also underlined a need for more accurate markers of prognosis to improve treatment and long-term outcomes.

Comparative Efficacy (DAS28 remission) of Targeted Immune Modulators for Rheumatoid Arthritis: A Network Meta-Analysis

Background The objective of the study was to evaluate the relative efficacy of targeted immune modulators (TIMs) in TIM-naïve/mixed (≤ 20% TIM-experienced) and TIM-experienced (> 20% TIM-experienced) adults with moderately-to-severe rheumatoid arthritis with an inadequate response or intolerance to conventional disease-modifying antirheumatic drugs (cDMARDs). Methods A fixed effects Bayesian network meta-analysis (NMA) was performed using published study-level data form 41 randomized controlled trials (RCTs), identified from 2 recent systematic literature reviews conducted by the Institute for Clinical and Economic Review, and 2 additional phase III trials for filgotinib (FINCH-1, FINCH-2). RCTs that compared TIMs to each other, cDMARD or placebo were included. Treatments included Janus kinase (JAK) inhibitors, tumor necrosis factor alpha inhibitors (TNFi), and other non-TNFis. Efficacy was defined as achieving remission with a DAS28 score < 2.6 at 12 and 24 weeks. Results In the 12-week analysis for the TIM-naïve/mixed population, all TIMs combined with cDMARD were more likely to achieve remission compared to cDMARD alone (statistically significant), with intravenous tocilizumab showing a substantially greater magnitude of effect (odds ratio = 19.36, 95% credible interval: 11.01, 38.16). Similarly, in the 24-week analysis, intravenous and subcutaneous tocilizumab showed the highest odds ratio of achieving DAS28 remission compared to cDMARD. Similar trends were observed for the analyses on monotherapy or TIM-experienced population. Conclusion This NMA demonstrated that tocilizumab is associated with a greater likelihood of remission (DAS28 < 2.6) at 12 and 24 weeks compared to most other TIMs including new JAK inhibitors, when used in combination with a cDMARD or as monotherapy, among TIM-naïve/mixed or TIM-experienced populations.

OP0034 DOES THE RISK OF VENOUS THROMBOEMBOLISM VARY WITH DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS?

Background:Patients with rheumatoid arthritis (RA) are at increased risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) (1). Several established risk factors of VTE, such as age, immobilization and comorbid conditions, occur more often patients with RA (2). In addition, inflammation may in itself also increase VTE risk by upregulating procoagolatory factors and causing endothelial damage (3). Recent reports indicate an increased risk of VTE in RA patients treated with JAK-inhibitors (4), pointing to the need to better understand how inflammation measured as clinical RA disease activity influences VTE risk.Objectives:To investigate the relationship between clinical RA disease activity and incidence of VTE.Methods:Patients with RA were identified from the Swedish Rheumatology Quality Register (SRQ) between July 1st2006 and December 31st2017. Clinical rheumatology data for these patients were obtained from the visits recorded in SRQ, and linked to national registers capturing data on VTE events and comorbid conditions. For each such rheumatologist visit, we defined a one-year period after the visit and determined whether a VTE event had occurred within this period or not. A visit followed by a VTE event was categorized as a case, all other visits were used as controls. Each patient could contribute to several visits. The DAS28 score registered at the visit was stratified into remission (0-2.5) vs. low (2.6-3.1), moderate (3.2-5.1) and high (>5.1) disease activity. Logistic regression with robust cluster standard errors was used to estimate the association between the DAS28 score and VTE.Results:We identified 46,311 patients with RA who contributed data from 320,094 visits. Among these, 2,257 visits (0.7% of all visits) in 1345 unique individuals were followed by a VTE within the one-year window. Of these, 1391 were DVT events and 866 were PE events. Figure 1 displays the absolute probabilities of a VTE in this one-year window, and odds ratios for VTE by each DAS28 category, using DAS28 remission as reference. The one-year risk of a VTE increased from 0.5% in patients in DAS28 remission, to 1.1% in patients with DAS28 high disease activity (DAS28 above 5.1). The age- and sex-adjusted odds ratio for a VTE event in highly active RA compared to RA in remission was 2.12 (95% CI 1.80-2.47). A different analysis, in which each patient could only contribute to one visit, yielded similar results.Figure 1.Odds ratios (OR) comparing the odds of VTE for DAS28 activity categories versus remission. Grey estimates are from unadjusted logistic regression models, black estimates are from logistic regression models adjusted for age and sex. Absolute one-year risk of VTE are estimated from unadjusted models.Conclusion:This study demonstrates a strong association between clinical RA inflammatory activity as measured through DAS28 and risk of VTE. Among patients with high disease activity one in a hundred will develop a VTE within the coming year. These findings highlight the need for proper VTE risk assessment in patients with active RA, and confirm that patients with highly active RA, such as those recruited to trials for treatment with new drugs, are already at particularly elevated risk of VTE.References:[1]Holmqvist et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308(13):1350-6.[2]Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-9.[3]Xu J et al. Inflammation, innate immunity and blood coagulation. Hamostaseologie. 2010;30(1):5-6, 8-9.[4]FDA. Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. 2019.Acknowledgments:Many thanks to all patients and rheumatologists persistently filling out the SRQ.Disclosure of Interests:Viktor Molander: None declared, Hannah Bower: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma