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High lipoprotein (a) [Lp (a)] levels are associated with worse long-term outcomes in patients undergoing percutaneous coronary intervention (PCI). However, there are limited studies investigating association between Lp (a) levels and long-term outcomes in the era of new generation drug-eluting stents (DES).A total of 495 patients with available data on Lp (a) who underwent PCI for de novo lesions with new generation DES were enrolled between 2013 and 2017. The primary endpoint was the major adverse cardiovascular event (MACE), which was defined as a composite of cardiac death, myocardial infarction, stent thrombosis, clinically driven target lesion revascularization, and revascularization for new lesions during 3 years. Patients were divided into 2 groups according to the Lp (a) level: high Lp (a) group (≥30 mg/dL: n = 109) and low Lp (a) group (30 mg/dL: n = 386). Multivariate Cox regression analysis was performed to identify the predictors for 3-year MACE.The incidence of 3-year MACE was significantly higher in high Lp (a) group than low Lp (a) group (33.0% vs. 15.9%, p 0.001). Multivariable analysis showed that Lp (a) level of ≥30 mg/dL was an independent predictor for 3-year MACE (HR 2.01, 95%CI 1.30-3.11, p = 0.002).High Lp (a) level was associated with worse long-term outcome even in the era of new generation DES.

Lipoprotein(a) [Lp(a)] is a risk factor for peripheral artery disease (PAD). However, the relationship between Lp(a) levels and clinical events after endovascular therapy (EVT) for the femoropopliteal artery in PAD patients remains unclear. Thus, this study aimed to assess the impact of Lp(a) levels on primary patency after EVT for de novo femoropopliteal lesions in PAD patients. A retrospective analysis was conducted on 109 patients who underwent EVT for de novo femoropopliteal lesions, and Lp(a) levels were measured before EVT between June 2016 and December 2019. Patients were divided into low Lp(a) [Lp(a) 30 mg/dL; 78 patients] and high Lp(a) [Lp(a) ≥ 30 mg/dL; 31 patients] groups. The main outcome was primary patency following EVT. Loss of primary patency was defined as a peak systolic velocity ratio 2.4 on a duplex scan or 50% stenosis on angiography. Cox proportional hazards analysis was performed to determine whether high Lp(a) levels were independently associated with loss of primary patency. The mean follow-up duration was 28 months. The rates of primary patency were 83 and 76% at 1 year and 75 and 58% at 2 years in the low and high Lp(a) groups, respectively (P = 0.02). After multivariate analysis, High Lp(a)[Lp(a) ≥ 30 mg/dL] (hazard ratio 2.44; 95% CI 1.10-5.44; P = 0.03) and female sex (hazard ratio 2.65; 95% CI 1.27-5.51; P 0.01) were independent predictors of loss of primary patency. Lp(a) levels might be associated with primary patency after EVT for de novo femoropopliteal lesions.

We measure characteristics of a transmitted WDM signal in an 80 km-long SMF under bi-directionally pumped DRA with incoherent-forward and coherent-backward pumps. The signal shows OSNR of 50.0 dB and RIN less than -140 dB/Hz.

Highly nonlinear fibers which can be utilized in all-optical signal processing is introduced. Characteristics of highly nonlinear fiber and requirements from various applications are summarized.

Aim: High levels of lipoprotein(a) [Lp(a)] are a risk factor for peripheral artery disease (PAD). However, the relationship between Lp(a) levels and the severity of femoropopliteal lesions in patients with PAD has not been systematically studied. This study aimed to assess the impact of Lp(a) levels on angiographic severity of femoropopliteal lesions in patients with PAD. Methods: We retrospectively analyzed a single-center database including 108 patients who underwent endovascular therapy for de novo femoropopliteal lesions and measured the Lp(a) levels before therapy between June 2016 and September 2019. Patients were divided into low Lp(a) [Lp(a) ＜30 mg/dL; 77 patients] and high Lp(a) [Lp(a) ≥ 30 mg/dL; 31 patients] groups. Trans-Atlantic Inter-Society Consensus (TASC) II classification, calcification [referring to the peripheral arterial calcium scoring system (PACSS) classification], and lesion length were compared between the groups. Results: The prevalence of TASC II class D (13% vs 38%, P ＜0.01) and severe calcification (PACSS 4) (6% vs 23%, P =0.02) was significantly higher and the lesion length longer (123±88 mm vs 175±102 mm, P ＜0.01) in the high Lp(a) group than in the low Lp(a) group. In multivariate analysis, Lp(a) ≥ 30 was an independent predictor for the prevalence of TASC II class D (HR=3.67, 95% CI 1.27–10.6, P =0.02) and PACSS 4 (HR=4.97, 95% CI 1.27–19.4, P =0.02). Conclusion: The prevalence of TASC II class D and severe calcification of femoropopliteal lesions was higher in patients with high Lp(a) than those with low Lp(a).

Although gender difference in long-term outcomes after acute myocardial infarction have been shown previously, impact of age on gender difference is still controversial. This study focused on the association between age and gender difference in long-term outcome. We analyzed data from 3,283 consecutive patients who were included in a prospective, nationwide, multicenter registry (Japan Registry of Acute Myocardial Infarction Diagnosed by Universal Definition) from 2012 to 2014. The primary end point was the major adverse cardiovascular event (MACE), which was defined as a composite of death, myocardial infarction, stroke, heart failure, and revascularization for unstable angina during 3 years. Patients were divided into 4 strata according to age: those with age65 years (group 1: n = 1161), 65 to 74 years (group 2: n = 954), 75 to 84 years (group 3: n = 866) and 84years (group 4: n = 302). Although the crude incidence of 3-year MACE was significantly higher in women than men (36.4% vs. 28.5%, p0.001), there was not significant gender difference in each group (group 1, 19.6% vs 19.0%, p = 0.74; group 2, 33.1% vs 28.3%, p = 0.25; group 3, 38.9% vs 39.6%, p = 0.54; and group 4, 54.0% vs 56.8%, p = 0.24). In conclusion, although women had higher crude incidence of 3-year MACE than men, there was no gender difference in each group.

BACKGROUND Patients with non-ST-elevation myocardial infarction (NSTEMI) have worse long-term prognoses than those with ST-elevation myocardial infarction (STEMI). HYPOTHESIS It may be attributable to more extended coronary atherosclerotic disease burden in patients with NSTEMI. METHODS This study consisted of consecutive 231 patients who underwent coronary intervention for myocardial infarction (MI). To assess the extent and severity of atherosclerotic disease burden of non-culprit coronary arteries, two scoring systems (Gensini score and synergy between percutaneous coronary intervention with Taxus and cardiac surgery [SYNTAX] score) were modified by subtracting the score of the culprit lesion: the non-culprit Gensini score and the non-culprit SYNTAX score. RESULTS Patients with NSTEMI had more multi-vessel disease, initial thrombolysis in myocardial infarction (TIMI) flow grade 2/3, and final TIMI flow grade 3 than those with STEMI. As compared to STEMI, patients with NSTEMI had significantly higher non-culprit Gensini score (16.3 ± 19.8 vs. 31.2 ± 25.4, p

ObjectivesThis study evaluated the comparative effectiveness of a tumour necrosis factor inhibitor (TNFi) versus a non-TNFi (biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs)) as the first-line treatment following conventional synthetic DMARDs, as well as potential modifiers of response, observed in US clinical practice.MethodsData were from a large US healthcare registry (Consortium of Rheumatology Researchers of North America Rheumatoid Arthritis Registry). The analysis included patients (aged ≥18 years) with a documented diagnosis of rheumatoid arthritis (RA), a valid baseline Clinical Disease Activity Index (CDAI) score of >2.8 and no prior bDMARD or tsDMARD use. Outcomes were captured at 1-year postinitiation of a TNFi (adalimumab, etanercept, certolizumab pegol, golimumab or infliximab) or a non-TNFi (abatacept, tocilizumab, rituximab, anakinra or tofacitinib) and included CDAI, 28-Joint Modified Disease Activity Score, patient-reported outcomes (including the Health Assessment Questionnaire Disability Index, EuroQol-5 Dimension score, sleep, anxiety, morning stiffness and fatigue) and rates of anaemia. Groups were propensity score-matched at baseline to account for potential confounding.ResultsThere were no statistically significant differences observed between the TNFi and non-TNFi treatment groups for outcomes assessed, except the incidence rate ratio for anaemia, which slightly favoured the TNFi group (19.04 per 100 person-years) versus the non-TNFi group (24.01 per 100 person-years, p=0.03). No potential effect modifiers were found to be statistically significant.ConclusionsThe findings of no significant differences in outcomes between first-line TNF versus first-line non-TNF groups support RA guidelines, which recommend individualised care based on clinical judgement and consideration of patient preferences.

Background The relationship between long-term outcome in patients with lower extremity artery disease (LEAD) and left ventricular (LV) diastolic dysfunction has not been systematically studied. The aim of this study was to assess the impact of LV diastolic dysfunction on the long-term outcome in patients with LEAD. Methods Two hundred LEAD patients (male 66 %, mean age 76 ± 9 years) with preserved LV systolic function assessed by echocardiography (ejection fraction ≥50 %) were enrolled from a single center database between January 2013 and May 2015. We divided the patients into two groups on the basis of LV diastolic dysfunction, which was diagnosed based on the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. The 3-year cumulative incidence of the primary endpoint was compared between LEAD patients with LV diastolic dysfunction and those without. The primary endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE: death, hospitalization for heart failure, myocardial infarction, and stroke). Multivariate analysis was performed to determine whether LV diastolic dysfunction was independently associated with the MACCE. Results LV diastolic dysfunction was identified in 31 % of LEAD patients. The mean observation period was 32 ± 21 months. The 3-year cumulative incidence of MACCE occurred more frequently in patients with LV diastolic dysfunction than those without (35 % vs 23 %, p = 0.01). In multivariate analysis, LV diastolic dysfunction (HR = 1.96, 95 % CI 1.09–3.55, p = 0.03) and critical limb ischemia (HR = 2.52, 95 % CI 1.24–5.10, p = 0.01) were an independent predictor for MACCE. Conclusion LV diastolic dysfunction increased the risk for MACCE in patients with LEAD.

Background Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-α to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab. Methods In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590). Results Greater reductions in C-reactive protein (CRP; − 94.0% vs. –24.0%), serum amyloid A (SAA; − 83.2% vs. –17.4%), total receptor activator of nuclear factor-κB ligand (RANKL; − 18.3% vs. 10.5%) and lipoprotein (a) (− 41.0% vs. –2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p N-terminal propeptide (P1NP) were observed with sarilumab vs. adalimumab at week 24 (22.8% vs. 6.2%, p = 0.027). Patients with high baseline SAA, CRP and matrix metalloproteinase-3 (MMP-3) were more likely to achieve clinical efficacy, including American College of Rheumatology 20% improvement criteria and Disease Activity Score (28 joints)-CRP Conclusion Sarilumab was associated with greater positive effects on bone remodelling and decreases in biomarkers of the acute-phase response, synovial inflammation and cardiovascular risk vs. adalimumab. High baseline concentrations of SAA, CRP and MMP-3 are predictive of clinical and patient-reported outcome responses to sarilumab treatment and prospective validation is warranted to confirm these results. Trial registration ClinicalTrials.gov, NCT02332590. Registered on 5 January 2015

Purpose Optical frequency domain imaging (OFDI) is widely used to characterize lipidic-atherosclerotic plaques, shown as signal-poor regions with diffuse borders, in clinical setting. Given that lipid components are common to both fibroatheroma (FA) and pathological intimal thickening (PIT), it is unclear whether OFDI can be used to accurately distinguish between FA and PIT. This study evaluated the differences in OFDI findings between FA and PIT in comparison with histopathology. Methods A total of 631 histological cross-sections from 14 autopsy hearts were analyzed for the comparison between OFDI and histological images. Of those, 190 (30%) sections were diagnosed with PIT and 120 (19%) with FA. All OFDI images were matched with histology and the OFDI signal attenuation rate was calculated from an exponential. The lipid length was measured longitudinally, and the lipid arc was measured with a protractor centered in the center of the lumen. Results There was no significant difference in the OFDI signal attenuation rate between FA and PIT (3.09 ± 1.04 versus 2.79 ± 1.20, p = 0.13). However, the lipid length was significantly longer and the maximum lipid arc was significantly larger in FA than in PIT (7.5 [4.3–10.3] mm versus 4.3 [2.7–5.8] mm, p < 0.0001, and 125 [101–174]° versus 96 [74–131]°, p < 0.0001, respectively). Conclusions OFDI may be capable of discriminating advanced lipid plaques from early stage atherosclerosis based on the longitudinal and circumferential extent of signal-poor region.

Objective.We evaluated the effect of sarilumab on patient-perceived impact of rheumatoid arthritis (RA) using the 7-domain RA Impact of Disease (RAID) scale.Methods.Two phase III, randomized, controlled trials of sarilumab in patients with active, longstanding RA were analyzed: (1) sarilumab 150 mg and 200 mg every 2 weeks plus conventional synthetic disease-modifying antirheumatic drugs (+csDMARD) versus placebo + csDMARD [TARGET (NCT01709578)]; and (2) sarilumab 200 mg versus adalimumab (ADA) 40 mg monotherapy [MONARCH (NCT02332590)]. Least-squares mean (LSM) differences in RAID total score (range 0–10) and 7 key RA symptoms, including pain and fatigue (baseline to Weeks 12 and 24), were compared. “Responders” by RAID total score were defined by improvements from baseline ≥ minimal clinically important difference (MCID), and ≥ patient-acceptable symptom-state (PASS) at endpoint.Results.Sarilumab 150 mg and 200 mg + csDMARD were nominally superior (p < 0.05) versus placebo + csDMARD and 200 mg sarilumab versus ADA 40 mg in LSM differences for RAID total score at weeks 12 (−0.93 and −1.13; −0.49, respectively) and 24 (−0.75 and −1.01; −0.78), and all effects of RA (except functional impairment in MONARCH Week 12). Effects were greater in physical domains (e.g., pain) than mental domains (e.g., emotional well-being). More patients receiving sarilumab versus placebo or ADA reported improvements ≥ MCID and PASS in total RAID scores at both assessments.Conclusion.Based on the RAID, sarilumab + csDMARD or as monotherapy reduced the effect of RA on patients’ lives to a greater extent than placebo + csDMARD or ADA monotherapy. (ClinicalTrials.gov: NCT01709578 and NCT02332590)

Background High lipoprotein(a) [Lp(a)] levels are a risk factor for peripheral artery disease (PAD). However, the association between Lp(a) levels and angiographic severity of PAD has not been systematically studied. Purpose The aim of this study was to assess the impact of Lp(a) levels on angiographic severity of femoropopliteal lesions in patients with PAD. Methods We retrospectively analyzed a single-center database including 108 patients (74±8 years, 69% male) who underwent endovascular therapy for de novo femoropopliteal lesions and measured Lp(a) levels before therapy between June 2016 and September 2019. Patients were divided into low Lp(a) [LP(a) Results Median Lp(a) was 16 (7–31) mg/dL.The prevalence of TASC II class D (13% vs 38%, P Conclusion Lp(a) was associated with angiographic severity of femoropopliteal lesions in patients with PAD. Comparison of angiographic severity Funding Acknowledgement Type of funding source: None

Background Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA. Methods Baseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6–7.1 pg/mL), medium (7.2–39.5 pg/mL), and high (39.6–692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID). Results At baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p p p Conclusions Patients with high baseline IL-6 levels reported better improvements in PCS, physical functioning domain, and AM-stiffness scores with sarilumab versus adalimumab and safety consistent with IL-6R blockade. Trial registration NCT02332590. Registered on 5 January 2015

We thank Zheng et al 1 for their interest in our study2 and for providing constructive comments. They mention that even though the baseline mean Clinical Disease Activity Index (CDAI) was not statistically different, the proportion of patients with moderate or high disease at baseline was different and this could have been a key effect modifier.1 We used standardised differences to evaluate variables at baseline. Calculation of the standardised difference not only accounts for the means of the two cohorts, but also the SD. We noticed that continuous CDAI was balanced across the two therapy classes (as listed in the manuscript table 1, SD=−0.015)2 and similarly observed for categorical CDAI (low/moderate/high; SD=0.0515; results not shown …

BACKGROUND Although self-expanding drug-eluting stents (DES) have recently shown superior outcomes for superficial femoral artery (SFA) lesions, optimal sizing of DES diameter in SFA intervention is unclear.Methods and Results:A total of 40 de novo SFA lesions were randomized 1:1 to receive self-expanding DES with either a 1-mm or 2-mm larger diameter than the reference vessel diameter. Follow-up optical coherence tomography (OCT) was scheduled 6 months after DES implantation to evaluate the vascular response to the stents. Volume index (VI) was defined as volume divided by stent length. The primary endpoint was neointimal VI at 6 months. Baseline reference vessel diameter was similar between the 1-mm larger diameter group and the 2-mm larger diameter group (5.0±0.8 mm vs. 4.7±0.9 mm, P=0.35). Stent diameter was 6.3±0.6 mm in the 1-mm larger group and 7.1±0.6 mm in the 2-mm larger group (P

Background The interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-α inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups. Methods Data were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200 mg every 2 weeks (q2w) either + MTX in MTX-IR patients (52 weeks) or + csDMARDs in TNF-IR/INT patients (24 weeks), and a monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w in MTX-IR/INT patients (24 weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment. Results The superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo + csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of n = 289) vs. patients n = 1819). Serious infections occurred in six patients aged ≥ 65 years receiving sarilumab, although the incidence of serious infections was generally higher in patients aged ≥ 65 years regardless of treatment. Conclusions Apart from ACPA status, there were no consistent signals indicating differential effects of sarilumab in any of the subpopulations assessed. Sarilumab demonstrated consistent efficacy and safety across a wide range of patients with RA. Trial registration ClinicalTrials.gov NCT01061736, registered on February 03, 2010; ClinicalTrials.gov NCT01709578, registered on October 18, 2012; ClinicalTrials.gov NCT02332590, registered on January 07, 2015

Background IL-6, a key cytokine in rheumatoid arthritis (RA) pathogenesis, is elevated in patient serum and synovial fluid. However, the impact of baseline IL-6 levels on patient-reported RA symptoms and health-related quality of life (HRQoL) following IL-6 blockade has not been explored. Sarilumab targets IL-6 receptor alpha, and sarilumab+methotrexate (MTX) significantly improved clinical and patient-reported outcomes vs MTX alone among MTX inadequate responders (IR) in MOBILITY/NCT01061736. This post-hoc analysis evaluated whether baseline IL-6 levels predict greater improvements in symptoms and HRQoL with sarilumab+MTX vs MTX. Methods 1,193 patients with moderate-to-severely active RA received MTX or MTX plus subcutaneous sarilumab at 200 mg (recommended dose) or 150 mg (recommended for management of laboratory abnormalities) every 2 weeks (q2w) and were grouped into tertiles according to baseline IL-6 levels. Patient-reported RA symptoms and HRQoL were measured at baseline and post-treatment (Weeks [W] 24 and 52). Results Baseline IL-6 tertiles among 1193 patients were 1.6-9.6 (low), 9.8-30.7 (medium), and 31.2-648.7 pg/mL (high). At baseline, patients with high IL-6 had greater disease activity, more radiographic structural damage, elevated CRP levels, and worse HRQoL (pain visual analog scale [VAS], SF36-physical component scores [PCS], and sleep VAS) vs those with low IL-6 (nominal p < 0.05) and generally reported greater improvements in symptoms and HRQoL with sarilumab+MTX vs placebo+MTX. Significant differences (nominal p < 0.005) between high and low tertiles were evident in improvement of pain VAS (W52) and SF-36 PCS (W24/W52) with sarilumab 200 mg q2w vs placebo, SF-36 mental component scores (both doses; W52) and FACIT-fatigue scores (both doses; W24/W52) vs placebo. Treatment-emergent adverse events were similar across IL-6 tertiles. Conclusion Among MTX-IR RA patients, high baseline IL-6 may predict better improvements in symptoms and HRQoL with sarilumab vs placebo, which was consistent with previous analyses across clinical/radiographic endpoints in the same study population. Disclosures V. Strand: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celltrion, CORRONA, Crescendo, Genentech/Roche, GSK, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi and U. J. Msihid: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. T. Kimura: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. A. Boyapati: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. G. St John: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. W. Wei: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc.

Background In RA patients, unacceptable pain (UP) may persist despite inflammation control (refractory pain [RP]). Sarilumab is indicated (either with methotrexate or as monotherapy if methotrexate is not tolerated/appropriate) for adults with moderately-to-severely active RA with an inadequate response or intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatics (csDMARD). The recommended dose is 200 mg every 2 weeks (q2w) with dose reduction to 150 mg if required for management of laboratory abnormalities. Three randomised controlled trials (RCTs) of subcutaneous sarilumab 150 or 200 mg q2w vs comparators showed meaningful improvements in pain. This analysis assessed UP and RP in these trials. Methods RCTs evaluated sarilumab 150 and 200 mg q2w vs placebo (+csDMARDs: MOBILITY/NCT01061736 and TARGET/NCT01709578) and sarilumab 200 mg q2w vs adalimumab 40 mg q2w (MONARCH/NCT02332590). Post-hoc analyses calculated odds ratios (ORs) of UP (based on patient acceptable symptom state on a threshold of visual analog scale pain >40 mm [0-100]), RP (UP+C-reactive protein Results Across all three trials, sarilumab 150 and 200 mg q2w had lower odds of UP (p < 0.05; ORs 0.39-0.46 vs placebo and 0.54 vs adalimumab). In MOBILITY, sarilumab 150 and 200 mg q2w had lower odds (p < 0.05) of RP vs placebo at Week 24 (ORs 0.60 [0.38,0.93] and 0.57 [0.37,0.87]) and Week 52 (ORs 0.64 [0.37,1.02] and 0.62 [0.37,1.02]), and RP-strict at Week 52 (0.41 [0.19,0.90] and 0.35 [0.16,0.76]). In TARGET, sarilumab 150 mg q2w had lower odds (p < 0.05) of RP-strict at Week 24. Higher pain was associated with worse FACIT-fatigue, HAQ, SJC and TJC scores (all p < 0.001). Conclusion Sarilumab was associated with lower odds of UP or RP vs adalimumab or placebo. Disclosures V. Bykerk: Consultancies; Abbvie, Amgen, Brainstorm Therapeutics, Bristol-Myers Squibb, Genentech, Gilead, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Scipher, Union Chimique Belge. Shareholder/stock ownership; Abbvie, Amgen, Brainstorm Therapeutics, Bristol-Myers Squibb, Genentech, Gilead, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Scipher, Union Chimique Belge. Grants/research support; AbbVie, Amgen, Brainstorm Therapeutics, Bristol-Myers Squibb, Genentech, Gilead, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Scipher, Union Chimique Belge. W. Wei: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc. S. Boklage: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc. T. Kimura: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc. S. Fiore: Shareholder/stock ownership; Sanofi. Other; Sanofi. G. St John: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc.

In patients with ST-elevation myocardial infarction (STEMI), delays in reperfusion attenuate the benefit of primary percutaneous coronary intervention (PCI) and associate with higher mortality rates. Although PCI operators are making their best effort in time saving for reperfusion, it is sometimes challenging and takes time to pass the guide wire across the target lesions. A totally occluded lesion in which a side branch was bifurcating at the proximal end of the occluded segment is one of the most technically challenging anatomies of the target lesion because it is difficult to identify the entry point of the occluded segment. A side branch technique, termed "Open Sesame Technique" (OST), has been previously introduced for chronic total occlusion (CTO) lesion in which a side branch was bifurcating at the proximal end of the occluded segment. We herein present two cases applying this technique in STEMI with totally occluded lesions at bifurcation as a culprit lesion, in which the entry point was not identified on the initial angiography. PCI were performed successfully using the OST in both cases, which resulted in saving procedural time and contrast volume without any complications. This technique can be effective not only in PCI for CTO lesions but also in primary PCI for STEMI cases with occluded bifurcation lesions.

We report a case of catheter-induced aortocoronary dissection at the ostium of anomalous left coronary artery (LCA) during percutaneous coronary intervention (PCI) for acute inferior myocardial infarction (MI). Urgent coronary angiography revealed the culprit lesion of MI was the proximal segment of the right coronary artery (RCA). The anomalous LCA arose from the right sinus of Valsalva the same as the RCA. Catheter-induced aortocoronary dissection at the ostium of RCA was extended to the ostium of anomalous LCA by contrast injection. The patient fell into hemodynamic collapse due to acute occlusion of the anomalous LCA. The patient underwent successful bailout stenting at the ostium of anomalous LCA under percutaneous cardiopulmonary support (PCPS). He was weaned from PCPS system five days after PCI and was discharged. This is the first report about bailout procedure for catheter-induced aortocoronary dissection at the ostium of anomalous LCA.

Primary hepatic angiosarcoma is a rare tumor originating from endothelial cells in the liver and accounts for approximately 1% of all hepatic malignant tumors. It is difficult to diagnose due to the lack of specific symptoms or tumor markers. No effective treatment exists, but complete surgical resection may achieve a good outcome. Since most primary hepatic angiosarcomas are already at an advanced stage at diagnosis, few reports describe tumors smaller than 2 cm. We report a case of surgery for a 1.7-cm sized primary hepatic angiosarcoma. Further studies are required to improve the preoperative diagnosis of primary hepatic angiosarcoma.

Endovascular therapy (EVT) has been accepted as a minimally invasive treatment for peripheral artery disease, and its applicability has been widened with the development of techniques and devices. A long, totally occluded lesion in the superficial femoral artery (SFA) is one of the most challenging lesions for EVT due to technical difficulties in wire-crossing. Recently, intentional subintimal recanalization is often considered as an alternative option for long SFA occlusions. Previous studies have shown that subintimal approach achieved superior technical success rate and similar patency rate, compared to conventional intraluminal approach. However, there is limited information about complications of the treatment with subintimal approach. Deep vein thrombosis (DVT) due to direct compression by pseudoaneurysm in the SFA, which subsequently develops pulmonary embolism (PE), is considered as a rare complication of subintimal angioplasty for the occlusive SFA lesion. We herein present a case of a patient who developed pseudoaneurysm formation in the SFA after EVT. Although initial EVT was performed successfully with subintimal approach, DVT and PE were caused by the SFA pseudoaneurysm at sub-acute phase following the initial procedure. The pseudoaneurysm was treated with implantation of a covered stent sealing the entry point, disappearing with no endoleak.

Background Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and are predictive of therapeutic responses in patients with RA. IL-6 has been implicated in fatigue, pain and depression in RA but a formal association with PROs has not been performed. Sarilumab, a fully human monoclonal antibody directed against IL-6Ra, is approved for treatment of moderate-to-severely active RA. The phase 3 MONARCH randomized controlled trial (NCT01061736) compared the efficacy and safety of sarilumab monotherapy vs adalimumab in RA patients who should not continue methotrexate treatment due to intolerance or inadequate responses. Greater reductions in disease activity and improvements in the clinical signs of RA and physical function were demonstrated with sarilumab vs adalimumab. A better understanding of the association between IL-6 levels and PROs is warranted to evaluate as a biomarker for guiding RA clinical decision-making. Objectives To evaluate, by post-hoc analysis, the potential of baseline IL-6 levels to differentially predict the improvement in PRO with sarilumab vs adalimumab in MONARCH. Methods Serum IL-6 levels were measured at baseline in 300/369 patients in the ITT population. Patients were categorized into high, medium, or low IL-6 tertiles levels. Between-group comparisons of differences at Week 24 in Short Form-36 (SF-36) physical and mental component summaries (PCS, MCS) and domain scores, Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, and morning stiffness visual analog scale (VAS) measures were performed within each tertile using a linear fixed effect model. In order to evaluate the differential effect of sarilumab vs adalimumab in the baseline high vs low IL-6 groups, an interaction test of treatment-by-baseline IL-6 group analysis was performed using low IL-6 group as the reference. Results At baseline, patients in the high IL-6 tertile presented a significantly worse MCS and morning stiffness scores (P Conclusion Evaluation of IL-6 biomarker associations with PROs indicate that patients with high IL-6 levels report better improvements with sarilumab vs adalimumab with safety profile consistent with IL-6R blockade. The effects of adalimumab treatment are stable based on IL-6 tertiles but higher with sarilumab, particularly in the high IL-6 tertile group. Effects on PCS scores are mainly driven by the PF domain, consistent with previous reports of marked improvements in pain with high IL-6 levels. * Significant between-group difference in change from baseline (P SF-36 domains: BP, bodily pain; GH, general health; RP, role-physical, MH, mental health; PF, physical functioning; RE, role emotional; SF, social functioning; VT, vitality. Acknowledgement Medical writing support was provided by Gauri Saal, MA Economics, Prime, Knutsford, UK and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests Vibeke Strand Consultant for: AbbVie, Amgen, Bayer, BMS, Boehringer Ingelheim, Celgene, Celltrion, CORRONA, Crescendo, EMD Serono, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kezar, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, Servier, UCB., Susan Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Toshio Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Florence Joly Shareholder of: Sanofi, Employee of: Sanofi, Anita Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Jerome Msihid Shareholder of: Sanofi, Employee of: Sanofi

Background Fatigue is a common symptom in RA and increasingly recognized as an important therapeutic target in disease management. Phase 3 randomized clinical trials (RCTs) have shown significant improvements in fatigue for sarilumab, based on the 13-item Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue measure. In TARGET (n=546) and MOBILITY (n=1197), patients receiving sarilumab 150 or 200 mg subcutaneous (SC) every 2 weeks (Q2W) achieved clinically meaningful improvements in fatigue vs placebo. In MONARCH (n=369), there was a trend towards greater improvement in fatigue scores for sarilumab 200mg mg Q2W vs adalimumab 40 mg Q2W monotherapies. To facilitate comparability of fatigue outcomes across studies and measures, the National Institutes of Health (NIH)-funded Patient Reported Outcomes Measurement Information System® (PROMIS®) initiative developed a fatigue item bank of 95 items that includes the FACIT-Fatigue scale within it. This allows FACIT-F scores to be cross-walked to the PROMIS T-score metric, including the subset of 10 FACIT-F items deemed most relevant to RA patients. Objectives To describe patient-level, cross-walked PROMIS-fatigue and scoring service 13- and 10-item PROMIS-fatigue scores from TARGET, MOBILITY and MONARCH. Methods FACIT-Fatigue scores were cross-walked to PROMIS-Fatigue (using look up tables at the individual patient level), with PROMIS-Fatigue 10- and 13-item T-scores derived from individual patient level data via the publicly available scoring service (http://www.healthmeasures.net). Between-group comparisons of differences (Δ) on least-square mean (LSM) Week 24 change-from-baseline (CFB) scores were evaluated between sarilumab 150 or 200 mg SC Q2W vs placebo (+conventional disease modifying anti-rheumatic drugs in both arms) in TARGET and MOBILITY (including Week 52 CFB) and sarilumab 200 mg SC Q2W vs adalimumab 40mg Q2W monotherapies in MONARCH. Results In TARGET and MOBILITY, Week 24 LSM CFB for cross-walked PROMIS-Fatigue scores ranged from −6.10 to −7.22 for sarilumab 150mg and −6.76 to −7.05 for sarilumab 200mg (−6.72 and −6.94 Week 52 CFB in MOBILITY, respectively) and −4.08 to −4.90 for placebo (−4.34 Week 52 CFB). ΔLSM were significant (p Conclusion Consistent with trial results shown for FACIT-Fatigue, following cross-walk to PROMIS-Fatigue and on PROMIS-Fatigue 13 and 10 T-scores, patients treated with sarilumab demonstrated statistically greater and clinically meaningful improvement in fatigue vs placebo and a trend towards greater improvement vs adalimumab. Converting FACIT-fatigue data to PROMIS-fatigue using either the patient level cross-walk or via the patient level scoring service provides a common metric for comparisons of fatigue outcomes across treatments for RA and against US clinical population reference scores. Green boxes P Acknowledgement Medical writing support was provided by Gauri Saal, MA Economics, Prime, Knutsford, UK and funded by Sanofi and Regeneron Pharmaceuticals, Inc. The study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests Clifton Bingham Grant/research support from: BMS, Consultant for: AbbVie, BMS, Eli Lilly, Genentech/Roche, Janssen, Pfizer, Sanofi/Regeneron, Susan Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Toshio Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., David Cella Consultant for: Sanofi and Regeneron Pharmaceuticals, Inc.

Background: Data-driven principal component (PC) and cluster analysis has the potential to identify previously unknown patient subgroups within a rheumatoid arthritis (RA) registry to establish prognosis, predict disease trajectory, and help inform treatment. Objectives: The Brigham and Women’s Rheumatoid Arthritis Sequential Study (BRASS), established in 2003, is a single-center, prospective observational registry cohort providing a comprehensive set of clinical disease activity measures in >1400 patients with RA. Our objective was to use PC and cluster analysis of baseline demographic, socio-economic, health and disease characteristics in BRASS to identify and characterize distinct patient clusters in RA. Methods: Patient variables recorded at entry into BRASS were refined and combined using PC analysis to reduce dimensionality and collinearity. The number of PCs was established by eigenvalue >1, cumulative variance, and interpretability. Patients were clustered using a k-means approach with non-hierarchical, exclusive, and complete clustering, with minimum cluster size 5% of population, and maximum 19 clusters. The final number of clusters was determined according to the cubic clustering criterion and pseudo F. Results: Analysis of baseline data from 1443 patients identified 41 PCs that capture the fundamental characteristics involved in RA. Cluster analysis distinguished 5 patient clusters. Each cluster reflected a different profile of PCs, and can be described based on overall health, RA disease activity and duration (Table). Key differentiators between clusters include comorbidity PCs (metabolic comorbidities predominate in cluster 1, neurologic in cluster 4, and orthopedic in cluster 5) and patient characteristics/social PCs (greatest number of doctor visits and family history of MI in cluster 3, greatest BMI in cluster 1, highest income in cluster 2, lowest income in cluster 5, and least emotional support in cluster 1). Conclusion: Data-driven cluster analysis of RA patient characteristics at entry into the BRASS registry identified five distinct patient phenotypes, providing a convenient method to potentially derive novel insights into the multifactorial drivers, commonly co-occurring health conditions, and manifestations of RA. Investigation of longitudinal outcomes in these different clusters in the BRASS registry and validation in an independent dataset is ongoing. Acknowledgement: Study funding and medical writing support (Matt Lewis, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests: Jeffrey R. Curtis Grant/research support from: Abbvie, Amgen, BMS, Corrona, Janssen, Lilly, Myriad, Pfizer, Roche/Genentech, UCB, Crescendo Bioscience Inc., Consultant for: Abbvie, Amgen, BMS, Corrona, Janssen, Lilly, Myriad, Pfizer, Roche/Genentech, UCB, Crescendo Bioscience Inc., Michael E. Weinblatt Shareholder of: Stock option: CanFite, Lycera, Scipher, Inmedix, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, CanFite, Corrona, Crescendo, GlaxoSmithKline, Gilead, Horizon, Lilly, Lycera, Merck, Novartis, Pfizer, Roche, Samsung, Scipher, Set Point, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin, Vivian Bykerk Grant/research support from: Mallinckrodt, BMS, Crescendo Biosciences, Sanofi/Regeneron., Consultant for: Amgen, Pfizer, UCB, Scipher, Sanofi/Genzyme/Regeneron, Christina Charles-Schoeman Grant/research support from: Bristol-Myers Squibb, AbbVie, and Pfizer, Consultant for: Regeneron-Sanofi, Pfizer, and Gilead, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi, Gregory St. John Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, Toshio Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Shen Zheng Consultant for: Sanofi, Clifton Bingham Grant/research support from: BMS, Consultant for: AbbVie, BMS, Eli Lilly, Genentech/Roche, Janssen, Pfizer, Sanofi/Regeneron, Grace Wright Consultant for: Abbvie, Amgen, BMS, Exagen, LILLY, Myriad Autoimmune, NOVARTIS, Pfizer, Sanofi Genzyme Regeneron, UCB, Speakers bureau: Abbvie, Amgen, BMS, Exagen, LILLY, Myriad Autoimmune, NOVARTIS, Sanofi Genzyme Regeneron, UCB, Martin Bergman Shareholder of: Johnson and Johnson (parent company of Janssen), Consultant for: AbbVie, Amgen, BMS, Celgene, Genentech/Roche, Janssen, Merck, Novartis, Pfizer, and Sanofi/Regeneron, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Genentech/Roche, Janssen, Merck, Novartis, Pfizer, and Sanofi/Regeneron, Kamala Nola Shareholder of: Gilead, Johnson & Johnson, Proctor & Gamble, Consultant for: Yes – Gilead, Sanofi Genzyme, Regeneron, Speakers bureau: Coherus, Daniel E. Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS Corbus, NIH, Novartis, Pfizer, Roche/Genentech, Consultant for: AbbVie, Actelion, Amgen, BMS, Cytori, Novartis, Pfizer, Roche/Genentech, Speakers bureau: CMC Connect (McCann Health Company), Nancy Shadick Grant/research support from: Mallinckrodt, BMS, Crescendo Biosciences, Sanofi/Regeneron.

Objective The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies. Methods Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression. Results In MONARCH, patients with high baseline IL-6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL-6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL-6 levels. In MOBILITY, compared to patients with low IL-6 levels (n = 397), patients with high IL-6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL-6 and C-reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles. Conclusion IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses.

Previous studies have reported that long-term prognosis of non-ST-elevation myocardial infarction (NSTEMI) was worse than that of ST-elevation myocardial infarction (STEMI). We hypothesized that coronary artery disease (CAD) in non-culprit lesion is more severe in NSTEMI. We compared with the

This study sought to assess the impact of polyvascular disease on severity of coronary artery disease (CAD) and clinical outcome in patients undergoing percutaneous coronary intervention (PCI) for stable angina. We retrospectively analyzed a single-center database of 283 patients (male 75 %, mean

Background In the MONARCH Phase 3 randomised controlled trial (RCT) [NCT02332590], sarilumab subcutaneous (SC) 200 mg every 2 weeks (q2w) improved clinical outcomes and multiple aspects of health status/health-related quality of life (HRQoL), as measured by the Medical Outcomes Survey Short Form (SF-36) questionnaire, to levels greater than adalimumab SC 40 mg q2w. Both treatments were administered as monotherapy in patients with active rheumatoid arthritis (RA) who had discontinued treatment with methotrexate. Depression/mood disorder is a common co-morbidity in people with RA. Objectives To explore whether observed differences in health status/HRQoL following treatment with sarilumab compared with adalimumab are also seen in the subgroup of patients in the MONARCH trial with probable depressive symptoms. Methods Post-hoc statistical analyses were performed. Patients were categorised as having probable major depressive disorder1 (PMDD; SF-36 mental health (MH) domain score ≤56) or probable depressed mood and anhedonia2 (PDMA; score ≤10 on both items of the MH domain: “Have You Felt Downhearted and Depressed” and “Have You Felt So down in the Dumps that nothing could cheer you up”). Least squares mean (LSM) differences in changes from baseline (CFB) in SF-36 domains at Week 24 were calculated for sarilumab PMDD/PDMA versus adalimumab PMDD/PDMA. Sensitivity analysis included adjustment for Disease Activity Score 28 C-reactive protein (DAS28-CRP) at baseline. Results Of the 369 patients from MONARCH, 250 (67.78%) were categorised with PMDD (mean age 52 years, 85% female) and 194 (52.6%) with PDMA (mean age 52 years, 87% female). Disease duration, DAS-28 CRP, tender and swollen joint counts (table 1) and SF-36 domain scores (figure 1) were similar between sarilumab and adalimumab within the PMDD and PDMA subpopulations at baseline. LSM differences in CFB in SF-36 domains were greater for sarilumab versus adalimumab at Week 24 in physical functioning (PF), bodily pain (BP), vitality (VT) and social functioning (SF) domains in both the PMDD and PDMA subgroups, and role-physical (RP) in the PMDD subgroup (nominal p Conclusions Among patients with RA and probable depressive symptoms, sarilumab SC 200 mg q2w monotherapy was more effective than adalimumab SC 40 mg q2w monotherapy in demonstrating clinically meaningful improvements in some domains of health status/HRQoL. This may be a function of the different target of sarilumab (soluble IL-6 receptor [sIL-6R]) and associated improvements in disease activity versus adalimumab (tumour necrosis factor [TNFα]). References [1] Matcham, et al. BMC Musculoskeletal Disorders2016;17:224. [2] Sun Y, et al. EULAR Congress2017; June 14–172017; Madrid, Spain. Acknowledgements Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest V. Strand Consultant for: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Corrona, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Samsung, Sandoz, Sanofi and UCB, O. Hagino Shareholder of: Sanofi, Employee of: Sanofi, S. Guillonneau Shareholder of: Sanofi, Employee of: Sanofi, S. Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., M. Reaney Shareholder of: Sanofi, Employee of: Sanofi, J. Sadeh Shareholder of: Sanofi, Employee of: Sanofi, N. Narcisse Consultant for: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., T. Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc.

Background Sarilumab (150 or 200 mg subcutaneously [SC] every 2 wks [q2w])+csDMARDs demonstrated efficacy in adults with moderate–to-severely active rheumatoid arthritis (RA) with intolerance or inadequate response to prior TNFi treatment in TARGET (NCT01709578). Patients with an initial refractory response (1° failure) to TNFi may respond differently to subsequent treatment vs those who initially respond but lose TNFi effectiveness (2° failure). Objectives This post hoc analysis examined efficacy and safety of sarilumab +csDMARDS in patients who had previously demonstrated 1° vs 2° TNFi failure. Methods TNFi failure (1° vs 2°) was investigator-determined on enrolment to TARGET. Patients who experienced 1° or 2° failure were randomised to placebo (pbo; n=75 and n=99), sarilumab 150 mg (n=72; n=91), or sarilumab 200 mg q2w (n=64; n=103), respectively. Disease activity, physical function (HAQ-DI), and safety were assessed at Wk 24. Results By Wk 24, ACR20/50/70 response rates and improvements in LS mean HAQ-DI were similar in both sarilumab dose groups and superior to pbo, irrespective of 1° vs 2° TNFi failure (table 1). Odds ratios for the benefit of sarilumab over pbo according to ACR response rates, HAQ-DI, DAS28-CRP, CDAI and SDAI (figure 1) showed no differences between patients with 1° vs 2° failures. No significant treatment by subgroup (1° vs 2° failure) interactions were observed. In the 1° failure group, treatment emergent adverse events (TEAEs; table 1) occurred in 59.7%, 65.6% vs 45.3% (sarilumab 150, 200 mg vs pbo, respectively) of patients; and in 73.6% and 63.1% vs 52.5% with sarilumab 150, 200 mg vs pbo, respectively, in the 2° failure group. There was only one TEAE leading to death (pbo group) and one case each of venous thrombosis (200 mg sarilumab q2w, 2°) and pulmonary embolism (150 mg sarilumab q2w, 2°). Conclusions Key efficacy and safety measures were similar in patients treated with sarilumab +csDMARDs, regardless of previous 1° or 2° failure with TNFis. Acknowledgements Study funding and medical writing support (Vicki Cronin, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, EMD-Serono, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, Consultant for: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, GSK, Eli Lilly, Novartis, Pfizer, Sanofi-Genzyme, UCB, A. Spindler: None declared, A. Kivitz Shareholder of: Novartis, Consultant for: AbbVie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma, Speakers bureau: Celgene, Genentech, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Horizon, D. Ching Grant/research support from: Sanofi, Lilly, Celgene, Pfizer, Galapagos, Gilead and Abbvie, Consultant for: Abbvie, E. Mangan Shareholder of: Regeneron, Pfizer, Employee of: Regeneron, T. Kimura Shareholder of: Regeneron, Employee of: Regeneron, M. Iglesias-Rodriguez Employee of: Sanofi, G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, Lilly, Merck Sharpe and Dohme, Pfizer, Sanofi, Roche, UCB, Speakers bureau: AbbVie, Lilly, Merck Sharpe and Dohme, Pfizer, Sanofi, Roche, UCB

Background Sarilumab is a human monoclonal antibody that binds membrane and soluble IL-6 and was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Among inadequate responders to a TNF inhibitor (TNFi), patients may respond differently to sarilumab depending on whether they had a primary (1°) failure or initially responded but then subsequently lost response (secondary [2°] failure). Objectives To understand if changes in patient reported outcomes (PROs) differ among patients with 1° or 2° TNFi failure. Methods In TARGET (NCT10709758), patients with intolerance or an inadequate response to TNFi were randomised to placebo or sarilumab 150 mg or 200 mg plus csDMARD. For patients with an inadequate response to TNFi (92% of the sample), 1° or 2° failure was investigator-determined at enrollment. The following PROs were assessed at Week 0 (treatment initiation) and Week 24: HAQ-DI, patient global assessment of disease visual analogue scale (VAS), pain VAS, SF-36, morning stiffness VAS, EQ-5D, and Rheumatoid Arthritis Impact of Disease (RAID) scale. All scales produce global (total) scores, except the SF-36 which has eight domains and two summary scores (physical and mental component scores [PCS and MCS]) and the EQ-5D which has a single index utility score and a global health VAS. The PRO change from baseline was analysed through mixed model repeated measures with treatment, region, number of prior TNFis, baseline of the PRO analysed, visit, treatment-by-visit interaction, 1° and 2°subgroup, treatment-by-subgroup interaction, and treatment-by-visit-by-subgroup interaction. Post-hoc analysis of the sarilumab 200 mg data are reported here as this is the recommended dose of sarilumab. Results In this post-hoc analysis, 174 of 181 patients in the placebo group and 167 of 184 in the sarilumab 200 mg group were classified as TNFi 1° or 2° failures (the remaining patients were classed as intolerant or other and not included in this analysis); 75 and 64 were 1° and 99 and 103 were 2° treatment failures in the placebo and the sarilumab 200 mg groups, respectively. At Week 24, changes in all PROs were numerically similar in the 1° or 2° TNFi failures for both the sarilumab 200 mg and placebo groups (table 1). Furthermore, treatment-by-subgroup interaction testing did not show a statistically significant interaction of TNFi failure status and PRO outcome (all interaction P-values>0.05). Treatment emergent adverse events occurred in 65.6% of sarilumab 200 mg patients in the 1° failure group and 63.1% in the 2° failure group and were consistent with safety data reported previously. Conclusions In TNFi inadequate response patients, following treatment with sarilumab 200 mg +csDMARD, changes in PRO outcomes were similar, regardless of whether they had experienced 1° or 2° TNFi failure, suggesting that sarilumab is suitable for both 1° and 2° TNFi failure patients. Acknowledgements The study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest V. Strand Consultant for: AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celltrion, CORRONA, Crescendo, Genentech/Roche, GSK, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sandoz, Sanofi and UCB, S. Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., M. Reaney Shareholder of: Sanofi, Employee of: Sanofi, M. Iglesias-Rodriguez Shareholder of: Sanofi, Employee of: Sanofi, T. Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc.

The instability of wealth effect on consumption over the business cycles is widely recognized in recent empirical studies. We develop a consumption and investment problem for an investor with direct preference for wealth where the drift and volatility of asset return switches between two regimes. Furthermore, the model is extended to allow the investor's borrowing rate to be higher than her risk-free rate. An utility-maximizing policy is derived explicitly such that optimal consumption-wealth ratio depends not only on both current and future regimes, but also on the transition across different regimes. Numerical simulation demonstrates that low frequent changes in regimes produce instability of consumption-wealth ratio, while high frequent regime-shifts produce stable consumption-wealth ratio. These features are enhanced by investor's wealth accumulation motive and tighter credit spread between borrowing rate and risk-free rate, both of which can be applied to explain the instability of consumption-wealth ratio observed in the U.S.

Background Helicobacter pylori eradication rates achieved with a first-line regimen of clarithromycin (CLR) combined with amoxicillin (AMX) and a proton pump inhibitor have recently fallen to ≤80% because of the increasing incidence of CLR resistance in Japan. This randomized multicenter trial aimed to compare the eradication success of 2 first-line triple therapy regimens: rabeprazole, amoxicillin, and clarithromycin (RAC) versus rabeprazole, amoxicillin, and metronidazole (RAM). Methods A total of 124 consecutive patients infected with H. pylori were randomized into one of two 7-day therapeutic regimens: RAC (n=60) or RAM (n=64). Eradication was confirmed by the C-urea breath test. Adverse effects were also assessed. Results Intention-to-treat and per protocol H. pylori eradication rates were 73.3%/77.2% in the RAC group and 90.6%/93.5% in the RAM group. The eradication rate of RAM therapy was significantly higher than that of RAC therapy. CLR, metronidazole, and AMX resistance was found in 36.2%, 2.1%, and 0% of patients, respectively. In addition, no relevant differences in adverse effects were observed. Conclusions Metronidazole-based therapy (RAM) was superior to standard CLR-based therapy (RAC) for first-line H. pylori eradication. This reflects the progressive increase in CLR resistance observed in Japan.

Background Efficacy and safety of sarilumab + csDMARDs in RA patients have been demonstrated. Objectives To compare sarilumab monotherapy with adalimumab monotherapy in the ITT population of adults with active RA from MONARCH (NCT02332590) and across predefined subgroups. Methods Adults (N=369) intolerant of, inappropriate for, or inadequate responders (IR) to MTX (per investigator judgment) received SC sarilumab 200 mg q2w or adalimumab 40 mg q2w monotherapy. The primary endpoint was change from baseline in DAS28-ESR at wk 24. Consistency of treatment response (sarilumab vs adalimumab) for this endpoint was assessed in prespecified subpopulations. Results At wk 24, sarilumab was superior to adalimumab in change from baseline (BL) in DAS28-ESR (-3.3 vs -2.2; P P =0.0074) and greater improvement in HAQ-DI (-0.6 vs -0.4; P =0.0037) and CDAI (-28.9 vs -25.2; nominal P =0.0013) vs adalimumab-treated patients. Extent of treatment effect with sarilumab vs adalimumab in change from baseline in DAS28-ESR at wk 24 was generally consistent ( P >0.05) across subgroups; significant treatment-by-subgroup interactions were observed for body mass index ( P =0.047) and baseline CRP ( P =0.006) (Figure). The magnitude of treatment effect for DAS28-ESR was greater in patients with lower BMI and higher baseline CRP. Treatment effect was generally similar for other efficacy endpoints assessed, including ACR20, HAQ-DI, and CDAI. Clinical and functional responses in RF+/ACPA+, RF+/ACPA-, RF-/ACPA+, and RF-/ACPA- patients were similar to overall study results. Incidence of AEs was similar in both groups, including incidences of infections and serious infections. The most common AEs were neutropenia and injection site erythema (sarilumab) and headache and worsening of RA (adalimumab). Conclusions Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy in the ITT population in change from baseline in DAS28-ESR. The extent of treatment effect with sarilumab vs adalimumab was generally consistent across subpopulations. Overall incidences of AEs and serious AEs and rates of infection and serious infection were similar between groups. Acknowledgements This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Medical writing support was provided by MedThink SciCom and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Bristol-Myers Squibb, MedImmune, Merck, Pfizer, Roche, and UCB, Consultant for: AbbVie, Bristol-Myers Squibb, MedImmune, Merck, Pfizer, Roche, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and UCB, Y. Lin Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, H. van Hoogstraten Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, T. Kimura Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Vargas Grant/research support from: Roche, Bristol-Myers Squibb, and Pfizer, Speakers bureau: Bristol-Myers Squibb, E. Lee Consultant for: Pfizer

Background Patients with RA experience a variety of signs and symptoms and report significant physical and psychological impairment. The RA Impact of Disease (RAID) scale is a disease-specific measure of the impact of RA on patients9 lives. RAID was assessed in two Phase 3 randomized trials of sarilumab, a human monoclonal antibody directed against the IL-6 receptor-α (TARGET [NCT01709578]; MONARCH [NCT02332590]). Objectives To evaluate patient-perceived impact of sarilumab on RA using the RAID scale vs either placebo + conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or adalimumab. Methods TARGET assessed sarilumab 150mg and 200mg added to csDMARDs vs placebo in patients with RA intolerant of or not responding to anti-TNF therapy. MONARCH assessed sarilumab 200mg monotherapy vs adalimumab 40mg monotherapy in patients with RA either intolerant of, inadequate responders to, or considered inappropriate candidates for continued treatment with methotrexate. Treatments were administered subcutaneously every 2 weeks. RAID has 7 single-item domains, each rated by patients on an 11-point numeric rating scale from 0 (absence) to 10 (extreme). A total score from 0 to 10 (with lower scores indicative of less impact of disease) is calculated by weighting responses for each item based on patient assessment of the relative importance of the item. RAID was assessed at baseline (BL), Weeks 12 and 24. Least square mean (LSM) changes from BL in total score (Weeks 12 and 24) and domains (Week 24 only) were analysed with a mixed model for repeated measures, including treatment, region, visit, and treatment-by-visit interaction (and prior csDMARD therapy in TARGET) as fixed effects and BL as a covariate. RAID was tested outside of trial hierarchy and statistical significance is not claimed; nominal p-values are provided. Post-hoc categorical change analyses were conducted to identify “responders” in the total score (improvements ≥ minimum clinically important difference from BL to Week 24 [absolute change of 3 or relative change of 50% in total score]). Patients discontinuing therapy/requiring rescue medication prior to endpoint were classified as non-responders. Results Sarilumab was superior (nominal p Conclusions Assessed using RAID, sarilumab either with csDMARDs or as monotherapy reduced the impact of RA on patients9 lives to a greater extent than placebo+csDMARDs or adalimumab monotherapy, with benefits shown on total RAID and all 7 individual domain scores. Acknowledgements This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest L. Gossec Consultant for: Abbvie, Celgene, Janssen, Lilly, Novartis, MSD, Roche, and UCB, V. Strand Consultant for: AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celltrion, CORRONA, Crescendo, Genentech/Roche, GSK, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals, Sandoz, Sanofi, and UCB, C. Proudfoot Shareholder of: Sanofi, Employee of: Sanofi, C. Chen Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, S. Guillonneau Shareholder of: Sanofi, Employee of: Sanofi, T. Kimura Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, H. van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, M. Reaney Shareholder of: Sanofi, Employee of: Sanofi